Formulation design, preparation and physicochemical characterizations of solid lipid nanoparticles containing a hydrophobic drug: effects of process variables

This study aimed to prepare solid lipid nanoparticles (SLNs) of a hydrophobic drug, tretinoin, by emulsification-ultrasonication method. Solubility of tretinoin in the solid lipids was examined. Effects of process variables were investigated on particle size, polydispersity index (PI), zeta potential (ZP), drug encapsulation efficiency (EE), and drug loading (L) of the SLNs. Shape and surface morphology of the SLNs were investigated by cryogenic field emission scanning electron microscopy (cryo-FESEM). Complete encapsulation of drug in the nanoparticles was checked by cross-polarized light microscopy and differential scanning calorimetry (DSC). Crystallinity of the formulation was analyzed by DSC and powder X-ray diffraction (PXRD). In addition, drug release and stability studies were also performed. The results indicated that 10mg tretinoin was soluble in 0.45±0.07 g Precirol? ATO5 and 0.36±0.06 g Compritol? 888ATO, respectively. Process variables exhibited significant influence in producing SLNs. SLNs with <120 nm size, <0.2 PI, >I30I mV ZP, >75% EE, and ～0.8% L can be produced following the appropriate formulation conditions. Cryo-FESEM study showed spherical particles with smooth surface. Cross-polarized light microscopy study revealed that drug crystals in the external aqueous phase were absent when the SLNs were prepared at ≤0.05% drug concentration. DSC and PXRD studies indicated complete drug encapsulation within the nanoparticle matrix as amorphous form. The drug release study demonstrated sustained/prolonged drug release from the SLNs. Furthermore, tretinoin-loaded SLNs were stable for 3 months at 4°C. Hence, the developed SLNs can be used as drug carrier for sustained/prolonged drug release and/or to improve oral absorption/bioavailability.     

Factors affecting drug encapsulation and stability of lipid-polymer hybrid nanoparticles

Lipid-polymer hybrid nanoparticles are polymeric nanoparticles enveloped by lipid layers that combine the highly biocompatible nature of lipids with the structural integrity afforded by polymeric nanoparticles. Recognizing them as attractive drug delivery vehicles, antibiotics are encapsulated in the present work into hybrid nanoparticles intended for lung biofilm infection therapy. Modified emulsification-solvent-evaporation methods using lipid as surfactant are employed to prepare the hybrid nanoparticles. Biodegradable poly (lactic-co-glycolic acid) and phosphatidylcholine are used as the polymer and lipid models, respectively. Three fluoroquinolone antibiotics (i.e. levofloxacin, ciprofloxacin, and ofloxacin), which vary in their ionicity, lipophilicity, and aqueous solubility, are used. The hybrid nanoparticles are examined in terms of their drug encapsulation efficiency, drug loading, stability, and in vitro drug release profile. Compared to polymeric nanoparticles prepared using non-lipid surfactants, hybrid nanoparticles in general are larger and exhibit higher drug loading, except for the ciprofloxacin-encapsulated nanoparticles. Hybrid nanoparticles, however, are unstable in salt solutions, but the stability can be conferred by adding TPGS into the formulation. Drug-lipid ionic interactions and drug lipophilicity play important roles in the hybrid nanoparticle preparation. First, interactions between oppositely charged lipid and antibiotic (i.e. ciprofloxacin) during preparation cause failed nanoparticle formation. Charge reversal of the lipid facilitated by adding counterionic surfactants (e.g. stearylamine) must be performed before drug encapsulation can take place. Second, drug loading and the release profile are strongly influenced by drug lipophilicity, where more lipophilic drug (i.e. levofloxacin) exhibit a higher drug loading and a sustained release profile attributed to the interaction with the lipid coat.     

