Curcumin Transferosome-Loaded Thermosensitive Intranasal in situ Gel as Prospective Antiviral Therapy for SARS-Cov-2.

Purpose: Immunomodulatory and broad-spectrum antiviral activities have motivated the evaluation of curcumin for Coronavirus infection 2019 (COVID-19) management. Inadequate bioavailability is the main impediment to the therapeutic effects of oral Cur. This study aimed to develop an optimal curcumin transferosome-loaded thermosensitive in situ gel to improve its delivery to the lungs. Methods: Transferosomes were developed by using 33 screening layouts. The phospholipid concentration as well as the concentration and type of surfactant were considered independent variables. The entrapment efficiency (EE%), size, surface charge, and polydispersity index (PDI) were regarded as dependent factors. A cold technique was employed to develop thermosensitive in-situ gels. Optimized transferosomes were loaded onto the selected gels. The produced gel was assessed based on shape attributes, ex vivo permeability enhancement, and the safety of the nasal mucosa. The in vitro cytotoxicity, antiviral cytopathic effect, and plaque assay (CV/CPE/Plaque activity), and in vivo performance were evaluated after intranasal administration in experimental rabbits. Results: The optimized preparation displayed a particle size of 664.3 ± 69.3 nm, EE% of 82.8 ± 0.02%, ZP of -11.23 ± 2.5 mV, and PDI of 0.6 ± 0.03. The in vitro curcumin release from the optimized transferosomal gel was markedly improved compared with that of the free drug-loaded gel. An ex vivo permeation study revealed a significant improvement (2.58-fold) in drug permeability across nasal tissues of sheep. Histopathological screening confirmed the safety of these preparations. This formulation showed high antiviral activity against SARS-CoV-2 at reduced concentrations. High relative bioavailability (226.45%) was attained after the formula intranasally administered to rabbits compared to the free drug in-situ gel. The curcumin transferosome gel displayed a relatively high lung accumulation after intranasal administration. Conclusion: This study provides a promising formulation for the antiviral treatment of COVID-19 patients, which can be evaluated further in preclinical and clinical studies.

Effective loading of incompatible drugs into nanosized vesicles: a strategy to allow concurrent administration of furosemide and midazolam in simulated clinical settings.

The current study aims to assess the use of nanocarriers to limit drug incompatibilities in clinical settings, and thus eliminating serious clinical consequences (e.g., catheter obstruction and embolism), and enhancing in vivo bioavailability and efficacy. As a proof-of-concept, the impact of loading well-documented physically incompatible drugs (i.e., furosemide and midazolam) into nanosized vesicles on in vitro stability and in vivo bioavailability of the two drugs was investigated. Furosemide and midazolam were loaded into nanosized spherical vesicles at high entrapment efficiency (ca. 62-69%). The drug-loaded vesicles demonstrated a sustained drug release patterns, high physical stability and negligible hemolytic activity. Physical incompatibility was assessed by exploiting microscopic technique coupled with image processing and analysis, dynamic light scattering and laser Doppler anemometry. Incorporation of drugs separately inside the nanosized vesicles dramatically decreased size and number of the precipitated particles. In vivo, the niosomal drug mixture demonstrated a significant improvement in pharmacokinetic profiles of furosemide and midazolam compared to the mixed free drug solutions, as evidenced by their longer circulation half-lives and higher area under the plasma-concentration time curves of both drugs. Nanocarriers could provide an auspicious strategy for circumventing drug incompatibilities, thus reducing adverse reactions, hospitalization period and improving therapeutic outcomes.

Stabilization and Movable Ligand-Modification by Folate-Appended Polyrotaxanes for Systemic Delivery of siRNA Polyplex.

