Delivery Of Acyclovir Research Articles

Formulation and evaluation of nano based drug delivery system for the buccal delivery of acyclovir

Oral bioavailability of acyclovir is limited, primarily because of low permeability across the gastrointestinal membrane. The purpose of this study is the prospective evaluation of buccal films impregnated with acyclovir loaded nanospheres as a drug delivery system to improve systemic bioavailability. Acyclovir polymeric nanospheres were prepared by double emulsion solvent evaporation technique. Nanospheres were embedded into buccoadhesive films (A1–A4) comprising of different concentrations of polymers (Eudragit RL 100, HPMC K15 and carbopol 974P). Films were characterized for physico-mechanical properties, mucoadhesive strength, hydration, drug release and ex vivo permeation. In vivo studies were carried out on rabbits to assess the pharmacokinetic profile of buccal film (A3) as compared to oral therapy. The prepared films demonstrated excellent physical properties, adequate hydration and buccoadhesive strength. In vitro drug release data inferred that the drug release was dependent on the composition of film. Ex vivo permeation studies indicated greater flux in film A3. In vivo studies revealed a significant enhancement in absorption of acyclovir (P<0.0001) with Cmax (∼3 folds) and AUC0-α (∼8 folds, P<0.0001) when compared to oral dosing. Moreover, the extended Tmax value (6h) signifies the potential of the prepared film to prolong acyclovir delivery. Given the promising results, the study concludes that the developed buccal film (A3) impregnated with acyclovir loaded nanospheres could be a promising approach for effective delivery of acyclovir.

Development and in vitro evaluation of acyclovir delivery system using nanostructured porous silicon carriers

The present work describes the preparation, surface modification, and characterization of three different porous silicon (PSi) carriers for the acyclovir delivery. Acyclovir was loaded into these carriers and in vitro release behaviour has been studied. Such carriers were characterized by a combination of scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, and X-ray diffraction. In vitro drug release studies showed slower release (up to 8h), and immediate release (up to 3h) from native and thermally oxidized PSi, respectively. Drug release kinetics studies of thermally oxidized PSi suggested diffusion controlled drug release whereas native PSi indicated a combination of both diffusion of acyclovir and erosion of the silicon scaffold as drug release mechanisms.

REVIEW ARTICLE Drug delivery approaches of an antiviral drug: A comprehensive review

The guanine derivative antiviral drug acyclovir (ACV) is one of the oldest molecules laying successful market until date, being commercially available in various dosage forms for oral, topical and parenteral administrations. Clinical application of this drug is superior to new antiviral agents due to its potential values such as suppression of recurrence, safety profile, minimal drug interactions, and being inexpensive. ACV is slightly water‐soluble, less permeable and poorly bioavailable, yet more potential antiviral molecule, the physicochemical modifications and novel dosage form approaches resulted with more than 100 research works within a decade. The survey of literature showed enormous reports on ACV formulation development, which includes modified tablets, particulate drug delivery, vesicular drug delivery, polymeric nanoparticles, bioadhesive systems, floating dosage forms, in situ gelling systems, transdermal delivery, implantable systems, emulsified dosage forms, polymeric films/patches, etc. As the drug could be administered via multiple routes for effective site targeted action at various doses, and attracted the attention of many researches, the review of the current approaches for the delivery of ACV could be more beneficial for the new scientists. This paper is a review of recent researches highlighting the development of newer techniques and novel dosage forms of ACV for better therapeutic efficacy, which were aimed at enhancing its solubility, permeability and bioavailability. Key words: Acyclovir, bioadhesive, complexation, floating, hydrogel, implant, particulate, vesicular

Controlled delivery of acyclovir from porous silicon micro- and nanoparticles

In this work, micro- and nanoparticles of porous silicon (PSi) are demonstrated to act as effective carrier for the controlled delivery of acyclovir (ACV). PSi films prepared by electrochemical etching were fractured by ultrasonication to prepare micro- and nanoparticles. PSi native particles were thermally oxidized (TOPSi) and thermally hydrosilylated using undecylenic acid (UnPSi). PSi particles with three different surface chemistries were then loaded with ACV by physical adsorption and covalent attachment. Such particles were characterized by scanning electron microscopy, dynamic light scattering, and Fourier transform infrared spectroscopy. In vitro ACV release experiments in phosphate buffered saline showed sustained release behaviour from both micro- and nanoparticles and order of release was found to be native PSi>TOPSi>UnPSi. Drug release kinetics study using Korsmeyer-Peppas model suggested a combination of both drug diffusion and Si scaffold erosion based drug release mechanisms.

