Co-delivery of Curcumin and Imatinib by Nanostructured Lipid Carriers in the Treatment of Lymphoma

The purpose of this study was to encapsulate curcumin and imatinib in nanostructures and target them with HDL for scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Introduction: Among numerous drug-delivery approaches, high-density lipoprotein (HDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs by their high affinity to SR-B1. In this study, we have investigated the enhancement of the therapeutic impact of curcumin, a naturally occurring polyphenol substance extracted from the roots of Curcuma Longa that has been extensively studied for its broad-spectrum anticancer effects by co-delivery with imatinib. The potential benefits of curcumin are, however, limited due to its poor water solubility and rapid degradation which results in low bioavailability on administration. The drug of choice in lymphoma is imatinib. Methods and Results: Curcumin and imatinib nanostructured lipid carriers (NLCs) were prepared by dissolving 10 mg of lecithin, 2 mg of stearyl amine, 25% of oleic acid and 7.5 mg of curcumin or 2.5 mg of imatinib in 2 ml of ethanol (mixed with 100 µl acetone or 100 µl chloroform) and then added to 20 ml of stirring deionized water including 0.5 % of Tween 80 at room temperature and was left for 3 hours for solvent evaporation. The NLCs were conjugated to HDL by EDC chemistry and then tested by MTT assay for their cytotoxicity on two types of lymphoma cells including; Ramus as B cell lymphoma expressing SR-B1 receptors and Jurkat as T cell lymphoma without SR-B1 receptors. The results showed the best designed nanoparticles had the particle size of 182 nm, zeta potential of -3 mV, curcumin and imatinib loading efficiency of 100 % and 98 %, respectively. They released imatinib and curcumin within 24 and 48 hours, respectively. The NLCs caused more significant cytotoxicity than each separate drug encapsulated in NLCs or free drugs. Conclusions: Co-delivery of curcumin and imatinib in NLCs targeted by HDL may be more useful than imatinib alone in the treatment of B cell lymphoma

Enhancement of Drug Solubility: Review Abstract Articles

Introduction: Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various  processes  have  been  developed  to  increase  the  solubility,  dissolution  rate  and bioavailability  of  these  active  ingredients  belonging  to  BCS  II  and  IV  classifications. Therefore, enhancement in the solubility of such drugs would be important to the pharmaceutical industry. There is a number of formulation approaches to resolve the problems of low solubility and low bioavailability of drugs. These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Nanotechnology can be used to resolve  the  problems  associated  with  these  conventional approaches  for  solubility  and  bioavailability  enhancement Methods and Results: There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increase efficiency and/or reducing side effects of drugs. This is true for parenterally, topically and orally administered solutions. Hence various techniques are used for the improvement of the solubility of poorly water soluble drugs including hydrotrophy, use of salt form, use of precipitation inhibitors, alteration of pH of the drug micro-environment, solvent deposition, precipitation pH adjustment, co-solvency, micellar solubilization, super critical fluid techniques, solid dispersions, complexation, micro-emulsions, solid solutions, eutectic mixtures, selective adsorption on insoluble carriers, evaporative precipitation into aqueous solutions, use of surfactants, use of amorphous, anhydrates, solvates and nanonisation. Conclusions: Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques used for the enhancement of the solubility of poorly soluble drugs like physical and chemical modification of have specific advantages and draw backs. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics

Dissolution enhancement of gliclazide using pH change approach in presence of twelve stabilizers with various physico-chemical properties

Purpose. The micronization using milling process to enhance dissolution rate is extremely inefficient due to a high energy input, and disruptions in the crystal lattice which can cause physical or chemical instability. Therefore, the aim of the present study is to use in situ micronization process through pH change method to produce micron-size gliclazide particles for fast dissolution hence better bioavailability. Methods. Gliclazide was recrystallized in presence of 12 different stabilizers and the effects of each stabilizer on micromeritic behaviors, morphology of microcrystals, dissolution rate and solid state of recrystallized drug particles were investigated. Results. The results showed that recrystallized samples showed faster dissolution rate than untreated gliclazide particles and the fastest dissolution rate was observed for the samples recrystallized in presence of PEG 1500. Some of the recrystallized drug samples in presence of stabilizers dissolved 100% within the first 5 min showing at least 10 times greater dissolution rate than the dissolution rate of untreated gliclazide powders. Micromeritic studies showed that in situ micronization technique via pH change method is able to produce smaller particle size with a high surface area. The results also showed that the type of stabilizer had significant impact on morphology of recrystallized drug particles. The untreated gliclazide is rod or rectangular shape, whereas the crystals produced in presence of stabilizers, depending on the type of stabilizer, were very fine particles with irregular, cubic, rectangular, granular and spherical/modular shape. The results showed that crystallization of gliclazide in presence of stabilizers reduced the crystallinity of the samples as confirmed by XRPD and DSC results. Conclusion. In situ micronization of gliclazide through pH change method can successfully be used to produce micron-sized drug particles to enhance dissolution rate