Influence of hydrophobe on the release behavior of vinyl acetate miniemulsion polymerization

Poly(vinyl acetate) (PVAc) nanoparticles containing antibiotic have been prepared by miniemulsion polymerization. To compare the effect of hydrophobe types, hexadecane and poly(vinyl acetate) were used as hydrophobe. The particle characteristics as the manufacturing condition were examined by particle size analyzer. As a result, the diameter of PVAc latexes was adjusted between 80 and 260 nm by homogenization conditions and amounts of surfactant. Also, the miniemulsion by using hexadecane showed the more long shelf stability and led to the more small particle size after polymerization, as compared with the case of using poly(vinyl acetate). This indicated that the use of poly(vinyl acetate) as a hydrophobe could not make the stable emulsion, but it could avoid volatile organic chemical problems in the final product. From the release profile of drug through UV spectra, the drug release was very slow and it could be seen that the release of drug encapsulated with PVAc was occurred with the polymer degradation.     

Formulation and pharmacokinetic evaluation of tetracycline-loaded solid lipid nanoparticles for subcutaneous injection in mice

The aim of this work was to prepare tetracycline-loaded solid lipid nanoparticles (Tet-SLN), and to evaluate the potential of these colloidal carriers for subcutaneous injection. Tet-SLN was prepared by microemulsion method and the preparation conditions were optimized by ternary phase diagram. At optimized process conditions, lyophilized Tet-SLN showed spherical particles with a mean diameter of 87.2±46.9 nm and a negative zeta potential of -6.69 mV, up to 1.7% tetracycline drug content was achieved after loading. In vitro release test showed a biphasic release profile for Tet-SLN and more than 80% of the drug was liberated from Tet-SLN in 48 h. After subcutaneous injection of Tet-SLN to mice, a considerable sustained release was observed; tetracycline in blood could be detected lasting 36 h, and lower concentrations of tetracycline in all tissues tested compared to the free tetracycline solution were observed. In conclusion, Tet-SLN can be prepared well by microemulsion method and subcutaneous injection of SLN provide a new perspective for drug sustained release.     

Luminescent, mesoporous, and bioactive europium-doped calcium silicate (MCS: Eu3+) as a drug carrier

Luminescent, mesoporous, and bioactive europium-doped calcium silicate (MCS: Eu) was successfully synthesized. The obtained MCS: Eu(3+) was performed as a drug delivery carrier to investigate the drug storage/release properties using ibuprofen (IBU) as the model drug. The structural, morphological, textural, and optical properties were well characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), N(2) adsorption/desorption, and photoluminescence (PL) spectra, respectively. The results reveal that the MCS: Eu exhibits the typical ordered characteristics of the mesostructure. This composite shows a sustained release profile with IBU as the model drug. The IBU-loaded samples still present red luminescence of Eu(3+) ((5)D(0)-(7)F(1,2)) under UV irradiation. The emission intensities of Eu(3+) in the drug carrier system vary with the amount of released IBU, making the drug release easily tracked and monitored. The system demonstrates a great potential for drug delivery and disease therapy.     

Synthesis, characterization and sustaining controlled release effect of mesoporous SBA-15/ramipril composite drug

A loading of ramipril in SBA-15 (Santa Barbara Amorphous) mesoporous material was studied. (SBA-15)-ramipril composite material was characterized by chemical analysis, infrared spectroscopy, powder X-ray diffraction, low temperature N₂ adsorption–desorption at 77 K characterization techniques. Ramipril drug release processes from SBA-15 host to simulated body fluid (SBF), simulated gastric juice (SGJ), simulated intestinal fluid (SIF) were monitored in a simulated way and actions of the sustained release of (SBA-15)-ramipril was studied. The results showed that the loading amount of ramipril drug in SBA-15 was 90.30 mg/g. The cumulative sustained release rate of ramipril composite drug in SBF achieved 99.7 % after 27 h. When the sustained release of composite drug in SGJ was 8 h, the maximum cumulative sustained release ratio achieved 54.9 %. When the sustained release of composite drug was 9 h in SIF, the maximum cumulative sustained release ratio achieved 34.9 %. The method described in this study is suitable for carrying ramipril drug on SBA-15, and a new carrier to load ramipril drug was found. Meanwhile, the efficacy of ramipril drug and time efficacy could be improved.     