Polymeric micelles for acyclovir drug delivery

Polymeric prodrug micelles for delivery of acyclovir (ACV) were synthesized. First, ACV was used directly to initiate ring-opening polymerization of ɛ-caprolactone to form ACV-polycaprolactone (ACV-PCL). Through conjugation of hydrophobic ACV-PCL with hydrophilic methoxy poly(ethylene glycol) (MPEG) or chitosan, polymeric micelles for drug delivery were formed. 1H NMR, FTIR, and gel permeation chromatography were employed to show successful conjugation of MPEG or chitosan to hydrophobic ACV-PCL. Through dynamic light scattering, zeta potential analysis, transmission electron microscopy, and critical micelle concentration (CMC), the synthesized ACV-tagged polymeric micelles were characterized. It was found that the average size of the polymeric micelles was under 200nm and the CMCs of ACV-PCL-MPEG and ACV-PCL-chitosan were 2.0mgL−1 and 6.6mgL−1, respectively. The drug release kinetics of ACV was investigated and cytotoxicity assay demonstrates that ACV-tagged polymeric micelles were non-toxic.

Topical delivery of acyclovir and ketoconazole

Context: Viral and fungal cutaneous manifestations are regularly encountered in immunocompromised human immunodeficiency virus/acquired immunodeficiency syndrome individuals and can be treated by drugs such as acyclovir and ketoconazole, respectively.Objective: The aim of this study was to determine whether the novel Pheroid™ delivery system improved the transdermal delivery and/or dermal delivery of acyclovir and ketoconazole when incorporated into semi-solid formulations.Materials and methods: Semi-solid products (creams and emulgels) containing these drug compounds were formulated, either with or without (control) the Pheroid™ delivery system. The stability of the formulated semi-solid products was examined over a period of six months and included the assay of the actives, pH, viscosity, mass loss and particle size observation. Vertical Franz cell diffusion studies and tape stripping methods were used to determine the in vitro, stratum corneum (SC)-epidermis and epidermis-dermis delivery of these formulations.Results and discussion: Stability tests showed that none of the formulations were completely stable. Acyclovir showed a biphasic character during the in vitro skin diffusion studies for all the tested formulations. The Pheroid™ cream enhanced the transdermal, SC-epidermis and epidermis–dermis delivery of acyclovir the most. The average amount of ketoconazole diffused over 12 h showed improved delivery of ketoconazole, with the Pheroid™ emulgel exhibiting the best transdermal and epidermis–dermis delivery.Conclusion: The Pheroid™ formulae increased transdermal penetration as well as delivery to the dermal and epidermal skin layers. The Pheroid™ emulgel and the Pheroid™ cream increased the topical delivery of ketoconazole and acyclovir, respectively.

Preparation and evaluation of novel in situ gels containing acyclovir for the treatment of oral herpes simplex virus infections.

The objective of this work was to develop an oral mucosal drug delivery system to facilitate the local and systemic delivery of acyclovir for the treatment of oral herpes infection caused by the herpes simplex virus (HSV). An in situ gelling system was used to increase the residence time and thus the bioavailability of acyclovir in oral mucosa. Temperature and pH trigged in situ gel formulations were prepared by cold method using polymers like poloxamer 407, carbopol 934, and HPMC. Glycerin and a mixture of tween 80 and ethanol (1 : 2 ratio) were used as the drug dissolving solvent. The pH of carbopol containing formulation was adjusted to pH 5.8 while the pH of poloxamer solution was adjusted to pH 7. These formulations were evaluated for sol-gel transition temperature, gelling capacity, pH, viscosity, spreadability, gel strength, drug content, ex-vitro permeation, and mucoadhesion. The gelation temperatures of all the formulations were within the range of 28–38°C. All the formulations exhibited fairly uniform drug content (98.15–99.75%). Drug release study of all the formulations showed sustained release properties. The release of drug through these in situ gel formulations followed the Higuchi model and Korsmeyer peppas model mechanism.