To achieve a systemic targeted delivery of siRNA using polymeric carriers, there is a dilemma between ligand modification and stabilization of the polyplex. Namely, ligand modification often leads to destabilization of the polyplex in the blood circulation. In fact, we previously developed cyclodextrin (CD)/polyamidoamine dendrimer conjugates (CDE) as siRNA carriers, and the interaction of CDE/siRNA was decreased by the conjugation with folate-polyethylene glycol, leading to the destabilization. To overcome this dilemma, in this study, folate-appended polyrotaxanes (Fol-PRX) were developed. Fol-PRX stabilized CDE/siRNA polyplex by intermolecularly connecting CDE molecules through a host-guest interaction between adamantane at the terminals of Fol-PRX and ß-CD in the polyplex. Moreover, the intermolecular connection of the polyplex with Fol-PRX provided movable folate moieties on the surface. As a result, Fol-PRXs enhanced the in vivo antitumor activity of the polyplex after intravenous administration, suggesting their utility as the dual-functional materials for systemic delivery of siRNA polyplexes.

Betaxolol-loaded niosomes integrated within pH-sensitive in situ forming gel for management of glaucoma.

Blindness and impaired vision are considered as the most troublesome health conditions leading to significant socioeconomic strains. The current study focuses on development of nanoparticulate systems (i.e., niosomes) as drug vehicles to enhance the ocular availability of betaxolol hydrochloride for management of glaucoma. Betaxolol-loaded niosomes were further laden into pH-responsive in situ forming gels to further extend precorneal retention of the drug. The niosomes were evaluated in terms of vesicle size, morphology, size distribution, surface charge and encapsulation efficiency. The optimized niosomes, comprised of Span® 40 and cholesterol at a molar ratio of 4:1, displayed particle size of 332 ± 7 nm, zeta potential of -46 ± 1 mV, and encapsulation efficiency of 69 ± 5%. The optimal nanodispersion was then incorporated into a pH-triggered in situ forming gel comprised of Carbopol® 934P and hydroxyethyl cellulose. The formed gels were translucent, pseudoplastic, mucoadhesive, and displayed a sustained in vitro drug release pattern. Upon instillation of the betaxolol-loaded niosomal gel into rabbits' eyes, a prolonged intraocular pressure reduction and significant enhancement in the relative bioavailability of betaxolol (280 and 254.7%) in normal and glaucomatous rabbits, were attained compared to the marketed eye drops, respectively. Hence, the developed pH-triggered nanoparticulate gelling system might provide a promising carrier for ophthalmic drug delivery and for improved augmentation of glaucoma.

Electrospun vancomycin-loaded nanofibers for management of methicillin-resistant Staphylococcus aureus-induced skin infections.

Skin damage exposes the underlying layers to bacterial invasion, leading to skin and soft tissue infections. Several pathogens have developed resistance against conventional topical antimicrobial treatments and rendered them less effective. Recently, several nanomedical strategies have emerged as a potential approach to improve therapeutic outcomes of treating bacterial skin infections. In the current study, nanofibers were utilized for topical delivery of the antimicrobial drug vancomycin and evaluated as a promising tool for treatment of topical skin infections. Vancomycin-loaded nanofibers were prepared via electrospinning technique, and vancomycin-loaded nanofibers of the optimal composition exhibited nanosized uniform smooth fibers (ca. 200 nm diameter), high drug entrapment efficiency and sustained drug release patterns over 48 h. In vitro cytotoxicity assays, using several cell lines, revealed the biocompatibility of the drug-loaded nanofibers. In vitro antibacterial studies showed sustained antibacterial activity of the vancomycin-loaded nanofibers against methicillin-resistant Staphylococcus aureus (MRSA), in comparison to the free drug. The nanofibers were then tested in animal model of superficial MRSA skin infection and demonstrated a superior antibacterial efficiency, as compared to animals treated with the free vancomycin solution. Hence, nanofibers might provide an efficient nanodevice to overcome MRSA-induced skin infections and a promising topical delivery vehicle for antimicrobial drugs.

