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The lack of trypsin in the intestines may end up with malnutrition; thus, trypsin replacement therapy is required in such cases. The main objective of this study is to formulate and evaluate polymeric nanocapsule (PNC) systems able to deliver trypsin to the small intestines with the minimal release in the stomach with the maximum biological activity. Four nanocapsule formulations were prepared by double emulsion/evaporation method as w/o/w and s/o/w. Particle size, encapsulation efficiencies, drug release in simulated gastric fluids (SGF) and simulated intestinal fluids (SIF), morphology, the biological activity of encapsulated trypsin and shelf-life stability were investigated for all formulations. All formulations had a spherical shape with submicron size, and encapsulation efficiency more than 80%. The biological activity of encapsulated trypsin was significantly affected by the amount of trehalose and whether the formulations were prepared as s/o/w or w/o/w (P < 0.05). Most of the encapsulated protein was released sustainedly at the target site (SIF) over 24 h with minimum amount release in the gastric fluids. Also, more than 90% of physical integrity trypsin encapsulated in all formulations was retained after storage under chilled conditions for six months. However, the enzymatic assay results show that with low trehalose content, the biological activity was low, while increasing the trehalose amount increased the shelf stability to reach around 100% after six months of the study. The results obtained in this research work clearly indicated a promising potential of controlled release polymeric nanocapsules containing trypsin to target the small intestine and protect trypsin from the harsh condition facing the proteins during the process of preparation or the period of storage.

The aim of this work is to enhance the dissolution of furosemide, a hydrophobic drug used in treating hypertension. Solid dispersion via lyophilisation was employed for this purpose. Sugar and oligosaccharide, trehalose and hydroxyl propyl-γ-cyclodextrin (HP-γ-CD), were used as carrier molecules. Complexation of drug molecules with cyclodextrins changes its physical properties, including solubility. Trehalose was selected as it is a hydrophilic molecule as well as it reduces the cellular oxidative stress. Binary solid dispersions at three weight ratios drug to sugar/oligosaccharide were prepared. Solid dispersions were compared with unprocessed drug molecules and the marketed product. Samples were characterized via Fourier transform infrared spectroscopy, differential scanning calorimetry and In vitro drug dissolution. All lyophilized samples showed a significant improvement (p < 0.05) in furosemide dissolution in the aqueous dissolution medium. The study introduces furosemide/HP-γ-CD and furosemide/trehalose freeze dried composites as potential candidate powders to formulate for example fast disintegrating tablets.

Background: Albumin-based nanoparticles have been used as drug carriers to improve therapeutic effect. This study aimed to produce sulfasalazine (SSZ)-loaded bovine serum albumin (BSA) nanoparticles by desolvation technique and characterize their physical properties. Drug loading effect was also investigated.\ud \ud Methods: SSZ albumin nanoparticles were batch produced by desolvation technique and lyophilized. Physical characteristics of nanoparticles including size distribution, zeta potential and entrapment efficiency were studied.\ud \ud Results: Nanoparticles were spherical and typically 200–400 nm with low polydispersity (PDI). The zeta potentials of nanoparticles ranged from −21 to −41 mV, which were attributed to BSA and SSZ. The highest actual drug loading was close to 0.5%w/w. The addition of 2% sucrose during lyophilization was essential to avoid cake collapse and the particle sizes increased slightly where their PDI values were low. Although the presence of sucrose led to a slight reduction in zeta potential, it had limited effect on zeta potential of the nanoparticles. The interactions between SSZ and formulation excipients were also confirmed with FTIR and DSC analyses.\ud \ud Conclusion: Desolvation technique produced stable sulfasalazine-loaded nanoparticles that can be administered parenterally.\ud \ud KEYWORDS: sulfasalazine; nanoparticle; albumin; physical property

Niosomes are colloidal vesicles that capable of encapsulating drugs as a carrier for drug delivery system. They are formed by self-assembly of a non-ionic surfactant with cholesterol and co-surfactant. In this work, cinnarizine-containing niosomes comprised of sorbitan monostearate (Span® 60), cholesterol and co-surfactant (Cremophor® ELP, Cremophor® RH40 or Solutol® HS15) were prepared using conventional thin film hydration and microfluidic methods. Effects on characteristics of niosomes with the presence of poorly water-soluble drug, cinnarizine in the niosomal formulations prepared using different methods and incorporation of different co-surfactants were studied and compared for their particle size, polydispersity index (PDI) and encapsulation efficiency. Dynamic light scattering was employed for particle size measurements and drug loading studies were analysed using high performance liquid chromatography (HPLC). The morphology of niosomes was characterized using optical light microscopy.