Lactosaminated-N-succinyl chitosan nanoparticles for hepatocyte-targeted delivery of acyclovir

The present study discusses lactose-acyclovir-N-succinyl chitosan nanoparticles (Lac-N-Suc-CSNP) using lactose as an asialoglycoprotein receptor (ASGPR) ligand for hepatic parenchymatic cells targeting. For this purpose, N-succinyl chitosan nanoparticles (N-Suc-CSNP) were prepared previously by ionotropic gelation method and lactose was conjugated to the free amino terminal group of chitosan. Lactose conjugation with N-Suc-CSNP was confirmed by FT-IR and zeta potential measurements. The Lac-N-Suc-CSNP obtained were characterized for their morphology, particle size, polydispersity index, and zeta potential. The Lac-N-Suc-CSNP showed spherical in shape with 220.3 ± 5.0 nm size range, +4.1 ± 0.2 mV zeta potential, 62.5 ± 1.2 % acyclovir entrapment efficiency and showed 27.3 ± 0.9 % cumulative acyclovir release up to 72 h. The acyclovir concentration from Lac-N-Suc-CSNP was found to be 19.9 ± 1.62 μg/g after 24 h administration revealed remarkably targeting potential to the hepatocytes and keep at a high level during the experiment. These results suggest that Lac-N-Suc-CSNP are potentially vector for hepatocytes targeting.

Encapsulation of Acyclovir in new carboxylated cyclodextrin-based nanosponges improves the agent's antiviral efficacy

Cyclodextrin-based nanosponges (NS) are solid nanoparticles, obtained from the cross-linking of cyclodextrins that have been proposed as delivery systems for many types of drugs. Various NS derivatives are currently under investigation in order that their properties might be tuned for different applications. In this work, new carboxylated cyclodextrin-based nanosponges (Carb-NS) carrying carboxylic groups within their structure were purposely designed as novel Acyclovir carriers. TEM measurements revealed their spherical shape and size of about 400 nm. The behaviour of Carb-NS, with respect to the incorporation and delivery of Acyclovir, was compared to that of NS, previously investigated as a drug carrier. DSC, XRPD and FTIR analyses were used to investigate the two NS formulations. The results confirm the incorporation of the drug into the NS structure and NS-Acyclovir interactions. The Acyclovir loading into Carb-NS was higher than that obtained using NS, reaching about 70% (w/w). In vitro release studies showed the release kinetics of Acyclovir from Carb-NS to be prolonged in comparison with those observed with NS, with no initial burst effect. The NS uptake into cells was evaluated using fluorescent Carb-NS and revealed the nanoparticle internalisation. Enhanced antiviral activity against a clinical isolate of HSV-1 was obtained using Acyclovir loaded in Carb-NS.

Development and optimization of thiolated dendrimer as a viable mucoadhesive excipient for the controlled drug delivery: An acyclovir model formulation

In the present study we report the development of novel thiolated dendrimers for mucoadhesive drug delivery. The thiolated dendrimers were synthesized by conjugating PAMAM dendrimer (G3.5)with cysteamine at two different molar ratios, i.e. 1:30 (DCys1) and 1:60 (DCys2). The thiolated dendrimers were further encapsulated with acyclovir (DCys1Ac and DCys2Ac) and the conjugates were characterized for thiol content, drug loading, drug release, and mucoadhesive behavior. The thiolated dendrimer conjugates showed thiol content of 10.56±0.34 and 68.21±1.84 μM/mg of the conjugate for DCys1 and DCys2, respectively. The acyclovir loading was observed to be highest in dendrimer drug conjugate (DAc) compared to other DCys1Ac and DCys2Ac conjugates. The thiolated dendrimers showed sustained release of acyclovir and showed higher mucoadhesion. The in vitro mucoadhesive activity of DCys2Ac was 1.53 and 2.89 fold higher mucoadhesion compared to DCys1Ac and DAc, respectively. These results demonstrated the usefulness of thiolated dendrimers as a mucoadhesive carrier and represent a novel platform for drug delivery. From the Clinical EditorThis study demonstrates the utility of thiolated dendrimers as mucoadhesive carriers as reported in an acyclovir delivery model system.