A Self-Nanoemulsifying Drug Delivery System for Enhancing the Oral Bioavailability of Candesartan Cilexetil: Ex Vivo and In Vivo Evaluation.

The drug delivery of candesartan cilexetil encounters an obstacle of low absolute oral bioavailability which is attributed mainly to its low aqueous solubility and efflux by intestinal P-glycoprotein (P-gp) transporters. However, the extent of P-gp contribution in the reduced oral bioavailability of candesartan cilexetil is not clear. In this study, a previously developed candesartan cilexetil-loaded self-nanoemulsifying drug delivery system (SNEDDS) was evaluated for its ability to increase the drug oral bioavailability via the inhibition of intestinal P-gp transporters. Despite the developed SNEDDS showing P-gp inhibition activity, P-gp-mediated efflux was found to have a minor role in the reduced oral bioavailability of candesartan cilexetil. On the other hand, the high surfactant concentration used in SNEDDS formulation represents a major challenge toward their widespread application especially for chronically administered drugs. The designed acute and subacute toxicity studies revealed that the degree of intestinal mucosal damage decreases as the treatment period increases. The latter observation was attributed to the reversibility of surfactant-induced mucosal damage. Thus, the developed SNEDDS could be considered as a promising delivery system for enhancing the oral bioavailability of chronically administered drugs.

Self-emulsifying drug-delivery systems modulate P-glycoprotein activity: role of excipients and formulation aspects.

Self-emulsifying drug-delivery systems (SEDDS) have been widely employed to ameliorate the oral bioavailability of P-glycoprotein (P-gp) substrate drugs and to overcome multidrug resistance in cancer cells. However, the role of formulation aspects in the reduced P-gp activity is not fully understood. In this review, we first explore the role of various SEDDS excipients in the reduced P-gp activity with the main emphasis on the effective excipient concentration range for excipient-mediated modulation of P-gp activity and then we discuss the synergistic effect of various formulation aspects on the excipient-mediated modulation of P-gp activity. This review provides an approach to develop a rationally designed SEDDS to overcome P-gp-mediated drug efflux.

Role of self-emulsifying drug delivery systems in optimizing the oral delivery of hydrophilic macromolecules and reducing interindividual variability.

Self-emulsifying drug delivery systems (SEDDS) have been widely employed to improve the oral bioavailability of poorly soluble drugs. In the past few years, SEDDS were extensively investigated to overcome various barriers encountered in the oral delivery of hydrophilic macromolecules (e.g., protein/peptide therapeutics and plasmid DNA (pDNA)), as well as in lowering the effect of food on drugs' bioavailability. However, the main mechanism(s) by which SEDDS could achieve such promising effects remains not fully understood. This review summarizes the recent progress in the use of SEDDS for protecting protein therapeutics and/or pDNA against enzymatic degradation and increasing the oral bioavailability of various drug substances regardless of the dietary condition. Understanding the underlying mechanism(s) of such promising applications will aid in the future development of rationally designed SEDDS. Entrapment of hydrophilic macromolecules in the oil phase of the formed emulsion is critical for protection of the loaded cargoes against enzymatic degradation and the enhancement of oral bioavailability. On the other hand, drug administration as a preconcentrated solution in the SEDDS preconcentrate allows the process of drug absorption to occur independently of the dietary condition, and thus reducing interindividual variability that results from concomitant food intake.

Nanostructured lipid carriers for improved oral delivery and prolonged antihyperlipidemic effect of simvastatin.