Nanocomposite Gels for Controlled Topical Delivery of Simvastatin

Abstract In this study, the lipophilic drug is solubilized using PF127-Chol micelles and then the solubilized drug was incorporated in to chitosan/HPMC gel in order to use as a wound dressing. Introduction: Simvastatin (Sim) is a HMG-COA reductase inhibitor, and is used conventionally for cholesterol reduction but recent studies demonstrated the potential of this agent for diverse pathologic conditions such as wound healing due to its antioxidant, anti-inflammatory, and antibacterial properties. However, the systemic bioavailability of Sim is very low (approximately 5%). Moreover, the systemic administration of Sim can cause several adverse effects such as myopathy and liver problems. Therefore, topical application of Sim can increase the accessibility of drug in wound area at lower systemic level and decrease the possible incidence of side effects. Methods and Results: Polymeric micelles containing Sim were prepared by the thin film hydration method and optimized using irregular full factorial design. The mean diameter, PDI, and zeta potential of the prepared drug loaded micelles were determined by dynamic laser scattering method using Malvern nanosizer. The gels were prepared using chitosan or/and HPMC at 3% (W/W). Bioadhesion was determined using a tensile strength machine. The in vitro release of Sim from different gel formulations was studied using dialysis method. Statistical analysis showed that solvent type had the most impact on the amount of drug loading and zeta potential. The optimized formulation suggested by desirability of 93.5% was prepared using 1 mg of Sim, 10 mg of copolymer, dichloromethane as the organic solvent, hydration time of 45 min, and hydration temperature of 25 oC. The release of the drug from nanomicelles was found to be biphasic and showed a rapid release in the first stage followed by a sustained release for 96 hrs. The gel-contained nanomicelles exhibited pseudo-plastic flow and more sustained drug release profile compared to nanomicelles. Conclusions: The results indicate the obtained composite gel has great potential for topical applications at the site of wounds

Optimizacija svojstava samoorganiziranja graft kopolimera metoksi poli(etilen glikola) i masnih kiselina pri pripravi nanonosača s uklopljenim etopozidom

The objective of this work was to study the effect of fatty acid chain length grafted to methoxy poly(ethylene glycol) (mPEG) on self assembling properties of micelles for etoposide delivery. Three amphiphilic copolymers were synthesized using mPEG, myristic acid, stearic acid and behenic acid through an esteric linkage. The particle size and zeta potential of the micelles were determined by the dynamic light scattering method. Etoposide was loaded into micelles by film casting using various drug/polymer ratios. Drug release was studied by the dialysis method. The structure of copolymers was confirmed by 1H NMR and FTIR. Critical micellar concentration (CMC) measurements showed that the longer hydrophobic chains formed more thermodynamically stable micelles. Among the prepared copolymers, etoposide showed the highest solubility in the mPEG-behenic copolymer. Drug loading efficiency depended on the hydrophobic chain length and drug/polymer ratio. The highest drug loading efficiency was found in mPEG-myristic micelles with 1:20 drug/polymer ratio. Micelles released 80 % of loaded drug within about 5 h.Cilj je rada bio ispitati svojstva samoorganiziranja micela pripravljenih od graft kopolimera metoksipolietilenglikola (mPEG) i masnih kiselina različite duljine lanca za uklapanje etopozida. Sintetizirana su tri amfifilna kopolimera povezivanjem miristinske, stearinske i behenične kiseline esterskom vezom s mPEG. Veličina i zeta-potencijal micela određeni su metodom dinamičkog raspršivanja svjetlosti. Micele s uklopljenim etopozidom pripravljene su film-metodom pri različitim omjerima lijeka i kopolimera. Oslobađanje lijeka iz micela ispitano je metodom dijalize. Struktura kopolimera potvrđena je 1H NMR i FTIR spektroskopijom. Određivanjem kritičnih micelizacijskih koncentracija utvrđeno je da se s povećanjem duljine hidrofobnog lanca na kopolimerima stvaraju termodinamički stabilnije micele. Među sintetiziranim kopolimerima, micele građene od kopolimera mPEG i behenične kiseline imaju najbolji solubilizacijski kapacitet za etopozid. Učinkovitost uklapanja lijeka u micele ovisi o duljini hidrofobnog dijela u kopolimeru i omjeru lijeka i kopolimera. Najveća učinkovitost uklapanja lijeka utvrđena je za micele mPEG i miristinske kiseline pri omjeru lijeka i kopolimera 1:20. Oko 80% uklopljenog lijeka oslobađa se iz micela tijekom 5 sati

Co- delivery of Venlafaxine and Doxycycline by films of Cellulose Nanofibers for diabetic foot ulcers

Introduction: About 15-25% of diabetic patients suffer from foot ulcers. Diabetic foot ulcers often require specialized treatment and multidisciplinary approach. the choice  of appropriate drug delivery system for antibiotics and pain refiner is an important remedy. Venlafaxine is an antidepressant drug of the serotonin-norepinephrine reuptake inhibitor (SNRI) class which is a safe and well-tolerated analgesic drug for neuropathic pain in diabetic’s foot ulcers.  On the other hand Doxycycline inhibits metalloproteinases activity through the chelation of calcium and zinc ions which inhibits extra cellular matrix destruction mediated by metalloproteinases. Films of cellulose nanofibers are biocompatible with excellent physical properties and can be appropriate choice for wound dressing in diabetic foot ulcers. In the present study, films of cellulose nanofibers were loaded by Venlafaxine and Doxycycline for simultaneous delivery to diabetic foot ulcers. Methods and Results: Doxycycline and Venlafaxine were dissolved in 10 cc water and then Films were putted on them and stirred for 24 hours to reach or until drugs are loaded drugs loading. Drug loading efficiency and release profiles were investigated by UV spectroscopy in 275 and 225 nm, respectively. The influence of the pH from 3 to 9 and the ratio of the drugs to carrier (1:1, 1:2 and 1:3) were assessed on the drug loading and release profiles. Efficiency of drugs loading was decreased by increase in  pH possibly due to the negative charge of cellulose and positive charge of Venlafaxine and Doxycycline in lower pH. On the other hand, the ratio of 1:2 of drugs to carrier was the most efficient ratio for drug loading that was 20% and 69% and also, 60% and 35% release for Venlafaxine and Doxycycline respectively. Conclusions: Films of cellulose nanofibers proved to be an appropriate carrier for co-delivery of Venlafaxine and Doxycycline as wound dressing. Further clinical studies are needed to evaluate their effectiveness in alleviating the inflammation and neuropathic pain of the diabetic foot ulcers

Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

The treatment of brain disorders is one of the greatest challenges in drug delivery because of a variety of main barriers in effective drug transport and maintaining therapeutic concentrations in the brain for a prolonged period. The objective of this study was delivery of valproic acid (VPA) to the brain by intranasal route. For this purpose, nanostructured lipid carriers (NLCs) were prepared by solvent diffusion method followed by ultrasonication and characterized for size, zeta potential, drug-loading percentage, and release. Six groups of rats each containing six animals received drug-loaded NLCs intraperitoneally (IP) or intranasally. Brain responses were then examined by using maximal electroshock (MES). The hind limb tonic extension:flexion inhibition ratio was measured at 15-, 30-, 60-, 90-, and 120-minute intervals. The drug concentration was also measured in plasma and brain at the most protective point using gas chromatography method. The particle size of NLCs was 154 ± 16 nm with drug-loading percentage of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo results showed that there was a significant difference between protective effects of NLCs of VPA and control group 15, 30, 60, and 90 minutes after treatment via intranasal route (P < 0.05). Similar protective effect was observed in rats treated with NLCs of VPA in intranasal route and positive control in IP route (P > 0.05). Results of drug determination in brain and plasma showed that brain:plasma concentration ratio was much higher after intranasal administration of NLCs of VPA than the positive control group (IP route). In conclusion, intranasal administration of NLCs of VPA provided a better protection against MES seizure