Development of solid lipid nanoparticles and nanostructured lipid carriers for improving ocular delivery of acyclovir

The objective of the present investigation was to improve the ocular bioavailability of acyclovir by incorporating it into solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). This required optimization of the process parameters, such as type of lipid, drug to lipid ratios, type and concentration of surfactants, and type and amount of liquid lipids used in the formulations. SLNs and NLCs were prepared by the modified hot oil in water microemuslion method. The prepared nanoparticles were evaluated for their particle size, zeta potential, entrapment efficiency, solid state characteristics, surface morphology, in vitro drug release, and permeation through excised cornea. The prepared nanoparticles were spherical and within the size range suitable for ocular drug delivery (400–777.56 nm). Incorporation of liquid oil in the structure of SLNs resulted in the formation of NLCs with high entrapment efficiency (25–91.64%) compared to SLNs (11.14%). The drug release from SLNs and NLCs was rather a surface-based phenomenon. In comparison to free drug solution, NLCs were capable of having faster permeation through the excised cornea indicating their potential enhanced corneal penetration properties. However, SLNs have reduced the permeation rate significantly. The results of the study suggest that SLNs can be successfully converted to physically superior NLCs, which have the potential to be developed further as ocular drug delivery systems for ACV.

Galactose decorated PLGA nanoparticles for hepatic delivery of acyclovir

The present study explores prospective of surface tailored nanoparticles for targeted delivery of acyclovir along with the interception of minimal side effects. Acyclovir loaded plain and galactosylated poly lectic co glycolic acid (PLGA) nanoparticles were efficiently prepared and characterized by Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), size, polydispersity index, zeta potential, and entrapment efficiency. The formulations were evaluated for in vitro drug release and hemolysis. Further, biodistribution study and fluorescent microscopic studies were carried out to determine the targeting potential of formulations. SEM revealed smooth morphology and spherical shape of the nanoparticles. In vitro, the galactosylated nanoparticles were found to be least hemolytic and exhibited a sustained release pattern. In vivo studies exhibited an augmented bioavailability, increased residence time and enhanced delivery of acyclovir to the liver upon galactosylation. It may therefore be concluded that galactose conjugated PLGA nanoparticles can be used suitably as vehicles for delivery of bioactives specifically to the hepatic tissues and may be thus exploited in the effective management of various liver disorders.

Evaluation of Acyclovir Cream and Gel Formulations for Transdermal Iontophoretic Delivery

Efficient iontophoretic transdermal delivery of hydrophilic drug molecules requires selection of appropriate aqueous formulation. In this study, oil/water cream and gel formulations were investigated for iontophoretic transdermal delivery of acyclovir (ACV), a model hydrophilic small-drug molecule, across hairless rat skin on Franz diffusion cells. Iontophoresis (0.2 mA/cm2) enhanced ACV delivery from both 5% cream (pH 6.8) and 4% gel (pH II) formulations. However, sixfold higher drug levels were delivered across the skin using gel formulation (12.25 +/- 4.04 microg/cm2) as compared with cream formulation (2.03 +/- 0.05 microg/cm2). Significantly higher drug levels were delivered when iontophoresis was performed at higher current density (0.32 mA/cm2; p < 0.05). Influence of formulation co-solvents (glycerin and propylene glycol) on drug delivery was also investigated in vitro using Franz cells and in vivo in hairless rats using microdialysis. Iontophoretic transdermal delivery of ACV was feasible and dependent on the selection of formulation components and delivery parameters.

Mucoadhesive Tablets for Controlled Release of Acyclovir

Mucoadhesive chitosan (CS) and/or hydroxypropyl-methylcellulose (HPMC) tablets for gastric drug delivery of acyclovir (ACV) have been developed in order to improve the ACV oral bioavailability. Swelling, bioadhesive and dissolution studies were carried out in two acidic media (pH 1.5 and 4) in order to determine the tablets behaviour in both fed and fasted states. All the designed tablets showed good mucoadhesive properties on gastric mucosa due to the presence of CS and/or HPMC. In vitro dissolution of ACV from tablets was influenced by the swelling behaviour of each polymer. All data release of the studied tablets fitted to Hopfenberg model, which describes drug release from tablets displaying heterogeneous erosion. HPMC and CS/HPMC tablets revealed a sustained release for 24 h, but a complete dissolution of the tablets was not produced at this time. On the contrary, tablets which contained only CS as polymer were able to release the total amount of ACV for 4 h, due to the CS imbibition and erosion processes in pH 1.5 medium. These results allowed us to conclude that CS is the excipient to be chosen to obtain gastroretentive formulations, due to its demonstrated gastric compatibility.