The purpose of the current study is to develop nanostructured lipid carriers (NLCs) for the delivery of the antihyperlipidemic drug simvastatin (SIM) to increase its extremely low oral bioavailability (<5%) and prolong its antihyperlipidemic effect. NLCs were prepared via emulsification-solvent evaporation technique followed by ultrasonication, and the effect of composition of the nanocarriers on the particle size, size distribution, surface charge, entrapment efficiency, drug release kinetics and physical stability was extensively studied. NLCs exhibited nanosized (<200nm) spherical morphologies with narrow size distribution and high drug entrapment efficiency (>75%), sustained drug release pattern, and negative surface charge (zeta potential of -35-40mV) that imparts sufficient electrostatic physical stability. When tested in vivo, SIM-NLCs of the optimal composition demonstrated improved and prolonged reduction in the total cholesterol and non-high density lipoprotein cholesterol levels, as compared to the drug suspension. After oral administration of a single dose of SIM-NLC, 4-fold increase in bioavailability was observed, as compared to the SIM suspension. Hence, NLCs might provide efficient nanodevices for the management of hyperlipidemia and promising drug delivery systems to enhance SIM oral bioavailability.

Development and in vitro/in vivo performance of self-nanoemulsifying drug delivery systems loaded with candesartan cilexetil.

Candesartan cilexetil is widely used in the management of hypertension and heart failure. The drug delivery encounters obstacles of poor aqueous solubility, efflux by intestinal P-glycoprotein and vulnerability to enzymatic degradation in small intestine. Self-nanoemulsifying drug delivery systems (SNEDDS) loaded with candesartan cilexetil were successfully developed to overcome such obstacles. Preliminary screening was carried out to select proper surfactant, co-surfactant and oil combination for successful SNEDDS formulation. All screened excipients were reported for their P-glycoprotein and cytochrome P450 3A4 (CYP3A4) modulation activity. Ternary and pseudo ternary diagrams were constructed to optimize the system. Peppermint oil and clove oil showed a high emulsification ability. The nature of obtained dispersions was identified to be nanoemulsions. Twenty-four formulations were evaluated for stability, robustness to dilution and self-emulsification efficiency. All formulations showed a very short emulsification time of <2min. The emulsification efficiency was significantly superior at pH6.8, at which the largest self-emulsifying region was also observed. Eight formulations were selected for further characterization according to cloud point measurement; mean droplet size, poly dispersity index (PDI) and zeta potential determination in addition to in vitro drug release study. All selected formulations showed very high cloud points (70-90°C), ultrafine mean droplet size (12±1.4 to 24.5±2.13nm), very low PDI values (0.015-0.1305) and almost a complete drug release after 12h. Formulation F15 (Peppermint oil 55% w/w: Cremophor RH40 25% w/w: Labrasol 20% w/w) was selected for further characterization. Its droplet size showed robustness to different dilution folds with different media and its TEM photograph showed spherical particles without any apparent aggregation even after 24h. Formulation F15 successfully controlled the systolic blood pressure of hypertensive rats for 24h with the maximum effect was observed after 2h. These results indicate that, SNEDDS could be promising delivery systems with a rapid onset of action and prolonged therapeutic effect of candesartan cilexetil.

Transdermal delivery of meloxicam using niosomal hydrogels: in vitro and pharmacodynamic evaluation.

Non-ionic surfactant vesicles were prepared using Span-60 and cholesterol in the mass ratios of 1:1, 2:1, 1:2 and 3:1 for transdermal delivery of an anti-inflammatory drug meloxicam (MXM). The drug encapsulation efficiencies and particle size were observed in the range of 32.9-80.7% and 56.5-133.4 nm, respectively. Three different gel bases were also prepared using Poloxamer-407, Chitosan and Carbopol-934 as polymers to study the performance of the in vitro release of the drug. Prepared gels were also converted into niosomal gels. In vitro release characteristics of MXM from different gels were carried out using dialysis membrane in phosphate buffer (pH 7.4). The poloxamer-407 gel or niosomal poloxamer-407 gel showed the superior drug release over the other formulations. The release data were treated with various mathematical models to assess the relevant parameters. The results showed that the release of MXM from the prepared gels and niosomal gels followed Higuchi's diffusion model. The flux of MXM was found to be independent on the viscosity of the formulations. The anti-inflammatory effects of MXM from different niosomal gel formulations were evaluated using carrageenan-induced rat paw edema method, which showed superiority of niosomal gels over conventional gels.

