Drug Delivery Letters - Volume 10, Issue 3, 2020

Background: Solubility and dissolution profile are the major factors which directly affect the biological activity of a drug and these factors are governed by the physicochemical properties of the drug. Crystal engineering is a newer and promising approach to improve physicochemical characteristics of a drug without any change in its pharmacological action through a selection of a wide range of easily available crystal formers. Objective: The goal of this review is to summarize the importance of crystal engineering in improving the physicochemical properties of a drug, methods of design, development, and applications of cocrystals along with future trends in research of pharmaceutical co-crystals. Co-crystallization can also be carried out for the molecules which lack ionizable functional groups, unlike salts which require ionizable groups. Conclusion: Co-crystals is an interesting and promising research area amongst pharmaceutical scientists to fine-tune the physicochemical properties of drug materials. Co-crystallization can be a tool to increase the lifecycle of an older drug molecule. Crystal engineering carries the potential of being an advantageous technique than any other approach used in the pharmaceutical industry. Crystal engineering offers a plethora of biopharmaceutical and physicochemical enhancements to a drug molecule without the need of any pharmacological change in the drug.

Background: To develop electro-sensitive transdermal drug delivery systems (ETDDS) using polyacrylamide-grafted-pectin (PAAm-g-PCT) copolymer hydrogel for rivastigmine delivery. Methods: Free radical polymerization and alkaline hydrolysis technique was employed to synthesize PAAm-g-PCT copolymer hydrogel. The PAAm-g-PCT copolymeric hydrogel was used as a reservoir and cross-linked blend films of PCT and poly(vinyl alcohol) as rate-controlling membranes (RCMs) to prepare ETDDS. Results: The pH of the hydrogel reservoir was found to be in the range of 6.81 to 6.93 and drug content was 89.05 to 96.29%. The thickness of RCMs was in the range of 51 to 99 μ and RCMs showed permeability behavior against water vapors. There was a reduction in the water vapor transmission rate as the glutaraldehyde (GA) concentration was increased. The drug permeation rate from the ETDDS was enhanced under the influence of electric stimulus against the absence of an electric stimulus. The increase in flux by 1.5 fold was recorded with applied electric stimulus. The reduction in drug permeability observed when the concentration of GA was increased. Whereas, the permeability of the drug was augmented as an electric current was changed from 2 to 8 mA. The pulsatile drug release under “on– off” cycle of electric stimulus witnessed a faster drug release under ‘on’ condition and it was slow under ‘off’ condition. The alteration in skin composition after electrical stimulation was confirmed through histopathology studies. Conclusion: The PAAm-g-PCT copolymer hydrogel is a useful carrier for transdermal drug delivery activated by an electric signal to provide on-demand release of rivastigmine.

Background: Solid lipid nanoparticles are lipid-based carriers that can be used for a range of drugs and biomolecules. However, most production methods currently used do not offer easy translation from laboratory preparation to scale-independent production. Objectives: Within this study, we have investigated the use of microfluidics to produce solid lipid nanoparticles and investigated their protein loading capability. In the development of this process, we have investigated and identified the critical process parameters that impact on the product attributes of the solid lipid nanoparticles. Methods: Solid lipid nanoparticles based on Tristearin and 1,2-Distearoyl-phosphatidylethanolaminemethyl- polyethyleneglycol conjugate-2000 were formulated using the NanoAssemblr® Benchtop system. The flow rate ratio, total flow rate and initial protein concentration were investigated as process parameters and the particle size, PDI, zeta potential, drug loading and drug release were measured as product attributes. Results: Our results demonstrate the suitability of microfluidics as a production method for solid lipid nanoparticles containing protein. In terms of key process parameters to consider, both the solvent to aqueous flow rate ratio and the total flow rate were shown to have a notable impact on particle size. Protein loading capacity was influenced by the solvent to aqueous flow rate ratio but was similar across all flow rates tested. Conclusion: Within this study, we outline a rapid and easy protocol for the scale-independent production of solid lipid nanoparticles. This process can support the rapid translation of production methods from bench to clinic.

Background: The solubility/dissolution of a drug in the gastrointestinal (GI) region and the permeability of a drug through the GI membrane are the two key parameters governing drug absorption. Poor aqueous solubility is the rate-limiting factor for the absorption of poorly soluble drugs through the GI region. Objective: The purpose of this work is to investigate the influence of two different hydrotropes, namely sodium benzoate (SB), and nicotinamide (NA), at different levels (10-40%) and in combination on the solubility and permeability of poorly soluble drug glibenclamide (GLB). The work will find out, whether the solubility enhancement of glibenclamide using hydrotropes and hydrotropic blends also affects the GI permeability of glibenclamide. Methods: A 32 full factorial design was employed to study the influence of hydrotropic blends of sodium benzoate and nicotinamide on the solubility and permeability of GLB. The solubility and permeability of drugs at different levels (10-40%) of hydrotropes (SB, NA) and their blends are determined using a magnetic stirrer and in vitro Franz diffusion cell, respectively. Results: The results of preliminary studies revealed an increase in the solubility and reduction in the apparent permeability of GLB as a function of increasing levels of both hydrotropes. Conclusion: In this work, it was found that an increase in solubility with hydrotropes results in a decrease in permeability of GLB. The solubility enhancement and the permeability decrease were observed more in hydrotropic blends in comparison to individual hydrotropes. Therefore, it is concluded that both factors, solubility and permeability, must be optimized to achieve appreciable gains in bioavailability.

Background: Buccal delivery of drugs can be used as an alternative administration route to conventional oral route avoiding the liver first-pass effect and improving patient compliance. Objective: The goal of this work was to develop dry emulsions for buccal delivery of ketoprofen, used as a lipophilic model drug. The influence of two vegetable oils, olive oil or wheat germ oil, in the presence of α-cyclodextrin and different drying techniques on the dry emulsion properties was evaluated. Methods: Emulsions were prepared by adding olive oil or wheat germ oil to an aqueous solution of α-cyclodextrin and subsequently dried through an oven, freeze-dryer or spray-dryer. Dry emulsions were characterized in terms of yield, encapsulation efficiency, morphology and drug solid-state. In vitro drug release and permeation studies were carried out to evaluate dry emulsion ability to release the drug and to allow its permeation through the esophageal porcine epithelium. Results: The formation of stable and milky emulsion was assured by cyclodextrin ability to interact with oil components obtaining an inclusion complex with amphiphilic property able to act as a surfaceactive agent. The drying process influenced the yield and the encapsulation efficiency, while no significant differences were observed between olive oil and wheat germ oil. Freeze-dried emulsions, selected as the best formulations, resulted in fast release of drug thereby ensuring its permeation across the epithelium. Conclusion: Dry emulsions prepared with a simple and easy method, using natural ingredients and avoiding synthetic surfactants and organic solvents, could be used for buccal delivery of lipophilic drugs.

Background: Alpha-tocopherol is a potent antioxidant involved in sperm protection particularly during cryopreservation. However, its poor solubility limits the optimal protection in aqueous solutions. Objective: The aim of this study was to enhance the solubility of α-tocopherol by the use of liposomes. Methods: The experimental approach included loading vitamin E in liposomes prepared by ethanol injection method and the optimization carried out by an experimental design. The optimum solution was characterized by high performance liquid chromatography and scanning electron microscope. Finely, the impact on sperm motility protection was studied by the freezing technic of bovine sperm. Results: The optimum solution was obtained when using 10.9 mg/ml of phospholipids, 1.7 mg/ml of cholesterol and 2 mg/ml of vitamin E. The liposome size was 99.86 nm, providing 78.47% of loaded efficiency. The results showed a significant positive impact on sperm motility after hours of preservation. Conclusion: In conclusion, the current results showed the interest of liposome preparation as an alternative to enhance vitamin E solubility and to protect spermatozoa during cryopreservation.

Introduction: Hydrodynamically balanced system (HBS) possesses prolonged and continuous delivery of the drug to the gastrointestinal tract which improves the rate and extent of medications that have a narrow absorption window. The objective of this work was to develop a Hydrodynamically Balanced System (HBS) of Metoprolol Succinate (MS) as a model drug for sustained stomach specific delivery. Methods: Experimental batches were designed according to 3(2) Taguchi factorial design. A total of 9 batches were prepared for batch size 100 capsules each. Formulations were prepared by physically blending MS with polymers followed by encapsulation into hard gelatin capsule shell of size 0. Polymers used were Low Molecular Weight Chitosan (LMWCH), Crushed Puffed Rice (CPR), and Hydroxypropyl Methylcellulose K15 M (HPMC K15M). Two factors used were buoyancy time (Y1) and time taken for 60% drug release (T60%; Y2). Results: The drug excipient interaction studies were performed by the thermal analysis method which depicts that no drug excipient interaction occurs. In vitro buoyancy studies and drug release studies revealed the efficacy of HBS to remain gastro retentive for a prolonged period and concurrently sustained the release of MS in highly acidic medium. All formulations followed zero-order kinetics. Conclusion: Developed HBS of MS with hydrogel-forming polymers could be an ideal delivery system for sustained stomach specific delivery and would be useful for the cardiac patients where the prolonged therapeutic action is required.

X-ray powder diffraction (XRPD) is a unique, solid-state analytical tool used to study the 3D structure of small or macromolecules by their x-ray diffraction or scattering patterns. X-ray diffraction by a crystal reflects the periodicity of crystal architecture; any imperfections within the crystal architecture can be easily identified by its poor diffraction pattern. Recently, an open crystallography database reported that more than 85 % of drug compounds are crystalline and exist in different polymorphic states. Physicochemical properties of pharmaceutical drug products composed of active pharmaceutical ingredients (APIs) and excipients are interdependent on the physical state and forms in which APIs are distributed in excipients that determine the in-vivo and ex-vivo performance of the product. Amorphous APIs have relatively higher dissolution and bioavailability than crystalline form but with lower phase stability. During the formulation development and storage phase, the conversion is higher that largely impacts the bioavailability of the drug product. In this manuscript, we have presented the case study of itraconazole and apigenin; both are crystalline APIs, that, with the help of solid dispersion technology, are converted into amorphous drug products with enhanced oral bioavailability. The realtime monitoring of the physical form of API in the formulation was possible with the help of XRPD and other supporting data obtained from differential scanning calorimeter (DSC), which can be correlated with the dissolution and in-vivo performance of the formulation.