Iontophoretic Delivery of Acyclovir: Intradermal Drug Monitoring Using Microdialysis and Quantification by Skin Extraction

The objective of this study was to investigate the effect of iontophoresis on the intradermal and transdermal delivery of acyclovir using hairless rat skin on a vertical Franz diffusion cell. In this study, cathodal iontophoretic delivery of acyclovir from a pH 11 formulation was explored. The effects of time of iontophoresis (10 min, 1 h, and 4 h) and current density (0.2, 0.3, and 0.5 mA/cm(2)) on skin permeation were examined. In vitro dermal microdialysis was performed to identify the drug depot formed in the dermis during iontophoresis. Acyclovir delivery into the receptor compartment was not influenced by current density or duration of current application. However, greater drug levels were delivered into the skin as a function of time of current application to form a drug depot. These results were further confirmed by in vitro dermal microdialysis in which higher drug levels were observed in dialysate in the 4 h iontophoresis group due to higher drug levels delivered into the skin layers as compared to 1 h iontophoresis group. Short duration iontophoresis enhanced acyclovir delivery into the skin layers rapidly and thus may be beneficial to improve treatment for cold sores (herpes labialis infection). Microdialysis could be used as a tool to simultaneously monitor drug levels in the tissue's interstitial fluid in real time in an in vitro setting. The objective of this study was to investigate the effect of current on the delivery of acyclovir into and across the skin using hairless rat skin mounted on glass diffusion cells. Acyclovir was delivered under negative polarity from a formulation with a very basic pH. The effect of current intensity and duration of application on delivery of acyclovir was investigated. The amount in the skin was also determined by inserting a probe into the skin with a semipermeable membrane that allows sampling of the drug that has entered the skin. When the current intensity or duration was increased, greater drug levels were seen in the skin but not across the skin. It was found that even short duration of current application can deliver acyclovir into the skin and this has potential use for treatment of cold sores.

Enhanced dermal delivery of acyclovir using solid lipid nanoparticles.

The present investigation was enthused by the possibility to develop solid lipid nanoparticles (SLNs) of hydrophilic drug acyclovir (ACV) and evaluate their potential as the carrier for dermal delivery. ACV-loaded SLNs (ACV-SLNs) were prepared by the optimized double emulsion process using Compritol 888 ATO as solid lipid. The prepared SLNs were smooth and spherical in shape with average diameter, polydispersity index, and entrapment efficiency of 262 ± 13nm, 0.280 ± 0.01, and 40.08 ± 4.39% at 10% (w/w) theoretical drug loading with respect to Compritol 888 ATO content. Differential scanning calorimetry and powder X-ray diffraction pattern revealed that ACV was present in the amorphous state inside the SLNs. In vitro skin permeation studies on human cadaver and Sprague-Dawley rat skin revealed 17.65 and 15.17 times higher accumulation of ACV-SLNs in the dermal tissues in comparison to commercially available ACV cream after 24h. Mechanism of topical permeation and dermal distribution was studied qualitatively using confocal laser scanning microscopy. While free dye (calcein) failed to penetrate skin barrier, the same encapsulated in SLNs penetrated deeply into the dermal tissue suggesting that pilosebaceous route was followed by SLNs for skin penetration. Histological examination and transdermal epidermal water loss measurement suggested that no major morphological changes occurred on rat skin surface due to the application of SLNs. Overall, it was concluded that ACV-loaded SLNs might be beneficial in improving dermal delivery of antiviral agent(s) for the treatment of topical herpes simplex infection.