Liposomal gels for site-specific, sustained delivery of celecoxib: in vitro and in vivo evaluation.

The objective of this work was to evaluate liposome-containing gel formulations for the sustained, site-specific delivery of celecoxib (CXB). Liposomes composed of phosphadtidylcholine (and various amounts of cholesterol (Ch) were prepared using thin film hydration and characterized for encapsulation efficiency, vesicle size, and drug-excipient interaction using differential scanning calorimetry and Fourier-transform infrared spectroscopy. The selected liposome formulation was incorporated in different gel formulations: the Ch ratio affected the encapsulation efficiency of the drug, by increasing Ch ratio up until 1:1 the encapsulation efficiency increased. Further increasing the Ch ratio resulted in decreasing encapsulation efficiency. In vitro drug release and skin permeation studies showed sustained release and enhanced permeation compared with gel formulations containing free drug. In the rat paw edema test, the anti-inflammatory activity of the selected liposomal gel formulation was higher and more sustained compared with that of the nonliposomal gel formulation containing free drug. These results suggest that the liposome-containing gels are promising formulations for sustained, site-specific delivery of CXB.

Solubility and dissolution enhancement of tadalafil using self-nanoemulsifying drug delivery system.

The aim of this study was to develop and evaluate self-nanoemulsifying drug delivery system (SNEDDS) of tadalafil (TDL) in order to enhance its aqueous solubility and dissolution rate. TDL SNEDDS were developed by aqueous phase titration method via construction of pseudo-ternary phase diagrams. The formulations which passed thermodynamic stability and self-nanoemulsification tests were further characterized in terms of droplet size, viscosity, % transmittance and drug content. Selected SNEDDS and drug suspension were subjected to in vitro drug release studies via dialysis membrane in phosphate buffer (pH 6.8). In vitro drug release studies showed 96.6% release of TDL from optimized SNEDDS F5 as compared to only 12.4% from drug suspension after 24 h of study. The results of solubility studies showed 1434 folds enhancement in TDL solubility from optimized SNEDDS F5 as compared to its aqueous solubility. Overall, these results indicated that developed SNEDDS could be successfully used to enhance solubility and dissolution rate of poorly soluble drugs such as TDL.

Formulation of immediate release pellets containing famotidine solid dispersions.

Famotidine (FM) is a potent H2-receptor antagonist used for the treatment of peptic ulcer. It has a low and variable bioavailability which is attributed to its low water solubility. In this study, the dissolution of the drug was enhanced by a preparation of solid dispersion using two hydrophilic carriers, namely Gelucire 50/13 and Pluronic F-127. The prepared solid dispersions were characterized by differential scanning calorimetry (DSC), which indicated that there were no signs of interaction of the drug with the carriers used in the case of solid dispersions containing higher polymeric contents (1:3 and 1:5). FM solid dispersions in the matrices of Gelucire 50/13 and Pluronic F-127 (1:3) were used to prepare pellets. The scanning electron microscope (SEM) images of pellets showed that the pellets have spherical shape and their size depends on the carrier used. The dissolution of the drug from either solid dispersion or pellets was performed. The dissolution study depicted that, the presence of the drug in solid dispersion enhanced its dissolution in comparison with the drug itself. Also, the drug release from the manufactured pellets was found to be improved in the case of solid dispersions (drug:carrier 1:3). A complete drug release occurred after 30 min from pellets containing solid dispersions, while only about 30% of the loaded FM was released from pellets containing untreated drug after 2 h.

Comparative topical delivery of antifungal drug croconazole using liposome and micro-emulsion-based gel formulations.