Novel niosomal formulations containing cinnarizine were developed to enhance its drug characteristics. In this work, niosomes (non-ionic surfactant vesicles) were prepared by conventional thin-film hydration (TFH) and microfluidic (MF) methods with sorbitan monostearate (Span&reg, 60), cholesterol, and co-surfactants (Cremophor&reg, ELP, Cremophor&reg, RH40 and Solutol&reg, HS15) as key excipients. The aim was to study the effect of cinnarizine on the characteristics of different niosomal formulations manufactured by using different methods. For effective targeted oral drug delivery, the efficacy of niosomes for therapeutic applications is correlated to their physiochemical properties. Niosome vesicles prepared were characterised using dynamic light scattering technique and the morphology of niosomes dispersion was characterised using optical microscopy. Dialysis was carried out to purify niosome suspensions to determine drug loading and drug release studies was performed to study the potential use of niosomal systems for cinnarizine.

Clinical applications of oral protein therapy for the treatment of various chronic diseases are limited due to the harsh conditions encounter the proteins during their journey in the Gastrointestinal Tract. Although nanotechnology forms a platform for the development of oral protein formulations, obtaining physiochemically stable formulations able to deliver active proteins is still challenging because of harsh preparation conditions. This study proposes the use of poly (D, L-lactic-co-caprolactone)-based polymeric nanocapsules at different monomers’ ratios for protein loading and oral delivery. All formulations had a spherical shape and nano-scale size, and lysozyme encapsulation efficiency reached 80% and significantly affected by monomers’ ratio. Trehalose and physical state of lysozyme had a significant effect on its biological activity (P

PURPOSE:\ud Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug.\ud \ud METHODS:\ud In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy.\ud \ud RESULTS:\ud The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min.\ud \ud CONCLUSIONS:\ud the physical mixing and freeze drying processes significantly increased the percentage of drug release with time.

Proteins can be encapsulated in niosomes as they are known to protect proteins against the surrounding env ironment. Niosomes of Span™ 65/cholesterol/pluronic ® F -127 were prepared by thin film hydration method. Insulin and lysozyme were chosen as model proteins. Niosomes were chara c-terised for morphology by Transmission Electron M icroscopy (TEM) and vesicles size using Dynamic Light Scattering. The entrapment efficiency of protein in niosomes was determined by complete vesi-cle disruption using 50:50% isopropanol:buf fer, followed by analysis of the resulting so lutions by HPLC method. Thermal behaviour of the niosomes was investigated using Differential Scanning Calo-rimetry (DSC). Protection of proteins against simulated gastric fluid (SGF) and simu lated intestinal fluid (SIF) were also assessed. The results showed that niosomes prepared with diffe r ent molar ratios % of Span™ 65, cholesterol and pluronic ® F -127 successfully produced with insulin and lysozyme. For insulin co n taining niosomes, the ratio % of 64.7 (Span™ 65): 32.3 (cholesterol): 3.0 (pluronic ® F - 127) produced the highest protein encapsulation eff i-ciency and the smallest vesicle size of 653.6 nm. For lysozyme containing niosomes, the maximum pr o tein encapsulation was found in 72.75/24.25/3.00% molar ratio of Span™ 65/cholesterol/pluronic ® F -127 niosomes with vesi cle size of 627.3 nm. The release study of proteins from the niosomal preparations in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) revealed that insulin and lysozyme efflux from the niosomes is a biphasic process. The results indicate that Span™ 65 niosomes could be developed as controlled release dosage forms for delivery of peptides and proteins such as insulin and lysozyme.

Silicified microcrystalline cellulose pellets with hydroxypropyl methylcellullose (HPMC) as modifier were prepared using a\ud mixed solvent as liquid binder. Pellets were produced using extrusion-spheronization with a mixed solvent consisting of water and isopropanol\ud as liquid binder. The key spheronization aid was Prosolv® SMCC 90. Low viscosity grade HPMC was incorporated aiming to\ud modify release of indometacin. Physical characteristics including breaking load, apparent density and flow properties, particle size distribution\ud and shape were determined. Drug loaded pellets were also tested for dissolution profiles. By adjusting liquid binder property, at\ud isopropanol to water ratio of 3.5 to 6.5, pellets of desirable size and shape with reasonable yields were obtained. Pellets exhibited good\ud flow property and they were mechanically strong. Pellet with higher HPMC content displayed a faster drug dissolution profile. This was\ud because low viscosity grade HPMC was not enough to create strong gel. Instead hydration of HPMC molecules increased matrix’s\ud hydrophilicity and weakened the structure of pellet faster. The release of indometacin was partly based on the erosion of hydrated\ud matrix. The presence of HPMC in the pellets would require a mixed solvent to produce desirable shape. Incorporation of HPMC had\ud modified drug release from the pellets without further coating. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47924.

This work aimed to investigate and optimise the effects of co-surfactants, hydration volume, and time on the entrapment of methylene blue (MB) within niosomes and the vesicle sizes of MB-loaded niosomes upon different storage temperatures. Niosomes were prepared by the thin film hydration method followed by gel permeation chromatography to obtain purified niosome suspensions. The probe sonication method was used to reduce the niosome vesicle size and distribution. Highest entrapment efficiencies (%EE) were determined for niosomal formulations containing Span® 60, cholesterol, and Cremophor® ELP (E2 and E3), which were prepared with a hydration volume of 5 mL. The hydration time was 15 min for E2 and 60 min for E3 (%EE = 40.1 ± 7.9% and 32.9 ± 10.1% for E3 and E2, respectively). The final lipid contents in the formulations were shown to have an impact on %EE.

Silicified microcrystalline cellulose (SMCC), Prosolv SMCC 50 was used as spheronization aid to manufacture pellets by extrusion and spheronization. Different ratios of SMCC to lactose were used to manufacture pellets using appropriate levels of water as liquid binder. Avicel PH101 based pellets were also manufactured for comparison of their physical properties. The ratio of liquid binder to spheronization aid was critical to produce pellets of desired size and shape. Extrudates composed of 20% aid could withstand only smaller spheronization force in order to be shaped into pellets. The successful products fulfilled the quality of pellets such as narrow size distribution and spherical in shape. The highest surface tensile strength was observed in pellets with equal ratio of lactose to SMCC while pellets having 20% aid disintegrated rapidly within 15 min. Furthermore, Prosolv SMCC 50 based pellets possessed a stronger surface tensile strength when compared with Avicel PH101 based pellets. In conclusion, Prosolv SMCC 50 has showed to be a good spheronization aid for extrusion and spheronization when used in the range of 20 to 80% content. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43829.

This study was aimed to investigate the effects of molar ratio of cholesterol to Span 60 and stabilizers (Solutol HS 15 or dicetyl phosphate (DCP)) on the entrapment of methylene blue, a model hydrophilic drug. The niosomes were prepared by the film hydration method and characterized for drug entrapment efficiency (EE), vesicle size, zeta potential and thermal properties of niosomal membrane. It was found that niosomal vesicles possessed median diameter ranging from 0.35 to 1.85 μm. The niosomes that were formulated with lower molar ratios of cholesterol to Span 60 of 0.33 and 0.50 produced significantly higher EE with both stabilizers when compared to cholesterol to Span 60 molar ratios of 1.0 and above (p < 0.05). The EE of niosomes stabilized with DCP was significantly higher (p < 0.05) than those prepared with Solutol HS 15 except at a molar ratio of cholesterol to Span 60 of 0.33. In conclusion, with low molar ratios of cholesterol to Span 60, more drugs could be entrapped within the niosomes regardless of the type of stabilizers. Furthermore, EE and median diameter of niosomes containing DCP were higher than those stabilized with Solutol HS 15.

The main objectives of this study were to improve the aqueous solubility and to modify in vitro dissolution profile of hydrophobic drug using self-emulsifying drug delivery systems (SEDDS). SEDDS were formulated using Capmul PG-12, Cremophor RH 40 and Tween 20 at different weight ratios and incorporated with Cinnarizine. The drug incorporation into pre-concentrate and drug solubility in phosphate buffer (pH 7.2) were investigated. In addition, the mean droplet size and drug release profile of the SEDDS were also determined. The drug incorporation was over 120 mg per 0.5 g pre-concentrate regardless of the composition of the formulations. The solubility of Cinnarizine in phosphate buffer (pH 7.2) was at least 1500 μM in the SEDDS. Formulations with only 10% w/w Capmul PG-12 were less than 20 nm in mean diameter while those produced with at least 20% w/w Capmul PG-12 were more than 100 nm regardless of the ratios of Cremophor RH 40 to Tween 20. SEDDS showed a significant increase of the mean percentage drug release than pure drug (p

The properties of spray dried PLA microparticles were affected by the choice of solvents, amount of ciclosporin and TPGS added. Ethyl acetate formed microparticle with smooth surface when compared to those produced by dichloromethane. The results of FTIR have not shown chemical interaction amongst PLA, ciclosporin and TPGS while thermal analysis showed physical interactions amongst these components. TPGS was found to lower Tg value of PLA by exerting a plasticizing effect while ciclosporin reverted this effect. When the content of TPGS increased from 2% (w/w) to 10% (w/w), the microparticles tended to agglomerate due to the lowering of the polymer Tg values at the employed spray drying temperature. In addition, a lesser amount of ciclosporin was found at the surface of the microparticle and resulted in smaller initial release of ciclosporin. When 2% (w/w) TPGS was used, the initial release of ciclosporin was enhanced and the microparticles formed were not agglomerated.

Physostigmine is an anti-cholinesterase used for the pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins. The aim of this study is to design a polymeric microparticle system for sustained release of physostigmine. In this paper, we have attempted to encapsulate physostigmine in microparticles made from poly( d , l -lactide-co-glycolide) (PLGA) with various contents of glycolide and poly( d , l -lactide) (PLA) using spray-drying and single emulsion techniques. It was found that during the single emulsion process, most of the physostigmine molecules were lost in the external aqueous phase. However, more than 90% encapsulation efficiency of physostigmine was obtained using the spray-drying technique. SEM micrographs revealed that spherical microparticles containing physostigmine with a smooth surface were yielded with PLA, PLGA 50:50, RG 502 (PLGA 50:50 with a lower molecular weight) and PLGA 65:35 but PLGA 85:15, PLGA 75:25 and PLGA 50:50 with a high concentration produced microparticles with irregular shapes. An increased inlet temperature yielded a higher physostigmine release rate from the PLA microparticles. Physostigmine release from the microparticles showed a biphasic pattern, characterized by an initial burst release followed by a sustained release for PLGA 65:35, PLGA 50:50 and RG 502 or a non-detectable release for PLGA 85:15, PLGA 75:25 and PLA. A sustained-release of physostigmine with a low initial burst over 1 week was achieved from RG 502 microparticles, which would be used as an injectable dosage form in our further animal studies.

Physostigmine, an anticholinergic drug, and its metabolite eseroline can be quantitated by high-performance liquid chromatography (HPLC) with photodiode-array detection. After addition of the structurally related internal standard (-)-N-methylphysostigmine, rat plasma samples were extracted and cleaned using a Varian Bond Elut C(18) column. The methanol-ammonia (98:2) eluate was evaporated to dryness and reconstituted with 0.01 M sodium dihydrogenphosphate (pH 3). Physostigmine and eseroline were separated on an Alltech Ultrasphere Silica column (250x4.6 mm I.D.; particle size 5 micrometer) at a flow-rate of 1 ml/min, with a mobile phase of 0.01 M sodium dihydrogenphosphate (pH 3)-acetonitrile (85:15). The limits of detection were 10 and 25 ng/ml for physostigmine and eseroline, respectively; the signal-to-noise ratio for this concentration was approximately 3:1. Spiked rat plasma containing 0.1-2.5 microgram/ml of physostigmine and eseroline gives good linearity. The average percentage recovery from five spiked plasma samples was 88.0+/-2.9 and 61.1+/-5.6% for physostigmine and eseroline, respectively. Within the concentration range 0.1-2.5 microgram/ml, the within-day precision was 1.9-8.3 and 3.0-7.7% for physostigmine and eseroline, respectively, and the between-day precision was 4.1-9.3 and 3.7-11% for physostigmine and eseroline, respectively. The method is rapid, simple and reliable, thus it is suitable for pharmacokinetic studies in the rat.

Xanthan gum (XG), a hydrophilic biopolymer with modified release properties, was used to produce directly compressed matrix tablets containing a model drug, sodium p-aminosalicylate. Three formulations were prepared, each containing a different calcium dihydrate salt: calcium chloride, calcium sulfate or dibasic calcium phosphate. The aim of the investigation was to relate the calcium ion content and solubility of the calcium salt to the in vitro drug release profile of the xanthan matrices. Tablet hydration, erosion and drug release were determined in distilled water using the British Pharmacopoeia (BP) paddle method. The data showed that the overall drug release was the greatest with addition of calcium sulfate, followed by calcium chloride and dibasic calcium phosphate. The chloride salt formulation displayed the greatest percentage erosion due to rapid mass loss during the initial phase, followed by those with sulfate or phosphate salts. As xanthan gel viscosity increased and drug release was also found to be lower, it can be concluded that drug release is influenced by the solubility of the salt present in the formulation, since these parameters determine the viscosity and structure of the gel layer.

Purpose: The study looked into the feasibility of producing pellet using Avicel CL611 as spheronization aid by the extrusion/spheronization technique.\ud \ud Methods: Pellets were formulated to contain either 20% or 40% Avicel CL611 and lactose monohydrate as the other sole ingredient. Water is used as liquid binder. Quality of pellets and extrudates were analyzed for size distribution, shape, surface tensile strength and disintegration profile.\ud \ud Results: More water was needed when higher Avicel CL611 fraction was used during the production of pellets. The pellets of larger size were obtained by increasing the water content. Pellets with aspect ratios of ∼1.1 were produced with high spheronization speed at short residence time. Higher tensile strength was achieved when increasing the water content and the fraction of Avicel CL611 during pellet production. These pellets also took longer time to disintegrate, nonetheless all the pellets disintegrated within 15 min. A positive linear relationship was obtained between the tensile strength and time for pellets to disintegrate.\ud \ud Conclusion: Strong but round pellets that disintegrate rapidly could be produced with Avicel CL611 as spheronization aid using moderately soluble compounds such as lactose.

The stabilisation of proteins using different excipients in dried forms for possible therapeutic use is extensively studied. However, the effects of excipients on proteins in crystallised forms are sparsely documented. Therefore, the influences of Pluronic®F-127 and Cremophor®EL (as surfactants) and β-cyclodextrin and inulin (as sugars) on stability and biological activity of lysozyme, a model protein, in spray dried and crystallised forms were investigated. Spray dried and crystallised lysozyme were prepared in absence and presence of the mentioned excipients in a concentration of 0.05% w/v. The protein formulations were characterised in both solution state (using biological assay, particle size analysis and protein concentration determination) and solid state (employing yield determination, scanning electron microscopic (SEM) examination, Fourier transform infrared (FT-IR) spectroscopy for secondary structure analysis and Differential Scanning Calorimetry (DSC) for thermal study). Also, protein samples were assayed for their biological activities after exposing to storage stability study for 20 weeks in solid states at 24 °C/76% relative humidity (RH) and in aqueous states at 24 °C. The results showed that lysozyme crystals with Cremophor®EL, Pluronic®F-127, β-cyclodextrin and inulin maintained protein thermal stability (as indicated by DSC) to greater extent compared with spray dried protein formulations. Also, Pluronic®F-127 was competent to recover 100% lysozyme from crystallisation protein solutions (as confirmed by yield determination); this surfactant was able to prevent aggregate formation within spray dried lysozyme (as demonstrated by particle size analysis). The presence of Pluronic®F-127, β-cyclodextrin and inulin preserved the protein biological activity in freshly prepared spray dried and crystallised samples. Pluronic®F-127 was competent to protect lysozyme in both spray dried and crystallised forms after storage. Pluronic®F-127 has proved to be a promising protectant of proteins. The improved stability of the spray dried and crystallised protein containing Pluronic®F-127 shows promise for delivery of proteins via inhalation (in a spray dried form which has particle size range suitable for inhalation as revealed by particle size analysis and SEM) and injectable routes (in spray dried and crystallised forms). The way excipients react with proteins is different in the case of spray drying and crystallisation techniques, hence the choice of the additives and the processing techniques play a great role in controlling protein properties, activity and stability as shown in this study.

The aim of this study was to produce cinnarizine loaded Eudragit(®) L100-55 microparticles by coacervation technique in order to achieve pH responsive drug release using hydroxypropyl methycellulose (HPMC) as stabilizer. The effect of enteric polymer: HPMC ratio on properties of microparticles was investigated with regard to particle size distribution, morphology, yield, encapsulation efficiency, in vitro drug release profiles and interaction between cinnarizine and Eudragit(®) L100-55. High drug encapsulation efficiency was seen in all microparticles. Particle diameter increased when the enteric polymer content was higher relative to HPMC. In vitro dissolution studies demonstrated that the drug release from the microparticles was dependent upon enteric polymer: HPMC ratio and particle size distribution. At the ratio of at least 3.75:1 of enteric polymer: HPMC, drug release was suppressed most significantly in low pH (hydrochloric acid as medium) while rapid drug release was observed in pH 7.4.