Stability and antimicrobial effect of amikacin-loaded solid lipid nanoparticles

Solid lipid nanoparticles (SLNs) of amikacin were designed in this study for pulmonary delivery to reduce the dose or its administration intervals leading to reduction of its toxicities especially in long term treatment. Nanoparticles of amikacin were prepared from cholesterol by solvent diffusion technique and homogenization. The size, zeta potential, loading efficiency, and release profile of the nanoparticles were studied. The conventional broth macrodilution tube method was used to determine the minimum inhibitory concentration (MIC) and minimum bacteriostatic concentration (MBC) of amikacin SLNs with respect to Pseudomonas aeruginosa in vitro. To guarantee the stability of desired SLNs, they were lyophilized using cryoprotectants. Results showed that considering the release profile of amikacin from the studied nanocarrier, MIC and MBC of amikacin could be about two times less in SLNs of amikacin compared to the free drug. Therefore, fewer doses of amikacin in SLNs can clear the infection with less adverse effects and more safety. Particle size enlargement after lyophilization of desired SLNs after two months storage was limited in comparison with non-lyophilized particles, 996 and 194 nm, respectively. Zeta potential of lyophilized particles was increased to +17 mV from +4 mV before lyophilization. Storage of particles in higher temperature caused accelerated drug release

Curcumin nanoparticles containing poloxamer or soluplus tailored by high pressure homogenization using antisolvent crystallization

Curcumin is a natural active constituent of Curcuma longa from Zingiberaceae family that shows many different pharmacological effects such as anticancer, antioxidant, anti-inflammatory, antimicrobial and antiviral effect. However, its bioavailability is profoundly limited by its poor water solubility. In this study antisolvent crystallization followed by freeze drying was used for the preparation of curcumin nanoparticles. The presence of different ratios of hydrophilic polymers (poloxamer 188 & soluplus) on physicochemical properties of curcumin nanoparticles was also investigated. In addition, the effect of high pressure homogenization (HPH) on solubility and dissolution properties of curcumin was investigated. All nanoparticle formulations were examined to determine their particle size distribution, saturation solubility, morphology (SEM), solid state (DSC, XRPD and FT-IR) and dissolution behavior. It was observed that curcumin crystallized in the presence of polymers exhibited better solubility and dissolution rate in comparison with original curcumin. The results showed that the concentration of the stabilizer and the method used to prepare nanoparticles can control the dissolution of curcumin. The crystallized nanoparticles showed polymorph 2 curcumin with lower crystallinity and higher dissolution rate. Curcumin nanoparticles containing 50% soluplus prepared via HPH method presented 16-fold higher solubility than its original form. In conclusion, samples crystalized and proceed with HPH technique showed smaller particle size, better redispersibility, higher solubility and dissolution rate in water compared with a sample prepared using a simple antisolvent crystallization process

Formulation of LDL Targeted Nanostructured Lipid Carriers Loaded with Paclitaxel: A Detailed Study of Preparation, Freeze Drying Condition, and In Vitro

In the present study, cholesterol nanostructured lipid carriers with various oleic acid content loaded with paclitaxel (PTX) were prepared by solvent emulsification-diffusion method using a Taguchi design. Size, zeta potential, entrapment efficiency, drug loading, and release percent of NLCs were measured. The results indicated that the most effective factors on the size were oleic acid content and surfactant percent. Zeta potential was more affected by the drug content. Drug to- lipid weight ratio was the most effective factor on entrapment efficiency and drug release from NLC. In the present work, the effect of lyophilization on the particle size and release properties of NLCs was also evaluated. The results revealed no differences between the characteristics of NLCs before and after freeze drying by using 25% w/w sorbitol as cryoprotectant. Cytotoxicity studies indicate that PTX associated with the NLC is also effective in HT-29 cell lines and enters the cancer cells selectively through the LDL receptor endocytic pathway. The IC50 values of free PTX solubilized in Cremophor EL and NLC-born PTX after 72 h exposure were  ng/mL and  ng/mL, respectively