The aim of this study was to develop liposomal-based (LBGF) and micro-emulsion-based (MBGF) gel formulations of croconazole to compare their topical delivery potential. Conventional gels were also prepared using various polymers such as sodium carboxymethyl cellulose (SCMC), Poloxamer 407, Carbopol 971P and chitosan. The in vitro release of croconazole from conventional gel formulations, LBGF and MBGF were carried out using cellophane membrane as permeation membrane. However, in vitro skin permeations studies of all formulations were carried out using rat skin. The results of the drug release/skin permeation studies indicated that the highest release was obtained from SCMC followed by chitosan, Poloxamer 407 and finally Carbopol 971P gel. Therefore, liposomes and micro-emulsions were loaded on Carbopol 971P gel. The drug release and skin permeation of croconazole from different LBGF and MBGF showed that MBGF had superior release/permeation than LBGF. MBGF having ethanol as co-surfactant showed higher release/permeation of drug than MBGF-containing propylene glycol. The analysis of data according to different kinetic models indicated that the release of drug from different LBGF and MBGF followed the Higuchi model. The antimicrobial activity of the different LBGF and MBGF of croconazole was carried out by measuring the inhibition zone (mm) and compared by the effect of miconazole cream as control. The different LBGF and MBGF showed an excellent activity against different species of fungi as compared with miconazole cream. Overall, these results indicated that developed LBGF and MBGF could have great potential for topical delivery of croconazole.

Physicochemical characterization and dissolution properties of meloxicam-gelucire 50/13 binary systems.

A solid dispersion of Meloxicam (MX), a poorly soluble, non steroidal anti-inflammatory drug, and Gelucire 50/13 was prepared by spray drying. Spherical microparticles were yielded with smooth surfaces as observed by scanning electron microscopy. According to differential scanning calorimetry and powder X-ray diffractometry analysis, MX was transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the crystalline peaks. The dissolution tests at pH 7.4 revealed that the dissolution rate of encapsulated MX was 2.5-fold higher than that of the corresponding physical mixture and fourfold higher than the drug alone, respectively. The microparticles prepared at a ratio of 1:4 (drug/Gelucire) exhibited a 4-fold higher anti-inflammatory activity on the paw edema of rats in comparison to the drug alone. All in all, this work reveals that spray drying is a suitable technique for preparation of solid dispersions with improved biopharmaceutical and pharmacological characteristics of MX.

The use of spray-drying to enhance celecoxib solubility.

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Technology evaluation: Kollicoat IR.

INTRODUCTION: Developments in industrial pharmacy are often linked to the discovery of pharmaceutical excipients. Although recently introduced as a material for immediate release coatings, Kollicoat IR already has other applications. AREAS COVERED: In this review, the different properties and pharmaceutical applications of Kollicoat IR as an excipient are discussed. In the first part, the chemical structure and the physicochemical characteristics are examined. The second part is a presentation of the available Kollicoat IR products followed by a brief overview of the preclinical studies completed for its use as an instant release coating material. EXPERT OPINION: Although the polymer was intended as an immediate release coating material for tablets, grafting PEG with polyvinyl alcohol to form this polymer provides physicochemical properties that lead to ever-broadening applications. Understanding its properties can lead to the development of a new use for Kollicoat IR. The addition of Kollicoat IR to an ethylcellulose or polyvinyl acetate tablet coat was successful at modifying the drug release rate. Designing a successful controlled release coat simply requires acknowledgment of the drug release mechanism from the mixture of polymers that includes Kollicoat IR. Moreover, the interaction between Kollicoat IR and poorly soluble drugs produces fast-dissolving solid dispersions prepared using hot stage extrusion, spray drying, or freeze drying.

Effects of Kollicoat IR and hydroxypropyl-beta-cyclodextrin on the dissolution rate of omeprazole from its microparticles and enteric-coated capsules.

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR nd hydroxypropyl-beta-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P < 0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40 min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR or hydroxylpropyl-beta-cyclodextrin is considered a promising way to improvement of drug dissolution.

Preparation and investigation of acetyl salicylic acid-caffeine complex for rectal administration.

An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration.