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Eslicarbazepine acetate (ESL) is antiepileptic agent which is approved for use as single therapy or in combination with other drugs. However, it suffers from poor oral bioavailability. Modulation of drug crystallinity can be utilized as an approach for enhancing drug dissolution.Accordingly, the aim of this study was to investigate possible eutectic system formation between eslicarbazepine with either tartaric acid or citric acid.Eslicarbazepine acetate was subjected to wet co-grinding with tartaric acid or citric acid at different molar ratios. The prepared formulations were assessed using Fourier-transform infrared (FTIR), X-ray powder diffraction (XRPD), differential scanning calorimetry in addition to dissolution studies.The characterization techniques confirmed eutectic system formation with tartaric and citric acid with the optimum molar ratio for eutexia being 1:1 for both substances. Development of eutectic systems significantly enhanced the dissolution rate of ESL. Increasing the ratio of tartaric acid higher than the optimum ratio for eutexia resulted in additional increase in drug dissolution rate. This suggested the impact of pH modification on drug dissolution rate. The enhanced dissolution rate in case of the formulations containing ESL and citric acid was accredited to combined effect of eutaxia and pH modulation. These explanations were proven from investigating the dissolution rate of the physical mixtures which were inferior in their dissolution rate compared with the prepared formulations.co-processing of ESL with either citric acid or tartaric acid resulted in hastened dissolution rate which was accredited to combined effect of eutexia with pH modification.

The aim of this study was to develop microemulsion (ME) formulation with possible phase transition into liquid crystals upon ocular application to enhance acetazolamide bioavailability. Pseudoternary phase diagrams were constructed using olive oil or castor oil (oily phase), Tween 80 (surfactant), and sodium carbonate solution (aqueous phase). Microemulsion and liquid crystal (LC) formulations were selected from the constructed phase diagrams and were evaluated for rheological properties and in vitro drug release. The efficacy of the developed formulations in reducing intraocular pressure (IOP) was assessed in vivo. In vitro release study showed slower release rate from LC and ME compared with drug solution with the release from LC being the slowest. Ocular application of acetazolamide ME formulations or aqueous solution resulted in significant reduction in IOP from baseline. The recorded Tmax values indicated faster onset of action for acetazolamide aqueous solution (1 h) compared with ME systems (3 h). However, the duration of action was prolonged and the reduction in IOP continued for up to 10 h in case of MEs, while that of aqueous solution was only for 4–5 h. The study suggested ME formulations for ocular delivery of acetazolamide with enhanced efficacy and prolonged duration of action.

WHO considers praziquantel (PZQ) as the drug of choice for treatment of Schistosoma mansoni infection but this requires high dose due to poor solubility and first pass metabolism. The aim of this w...

Cancers are life threatening diseases and their traditional treatment strategies have numerous limitations which include poor pharmacokinetic profiles, non-specific drug distribution in the body tissues and organs and deprived tumor cells penetration. This attracted the attention of researchers to tailor efficient drug delivery system for anticancer agents to overcome these limitations. Liposomes are one of the newly developed delivery systems for anticancer agents. They are vesicular structures, which were fabricated to enhance drug targeting to tumor tissues either via active or passive targeting. They can be tailored to penetrate tumor cells membrane which is considered the main rate limiting step in antineoplastic therapy. This resulted in enhancing drug cellular uptake and internalization and increasing drug cytotoxic effect. These modifications were achieved via various approaches which included the use of cell-penetrating peptides, the use of lipid substances that can increase liposome fusogenic properties or increase the cell membrane permeability toward amphiphilic drugs, surface modification or ligand targeted liposomes and immuno-liposomes. The modified liposomes were able to enhance anticancer agent’s cellular uptake and this was reflected in their ability to destroy tumor tissues. This review outlines different approaches employed for liposomes modification for enhancing anticancer agent’s cellular uptake.

WHO considers praziquantel (PZQ) as the drug of choice for treatment of

Lopinavir is an antiretroviral, antiparasitic agent and recently utilized in treatment of COVID-19. Unfortunately, lopinavir exhibited poor oral bioavailability due to poor dissolution, extensive pre-systemic metabolism, and significant P-glycoprotein intestinal efflux. Accordingly, the aim was to enhance dissolution rate and intestinal absorption of lopinavir. This employed co-processing with menthol which is believed to modify crystalline structures and inhibit intestinal efflux. Lopinavir was mixed with menthol at different molar ratios before ethanol assisted kneading. Formulations were evaluated using FTIR spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and dissolution studies. Optimum ratio was utilized to assess lopinavir intestinal permeability. This employed in situ rabbit intestinal perfusion technique. FTIR, DSC and XRD indicated formation of lopinavir-menthol co-crystals at optimum molar ratio of 1:2. Additional menthol underwent phase separation due to possible self-association. Co-crystallization significantly enhanced lopinavir dissolution rate compared with pure drug to increase the dissolution efficiency from 24.96% in case of unprocessed lopinavir to 91.43% in optimum formulation. Lopinavir showed incomplete absorption from duodenum and jejuno-iliac segments with lower absorptive clearance from jejuno-ileum reflecting P-gp efflux. Co-perfusion with menthol increased lopinavir intestinal permeability. The study introduced menthol as co-crystal co-former for enhanced dissolution and augmented intestinal absorption of lopinavir.

Development of fixed dose combinations is growing and many of these drug combinations are being legally marketed. However, the development of these requires careful investigation of possible physicochemical changes during co-processing. This requires investigation of the effect of co-processing of drug combination in absence of excipients to maximize the chance of interaction (if any). Accordingly, the aim was to investigate the effect of co-processing of ezetimibe and atorvastatin on drugs dissolution rate. The objective was extended to in vitro in vivo correlation. Drugs were subjected to wet co-processing in presence of ethanol after being mixed at different ratios. The prepared formulations were characterized using FTIR spectroscopy, X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and in vitro dissolution testing. These investigations proved the possibility of eutectic system formation after drugs co-processing. This was reflected on drugs dissolution rate which was significantly enhanced at dose ratio and 2:1 atorvastatin:ezetimibe molar ratio compared to the corresponding pure drugs. In vivo antihyperlipidemic effects of the co-processed drugs were monitored in albino mice which were subjected to hyperlipidemia induction using poloxamer 407. The results showed significant enhancement in pharmacological activity as revealed from pronounced reduction in cholesterol level in mice administering the co-processed form of both drugs. Besides, histopathological examinations of the liver showed marked decrease in hepatic vacuolation. In conclusion, co-processing of atorvastatin with ezetimibe resulted in beneficial eutexia which hastened the dissolution rate and pharmacological effects of both drugs.Graphical abstract.

Development of fixed dose combinations is growing and many of these drug combinations are being legally marketed. However, the development of these requires careful investigation of possible physicochemical changes during co-processing. This requires investigation of the effect of co-processing of drug combination in absence of excipients to maximize the chance of interaction (if any). Accordingly, the aim was to investigate the effect of co-processing of ezetimibe and atorvastatin on drugs dissolution rate. The objective was extended to in vitro in vivo correlation. Drugs were subjected to wet co-processing in presence of ethanol after being mixed at different ratios. The prepared formulations were characterized using FTIR spectroscopy, X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and in vitro dissolution testing. These investigations proved the possibility of eutectic system formation after drugs co-processing. This was reflected on drugs dissolution rate which was significantly enhanced at dose ratio and 2:1 atorvastatin:ezetimibe molar ratio compared to the corresponding pure drugs. In vivo antihyperlipidemic effects of the co-processed drugs were monitored in albino mice which were subjected to hyperlipidemia induction using poloxamer 407. The results showed significant enhancement in pharmacological activity as revealed from pronounced reduction in cholesterol level in mice administering the co-processed form of both drugs. Besides, histopathological examinations of the liver showed marked decrease in hepatic vacuolation. In conclusion, co-processing of atorvastatin with ezetimibe resulted in beneficial eutexia which hastened the dissolution rate and pharmacological effects of both drugs.Graphical abstract.

Nateglinide is a non-sulphonylurea which was approved for treatment of type II diabetes mellitus. Its pH dependent slow dissolution resulted in variable oral bioavailability. This work presents Co-crystallization as a strategy for enhanced dissolution rate of nateglinide. The study was extended to investigate the effect of this dissolution enhancement on the hypoglycemic effect of the drug in diabetic rats. Sucralose was utilized as a co-crystal co-former at two different molar ratios (1:1 and 1:2, drug to sugar). The co-crystal formulations were prepared utilizing wet co-grinding technique in presence of acetone. The Co-crystallization process was monitored using infrared spectroscopy, thermal analysis and X-ray diffraction. Drug dissolution was monitored before and after processing with and without sucralose. The optimum co-crystalline product was evaluated for hypoglycemic effect with reference to the unprocessed drug. The study revealed polymorphic conversion of nateglinide after precipitation from acetone. Co-crystals were formed with 1:2 drug to sucralose (molar ratio) being optimum for co-crystallization process. The developed co-crystals exhibited fast drug dissolution and resulted in faster and more extensive reduction in blood glucose level compared with the unprocessed drug. The study thus introduced co-crystallization technique for enhanced dissolution rate and hypoglycemic efficacy of nateglinide.

Cefdinir is an orally active antimicrobial agent used in treatment of various respiratory tract infections. It is a class IV drug having low dissolution rate which resulted in poor oral bioavailability. Nanographene oxide was utilized as a drug carrier to enhance the dissolution rate and antibacterial activity of cefdinir. Synthesis of graphene oxide was achieved using purified natural graphite powder. This employed the modified Hummers' method followed by ultrasonication for exfoliation of the graphite oxide in ethanol to produce nanographene oxide sheets. Cefdinir was loaded on nanographene oxide alone or in combination with HPMC or PVP. The prepared formulations were characterized using FTIR, DTA, PXRD, TEM, SEM and dissolution rate studies. The study was extended to investigate the antibacterial activity of the prepared formulations by measuring MIC, MBC and the activity against biofilm forming bacteria. The characterization techniques suggest intercalation of drug particles in the space between the sheets of nanographene oxide. This was reflected on the drug dissolution rate which was significantly enhanced. This enhancement was superior in the formula containing HPMC. All the prepared formulation showed reduction in the MIC of cefdinir and this reduction was more pronounced in the formula containing HPMC. Loading of cefdinir on different nanographene formulae resulted in significant reduction in the persistence of biofilm compared with drug solution. Loading cefdinir on nanographene oxide is a promising strategy for enhanced dissolution rate and antibacterial activity.

Co-application of local anesthetics as lidocaine and nonsteroidal anti-inflammatory drugs (NSAIDs) can enhance local analgesia. Co-formulation of lidocaine with NSAIDs can modulate physicochemical properties like melting point which can affect transdermal delivery. The purpose was to probe lidocaine as eutectic forming drug for enhanced transdermal delivery of a series of NSAIDs with increasing melting points. NSAIDs included ketoprofen, flurbiprofen, aceclofenac, tenoxicam and meloxicam. Each drug was co-ground with lidocaine at increasing molar ratios. The products were characterized by thermal analysis and Fourier-transform infrared (FTIR). Saturated aqueous solutions containing excess of optimum NSAID/lidocaine were evaluated for transdermal delivery with reference to the corresponding saturated aqueous solution of each drug. Thermal analysis and FTIR suggested eutectic system formation. Drugs with lower melting points formed eutectic with smaller proportion of lidocaine. Ketoprofen, flurbiprofen and aceclofenac separated as oily liquid from the saturated aqueous solution of their mixtures with lidocaine. Eutectic mixtures of lidocaine with tenoxicam and meloxicam melted above 50 °C and separated from saturated aqueous solution as solid system. Eutexia increased the transdermal flux of NSAIDs. The extent of increase depended on the melting point of the developed system. The study introduced lidocaine as eutectic co-former for enhanced skin delivery of NSAIDs.

Alginate and chitosan are naturally derived biocompatible biodegradable polymers which are extensively applied in drug delivery. Alginate can be combined with chitosan to form polyelectrolyte complexes which can control the gelling strength and/or porosity of the delivery system. This can modulate the rate of drug release. This extended the application of alginate-chitosan combinations in drug delivery. Alginate and chitosan were dispersed in liquid system which undergoes in situ gelation after oral administration with the resulting gel controlling drug release rate in gastric and intestinal environment. Alginate-chitosan combinations can be devised into particulate systems of varying size for various routes of drug administration. The film forming and bioadhesive properties of this combination extended the scope of their application to transdermal patches, ocular, nasal and vaginal delivery. This combination showed high potential for tissue engineering and wound dressing. This chapter summarizes the applications of this combination with emphasis on controlled drug delivery.

The study investigated chitosan coated nanostructured lipid carriers (NLCs) for oral delivery of albendazole in treatment of trichinellosis. NLCs comprised precirol and oleic acid with Tween and Span 80. Dicetylphosphate was used as charging agent to allow chitosan coating. Trichinella spiralis infected mice were used and albendazole suspension, coated or uncoated NLCs were orally administered at different stages of infection. NLCs were spherical with size of 188 and 200 nm for coated and uncoated NLC, respectively. Treatment during intestinal phase reduced worm count with NLCs showing better rank. This was reflected further by reduced larvae count and improved histopathological features. Starting treatment in the migrating phase reduced larval count by 62.9, 99.6 and 89.5 % after administration of suspension, coated and uncoated NLCs, respectively. The same rank was recorded for the encysted phase. NLCs enhanced the efficacy of albendazole against Trichinella spiralis compared with suspension with chitosan coated NLCs being superior.

The history of vesicular skin drug delivery has been started in early 1980s with liposomes made of dipalmitoylphosphatidylcholine (DPPC) and cholesterol (CH) increasing skin deposition and reducing systemic absorption. Twelve years later, a new class of vesicles has been reported to penetrate intact skin delivering therapeutic moieties to the systemic circulation. These vesicles comprised phosphatidylcholine (PC) with edge activators and were termed Transfersomes. Surfactants were used as edge activators and were considered responsible for vesicle deformation providing their unique characteristics. This attracted the attention of researchers to employ vesicular nanostructures in transdermal drug delivery. The effect of vesicle composition on transdermal delivery was studied with various materials substituting surfactants. This developed different vesicles to which alternative terminology was used with variable results being recorded by investigators. For example, skin penetration enhancers were included in the vesicles to impart deformability. This was modified further by adding lyso PC as well to develop invasomes. High ethanol concentration was used as vesicular component to create Ethosomes. A cationic agent was used in the vesicles with biocompatible solvent to develop leciPlex. Stratum corneum lipids were used to devise vesicles which showed good potential for skin drug delivery and were termed stratum corneum lipid liposomes (SCLL). Another research track employed surfactants with CH to develop niosomes which delivered drugs into and through skin. Once again, the efficacy of these vesicles depended on their composition with some of them being flexible enough to advance into and through the skin. The use of vesicle proconcentrates provided another promising research strategy with higher feasibility for scaling up. This chapter will summarize the work done using different vesicular nanostructures in transdermal drug delivery.

Microemulsions (MEs) are isotropic transparent liquid systems of water, oil, and amphiphile. Three types of MEs have been identified, including oil-in-water (O/W ME) in which water represents the continuous phase; water-in-oil (W/O ME), which has water as the internal phase; and the water and oil bicontinuous ME, which comprises comparable amounts of aqueous and oily phases. MEs can be developed by mixing the oily phase with water in the presence of suitable surfactant/cosurfactant system. The relative proportions of these components affect the phase behavior of the developed systems. The composition and phase behavior of any ME can be modified by dilution with water or loss of volatile constituent such as volatile oil or cosurfactant. Dilution can take place after administration whereby ME can mix with biological fluids such as the tears or the sweat after ocular or skin application, respectively. Dilution can take place after intramuscular injection or oral administration as well. The volatile component can evaporate after topical application. The resulting change in the phase behavior can be associated with a change in the viscosity and/or solubilizing power of the system. The later may lead to supersaturation which together with the viscosity change can at least affect the rate of drug release with a potential variation in drug delivery efficiency. These effects attracted the attention of scientists to employ phase transition MEs as promising drug delivery systems. This chapter will summarize the attempts made in this direction. Based on the delivery route, this chapter has been divided into sections such as ocular drug delivery, transdermal drug delivery, parenteral drug delivery, and oral drug delivery. The final conclusion and future perspective are also presented.

Dissolution enhancement is a promising strategy for improving drug bioavailability. Co-crystallization of drugs with inert material can help in this direction. The benefit will become even greater if the inert material can form co-crystal while maintaining its main function as excipient. Accordingly, the objective of the current study was to investigate xylitol as a potential co-crystal co-former for felodipine with the goal of preparing felodipine sublingual tablets. Co-crystallization was achieved by wet co-grinding of the crystals deposited from methanolic solutions containing felodipine with increasing molar ratios of xylitol (1:1, 1:2 and 1:3). The developed co-crystals were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) before monitoring drug dissolution. These results reflected the development of new crystalline species depending on the relative proportions of felodipine and xylitol with complete co-crystallization of felodipine being achieved in the presence of double its molar concentration of xylitol. This co-crystal formulation was compressed into sublingual tablet with ultrashort disintegration time with subsequent fast dissolution. Co-crystal formation was associated with enhanced dissolution with the optimum formulation producing the fastest dissolution rate. In conclusion, xylitol can be considered as a co-crystal co-former for enhanced dissolution rate of drugs.

Development of oral disintegrating tablets requires enhancement of drug dissolution and selection of sweetener. Co-crystallization of drugs with inert co-former is an emerging technique for enhancing dissolution rate. The benefit of this technique will become even greater if one of the sweeteners can act as co-crystal co-former to enhance dissolution and mask the taste. Accordingly, the objective of this work was to investigate the efficacy of sucralose as a potential co-crystal co-former for enhancing the dissolution rate of hydrochlorothiazide. This was extended to prepare oral disintegrating tablets. Co-crystallization was achieved after dissolving hydrochlorothiazide with increasing molar ratios of sucralose in the least amount of acetone. The co-crystallization products were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and powder X-ray diffraction. These measurements indicated that co-crystallization process started at a drug sucralose molar ratio of 1:1 and completed at 1:2. The developed co-crystals exhibited faster drug dissolution compared with the control, with co-crystal containing the drug with sucralose at 1:2 molar ratio being optimum. The later was used to prepare fast disintegrating tablets. These tablets had acceptable physical characteristics and showed fast disintegration with subsequent rapid dissolution. The study introduced sucralose as co-crystal co-former for enhanced dissolution and masking the taste.

Co-crystallization of drugs with benign co-formers is promising for enhancing dissolution rate of poorly soluble drugs. The selection of safe and pharmacologically inert co-formers is a critical step in this process. Accordingly, the objective of this work was to investigate aerosil 200 as a potential co-former for the preparation of hydrochlorothiazide co-crystal. Co-crystal formation involved acetone assisted co-grinding after mixing hydrochlorothiazide with increasing molar ratios of aerosil (1:1, 1:2 and 1:4). The prepared formulations were subjected to Fourier transform infrared spectroscopy, differential thermal analysis, and powder X-ray diffraction studies. These investigations provided evidence for co-crystal formation between the drug and aerosil. Complete co-crystallization was even achieved at the lowest tested concentration of aerosil suggesting that the stoichiometric ratio of co-crystal formation is 1:1 molar ratio. The dissolution studies revealed faster dissolution rate of the drug from co-crystals compared to the pure unprocessed drug or that which was subjected to wet grinding in absence of aerosil. Increasing the molar ratio of aerosil increased the amount dissolved in the first 5 min. This may be attributed to adsorption of the formed co-crystal on the surface of excess aerosil. In conclusion, aerosil can be considered as co-crystal co-former with potential future application.

This study investigated simultaneous transdermal delivery of indomethacin and benzocaine from microemulsion. Eucalyptus oil based microemulsion was used with Tween 80 and ethanol being employed as surfactant and cosurfactant, respectively. A microemulsion formulation comprising eucalyptus oil, polyoxyethylene sorbitan momooleate (Tween 80), ethanol and water (20:30:30:20) was selected. Indomethacin (1% w/w) and benzocaine (20% w/w) were incorporated separately or combined into this formulation before in vitro and in vivo evaluation. Application of indomethacin microemulsion enhanced the transdermal flux and reduced the lag time compared to saturated aqueous control. The same trend was evident for benzocaine microemulsion. Simultaneous application of the two drugs in microemulsion provided similar enhancement pattern. The in vivo evaluation employed the pinprick method and revealed rapid anesthesia after application of benzocaine microemulsion with the onset being 10 min and the action lasting for 50 min. For indomethacin microemulsion, the analgesic effect was recorded after 34.5 min and lasted for 70.5 min. Simultaneous application of benzocaine and indomethacin provided synergistic effect. The onset of action was achieved after 10 min and lasted for 95 min. The study highlighted the potential of microemulsion formulation in simultaneous transdermal delivery of two drugs.