Formulation development of a filter-sterilizable lipid emulsion for lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist

KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. The objective of the present study was to develop an injectable formulation of KW-3902, that was water-insoluble and less than 1 microg/ml, and so lipid emulsion was selected as a favorable formulation. Changing the mixing ratio of oil to lecithin, the particle size of the lipid emulsion was controlled, and by adjusting the mixing ratio of oil/lecithin=1:1, the weight ratio, a lipid emulsion with a mean particle size of 130 nm was prepared. This small particle size makes this emulsion filter-sterilizable, which is a favorable feature for heat labile products. The stability of the KW-3902 lipid emulsion was assessed from the viewpoint of the electrostatic repulsion, and by including the oleic acid a stable lipid emulsion was developed, which was stable for at least 12 months at 10 and 25 degrees C and for 3 months at 40 degrees C. The feature of this small particle size emulsion was also characterized by comparing it with a conventional emulsion (oil/lecithin=1:0.12, the weight ratio, particle size is 220 nm). The release of KW-3902 from the oil particles was measured and the apparent permeability of KW-3902 was calculated from the equation according to Fick's theory. The apparent permeability, P, of KW-3902 was not affected by the particle size of the emulsion (1.78x10(-11) cm/s for the small emulsion and 1.76x10(-11)cm/s for the conventional emulsion). The distribution mode of KW-3902 in the lipid emulsion was also discussed by considering the findings of the permeability and solubility of KW-3902.     

Ascorbic acid in cosmetic formulations: Stability,in vitro release,and permeation using a rapid,inexpensive, and simple method

Ascorbic acid (AA) is involved in important metabolic processes in the human body. However, its chemical instability requires the assessment of products containing AA. The aim of this study was to develop systems that improve AA stability and to evaluate its release profile, permeation, and skin retention in vitro. For this purpose, we prepared binary systems consisting of propylene glycol and water, microemulsions, liquid crystalline systems, and an emulsion. The AA content in these systems was evaluated over time by measuring the inhibition of 1,1-diphenyl-2-picrylhydrazyl (DPPH). Our results demonstrated that the binary systems and molecular aggregates were less stable and effective than the emulsion. Thus, in vitro AA release, skin permeation, and retention were evaluated using the emulsion. Our results indicate that AA exhibits low release and permeation levels and a high retention rate in the skin, characteristics desirable in cosmetic products.     

Incorporation methods for cholic acid chitosan-g-mPEG self-assembly micellar system containing camptothecin

A water-insoluble anticancer agent, camptothecin (CPT) was incorporated to a polymeric micelle carrier system preparing from cholic acid chitosan-grafted poly (ethylene glycol) methyl ether (CS-mPEG-CA). CS-mPEG-CA formed a core–shell micellar structure with a critical micelle concentration (CMC) of 7.08 μg/ml. Incorporation efficiency was investigated by varying physical incorporation method and initial drug loading. Among three incorporation methods (dialysis, emulsion and evaporation methods), an emulsion method showed the highest CPT incorporation efficiency. Increasing the initial CPT loading from 5 to 40%, the incorporation efficiency decreased. In all examined CPT-loaded CS-mPEG-CA micelles, 5% initial drug loading showed the highest drug incorporation efficiency. Release of CPT from the micelles was sustained when increasing the initial CPT loading. This indicates the importance of incorporation method and the initial drug loading to obtain the optimum particle size with high drug loading and sustained drug release. When compared to the unprotected CPT, CPT-loaded CS-mPEG-CA micelles were able to prevent the hydrolysis of the lactone group of the drug. This novel CS-mPEG-CA polymer presents considerable potential interest in the further development of CPT carrier.     

KETAMINE-IN OIL-IN-WATER MULTIPLE EMULSION FOR PROLONGED DRUG RELEASE

A preparation of Ketamine [2-(Chlorophenyl)-2-(methylamino) cyclohexanone, C₁₃H₁₆ClNO, anesthetic agent] in oil in water multiple emulsion for prolonged drug release was formulated and evaluated. Ketamine, the cyclohexylamine, is used as a short-acting anaesthetic in humans and in some animal species [1]. Ketamine is poorly bound to plasma proteins and has a half-life of approximately 4 hours following intravenous injection [2]. Ketamine leaves the blood very rapidly to be distributed into the tissues with a high lipid solubility [2]. The recommended dosage of intravenous Ketamine is 2.5-20mg/kg [3]. The LD50 injected intraperitoneally in mice and rats is 100 times the intravenous and 30 times the intramuscular dose used in humans.

The objective of this study was to test the concept that a multiple emulsion could be formulated which has high porosity and lower viscosity at 37°C consistent with its intended use for sustained drug release and to prolong the half-life of the anesthesia. The results showed that the Ketamine (100mg/ml in inner phase) released 8.2% at 10 minutes, 67.0% at 30 minutes, and 95.5% at 60 minutes from the Ketamine/O/W multiple emulsion in a well-controlled manner.     

Morphological and Thermal Properties of Vesicular Phospholipid Gels Studied by DSC,Rheometry and Electron Microscopy

Semisolid phospholipid preparations have been well known for several years and are still investigated as drug carrier systems, e.g. for potential cancer therapy. They may be applied parenterally as semisolid vesicular phospholipid gels suitable as implants for sustained drug release or as liposomal preparations after redisperging the stable storage form. Due to enhanced stability, mixtures of hydrated phospholipids and cholesterol are more suitable than natural unsaturated phospholipids. In order to describe characteristics of vesicular phospholipid gels, only a few techniques may be useful. Especially the structure of the semisolid preparation is not yet completely understood. We tried to get some more information about these systems by using a combination of freeze-fracture electron microscopy, differential scanning calorimetry and rheometry to elucidate, on the one hand, the inner structure or homogeneity and, on the other, the thermotropic phase transition of the three-dimensional lipid network and the temperature dependency of the fluidity/viscosity of the samples. Using freeze-fracture electron microscopy we found coexisting phospholipid domains of lamellar sheets and vesicular structures. With the help of differential scanning calorimetry the reasons for the different phase behaviour were elucidated. Rheometric measurements show increased intermediate viscosity at the thermotropic phase transition of the lipid bilayers, possibly induced by interacting membrane defects. This revised version was published online in August 2006 with corrections to the Cover Date.     

Formulation studies on a topical gel of tretinoin�Cdimethyl-beta-cyclodextrin complex

The aim of this work was to develop and characterize a 0.05% tretinoin hydrogel formulations in which tretinoin is free or complexed with dimethyl-beta-cyclodextrin in order to compare the main advantages of its complexation. Theoretically, the complexation will mainly allow to: overcome drug low solubility in water and low stability; enhance the drug release by promoting skin absorption and alleviate of drug inducing local irritation. The hydrogels prepared were both microbiological and physically stable during 30 days. However, the chemical stability was less encouraging. The complexed tretinoin gel had also a higher releasing profile than the free tretinoin gel. This study has demonstrated that it is possible to obtain a microbiological and physically stable gel formulation with good releasing profile.     

Ciprofloxacin Loaded Alginate/Chitosan and Solid Lipid Nanoparticles,Preparation, and Characterization

The aim of the present study was to develop controlled drug delivery systems based on nanotechnology. Two different nanocarriers were selected, chitosan-alginate nanoparticles as hydrophilic and solid lipid nanoparticles as lipophilic carriers. Nanoparticles were prepared and characterized by evaluating particle size, zeta potential, SEM pictures, DSC thermograms, percentage of drug loading efficiency, and drug release profile. The particle size of SLNs and Chi/Alg nanoparticles was 291 ± 5 and 520 ± 16. Drug loading efficiency of Chi/Alg and SLN particles were 68.98 ± 5.5% and 88 ± 4.5%. The drug release was sustained with chitosan-alginate system for about 45 hours whereas for SLNs >98% of the drug was released in 2 hours. Release profile did not change significantly after freeze drying of particles using cryoprotector. Results suggest that under in vitro condition chitosan/alginate systems can act as promising carriers for ciprofloxacin and may be used as an alternative system in sustained delivery of ciprofloxacin.     