Fatty Acid Extract From Cod‐liver Oil: Activity Against Herpes Simplex Virus and Enhancement of Transdermal Delivery of Acyclovir In‐vitro

The effects of a fatty acid extract from cod-liver oil on herpes simplex virus type 1 (HSV-1) and on the transdermal delivery of acyclovir were evaluated. The solubilizing effect of various alcohols and other solvents on acyclovir was also investigated. Both the fatty acid extract and an ointment containing the extract possess notable antiviral activity against HSV-1. A 1% fatty acid extract caused a 50000-fold or greater reduction of viral infectivity in 10 min. An ointment, containing 30% extract, inactivated the virus about 1.5 million-fold. Acyclovir had the greatest solubility in polyvalent alcohols, such as propylene glycol. The largest acyclovir flux through hairless mouse skin was obtained from a cream vehicle containing 30% extract and about 30% propylene glycol.

Acyclovir skin depot characterization following in vivo iontophoretic delivery

Current Herpes labialis infection treatment by oral, parenteral or topical routes is inefficient. The objective of this study was to investigate the use of iontophoresis for improved topical delivery of acyclovir (ACV) in vivo in hairless rat. Iontophoresis was performed for 10 min using a 5% ACV gel formulation. Tape stripping and skin extractions were performed at different time points following treatment for drug quantification in stratum corneum (SC) and underlying skin, respectively. Fourfold more ACV was detected in the SC immediately following 10-min iontophoresis as compared with passive delivery. Similarly, high ACV levels (29.27±3.52 μg/cm(2)) were achieved in the underlying skin following a single 10-min iontophoretic treatment while no drug detected following passive delivery (P<0.05). At 24-h post-iontophoresis, ACV levels in the SC decreased with a corresponding increase in the underlying skin due to drug migration. After 24-h post-iontophoresis, drug levels gradually decreased in both skin compartments until no ACV was detected at 72-h post-iontophoresis. Iontophoretic delivery of ACV resulted in high drug levels in skin layers to form a drug depot, which persisted over 2-3 days.

Colloidal dispersions for the delivery of acyclovir: A comparative study

This paper describes a comparative study on the performances of ethosomes and solid lipid nanoparticle as delivery systems for acyclovir. Ethosomes were spontaneously produced by dissolution of phosphatidylcholine and acyclovir in ethanol followed by addition of an aqueous buffer while solid lipid nanoparticle were produced by homogenization and ultrasonication. Both colloidal systems were morphologically characterized by cryo-transmission electron microscopy. The encapsulation efficiency was 94.2±2.8% for ethosomes and 53.2±0.2% for solid lipid nanoparticle. Concerning Z potential, both formulations are close to neutrality. The diffusion coefficients of the drug from ethosomes and solid lipid nanoparticle, determined by a Franz cell method, were 9.4 and 1.2-fold lower as compared to the free acyclovir in solution, thus evidencing the ability of both colloidal systems in enhancing the diffusion of the drug. The antiviral activity against HSV-1 of both systems was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that no significant differences in the antiviral activity were observed by acyclovir in the free or loaded forms. Taken together these results, colloidal systems could be interesting to mediate the penetration of acyclovir within Vero cells.

In vitro Evaluation of Acyclovir/Chitosan Floating Systems.

Chitosan (CS) floating lyophilized formulations (L) for gastric drug delivery of acyclovir (ACV) have been developed. The freeze-dried formulations were obtained from acidic aqueous suspensions prepared with different ACV/CS ratios. No changes in ACV crystallinity were observed during X-ray diffraction powder studies as a consequence of the manufacturing process. Considering that fed and fasted states modified the intragastric pH, swelling and in vitro dissolution studies were carried out in different acidic media (0.1 M HCl and progressive pH medium) in order to understand the influence of these physiological states on ACV/CS formulations. Swelling behavior of the floating lyophilized formulations was dependent on CS and ACV proportions within L and on medium nature due to pH dependent CS solubility. Furthermore, no interactions between ACV and CS were detected in solid state according to the X-ray studies. In vitro dissolution of ACV from L was influenced by the swelling behavior. However, it is feasible to optimize the ACV/CS ratios to achieve a desired formulation that releases the total quantity of ACV at a specific time. Moreover, floatability was assessed by buoyancy tests. The results demonstrated that the freeze-drying process achieved effective floating systems capable of remaining within the stomach while the total amount of ACV is released from L.