Structural characterization of novel phospholipid lipid nanoparticles for controlled drug delivery

Drug-phospholipid lipid nanoparticles (DPLNs) are prepared by incorporating drug-phospholipid complexes (DPCs) with a liquid lipid. DPLNs demonstrated interesting properties including increased encapsulation capacity, improved stability and controlled drug release profile. A comprehensive characterization of DPLNs was presented and then a schematic model was suggested according to the characterization results. Transmission electron microscopy and scanning electron microscope measurements showed the morphology of DPLNs. X-ray diffraction exhibited a predominantly amorphous structure for DPCs and totally amorphous for DPLNs. Laser confocal scanning microscopy revealed the relative position of DPCs and liquid lipid, showing that DPLNs formed a homogeneous system. Fluorescence spectra and electron spin resonance further confirmed the chemical environment inside the DPLNs in a non-invasive way.     

Quick synthesis of lipid-polymer hybrid nanoparticles with low polydispersity using a single-step sonication method

Lipid-polymer hybrid nanoparticle, consisting of a hydrophobic polymeric core and a lipid monolayer shell, represents a new and promising drug delivery platform that has shown controllable particle size and surface functionality, high drug loading yield, sustained drug release profile, and excellent in vitro and in vivo stability. These lipid monolayer-coated polymeric nanoparticles are typically fabricated through a modified nanoprecipitation method, which involves sample heating, vortexing, and solvent evaporation. Herein we report a new and fast method to synthesize lipid-polymer hybrid nanoparticles with controllable and nearly uniform particle size. Using a bath sonication approach, we demonstrate that the whole hybrid nanoparticle synthesis process can be completed in about 5 min compared with a few hours for previous synthesis approaches. The size and polydispersity of the resulting nanoparticles can be readily controlled by tuning the relative concentrations of individual building components. Colloidal stability tests of the synthesized hybrid nanoparticles in PBS buffer and serum show no signs of aggregation over a period of 5 days. The present method improves the production rate of the hybrid nanoparticles by near 20-fold while not compromising the physicochemical properties of the particles. This work may facilitate the bench-to-bedside translation of lipid-polymer hybrid nanoparticles as a robust drug nanocarrier by allowing for fabricating a large amount of these nanoparticles at high production rate.     

Formulation and In Vitro Evaluation of Sustained Release Microspheres of Diltiazem Hydrochloride Prepared by Emulsification-Internal Gelation Method

The present work describes the formulation of alginate microspheres containing diltiazem hydrochloride by the emulsification-internal gelation method with the use of barium carbonate as a cross-linking agent. The effect of various factors (the concentration of alginate and barium chloride) on the drug loading efficiency and in vitro release were investigated. Fourier transform infrared microscopy (FTIR) and differential scanninig calorimetry (DSC) analysis confirmed the absence of any drug polymer interaction. X-ray diffraction (XRD) pattern showed that there is a decrease crystallinity of the drug. The in vitro drug release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from microcapsules. The stability studies of drug-loaded microcapsules showed that the drug was stable at different storage conditions.     

A green chemistry approach towards synthesizing hydrogel for sustained ocular delivery of brinzolamide: In vitro and ex vivo evaluation

Brinzolamide is a carbonic anhydrase inhibitor used in the eye drop form for the treatment of glaucoma. It requires frequent dosing to attain therapeutic concentration. Therefore, this study aimed to prepare sustained ocular drug delivery of brinzolamide. The objective of the study was to prepare a hydrogel loaded with a nanostructured lipid carrier (NLC) of brinzolamide. The hydrogel was prepared by a green synthesis approach using genipin as a natural crosslinking agent and polymers such as carboxymethyl chitosan and poloxamer 407. The melt emulsification-ultra sonication method was used to prepare a nanostructured lipid carrier of brinzolamide, which was loaded into a hydrogel using a swelling and loading method. The NLC formulation has shown small particle sizes of 111.20 ?± ?2.15 ?nm, polydispersity index of 0.280 ?± ?0.005 and % entrapment efficiency of 82.16% ?± ?0.14%. The NLC-loaded hydrogels of brinzolamide formulations were studied for swelling properties and showed temperature and pH-responsive swelling behavior. The optimized hydrogel formulation has been studied for in vitro drug release and showed drug release for a longer duration (24 ?h) than marketed eye drops (8 ?h). In an ex vivo study, hydrogel formulations showed transcorneal permeability 4.54 times greater than marketed eye drops. The hydrogel formulation of brinzolamide produced by the green synthesis method has shown sustained-release properties with no sign of ocular irritation. Hence, the hydrogel of brinzolamide-loaded NLC would be the potential drug delivery approach in the near future for sustained ocular drug delivery in glaucoma management.     

Loading of 5-aminosalicylic in solid lipid microparticles (SLM)

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine, is the most commonly used drug for treating patients with inflammatory bowel disease (IBD). Its bioavailability is low, i.e. 20–30% upon oral administration and 10–35% by rectal administration. As the extent of 5-ASA absorption is very much dependent on the time-length, the drug is retained in the colon, a way to increase drug retention is the use of orally administered sustained released formulations. Solid lipid microparticles (SLM) are a viable option for site-specific targeted delivery in compressed tablets produced by direct compaction. In this study, we describe the development and characterization of 5-ASA-loaded SLM for sustained release. The solubility of 5-ASA in different types of solid lipids (e.g. cetyl palmitate, cetyl alcohol, and cetearyl alcohol) was evaluated to select the best lipid as the inert matrix-forming agent to control the release of the drug. SLM dispersions were prepared using the hot emulsification method employing the selected solid lipid, lecithin (Lipoid^®) as surfactant, dimethyl sulphoxide, and acetone stabilized with Arlacel^®. The characterization was performed by differential scanning calorimetry, thermogravimetric analysis, wide-angle x-ray diffraction, Fourier transform infrared spectroscopy measurements, optical microscopy, and scanning electron microscopy. Results show that the best lipid for dissolving the 5-ASA was cetyl palmitate and that the melting process did not affect the chemical stability of the materials. The thermal analysis suggests that 5-ASA was successfully encapsulated with the microparticles, of spherical shape and uniform size distribution.

     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

Physicochemical properties of structured phosphatidylcholine in drug carrier lipid emulsions for drug delivery systems

Drug carrier emulsions were prepared with structured phosphatidylcholine (PC-LM) which has both a long hydrocarbon chain and a medium hydrocarbon chain, and the characteristics of PC-LM as an emulsifier were investigated by measuring the creaming ratio, the surface tension of the emulsion system, and the mean particle size and zeta potential of the oil droplets in emulsions. The emulsion prepared with PC-LM as an emulsifier kept the condition and the ratio of separation was lower than those with purified egg yolk lecithin (PEL). The mean particle size of the emulsion prepared with PC-LM was smaller than that with PEL when using only sonication, approximately 250 nm. When using a high-pressure homogenizer after sonication, the mean emulsion size with PC-LM was also smaller than with PEL, approximately 150 nm. The surface tension of the various emulsions and the zeta potential of the emulsion droplets were measured to investigate the stability of the systems. In emulsions with PC-LM or PEL, the surface tension as an index of stability increased as the pressure of the homogenizer increased. Moreover, the zeta potential of the emulsion droplets prepared with PC-LM also increased with an increase in pressure of the homogenizer. As a result, it was found that the drug carrier emulsion prepared with PC-LM had significant advantages in terms of stability and mean diameter. We considered it could be used for the preparations of nanoparticle dispersion systems in drug delivery systems.