Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate

Objectives The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs). Methods Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5: 1, 10: 1 and 12.5: 1 lipid: drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex‐vivo drug permeation tests using porcine epidermis. Key findings SLMs had particle sizes of 18–45 μm, while SLNs showed a mean diameter of 130–270 nm. The encapsulation efficiency was 80–100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid. Conclusions The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.     

Solid lipid microparticles: formulation, preparation, characterisation, drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The in vitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary in vivo aspects (in vivo drug release studies, biocompatibility studies and in vivo fate) are also considered.     

Solid lipid microparticles: formulation,preparation, characterisation,drug release and applications

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The invitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary invivo aspects (invivo drug release studies, b-iocompatibility studies and invivo fate) are also considered.     

Development of a spray congealing process for the preparation of insulin-loaded lipid microparticles and characterization thereof.

A spray congealing process for the preparation of protein-loaded microparticles was developed. The influence of the process parameters atomization pressure and spraying temperature on particle size and process yield was investigated by experimental design. The employed spray congealing technique enabled the production of microparticles with yields ranging from 79% to 95% and median particle sizes (d(0.5)) from 182.2 to 315 microm. Insulin lipid microparticles could be prepared without any loss of insulin during the preparation process and the protein stability was not affected by the spray congealing process as investigated by HPLC-MS analysis. The stability of insulin encapsulated in lipid microparticles under release conditions over 28 days was assessed by investigating the residual insulin content. Starting after 3 days of release, a continuous increase of desamidoinsulin in the remaining particles of up to 7.5% after 28 days was observed. An additional degradation product was detected by HPLC and HPLC-MS analysis and identified as a covalent insulin dimer by MALDI-ToF. The microparticles did not show a burst release and testing the insulin lipid microparticles in a fibrin gel chondrocyte culture revealed that the released insulin was bioactive and had a significant effect on chondrocyte extracellular matrix production.     

The effect of homogenization method on the properties of carbamazepine microparticles prepared by spray congealing

Abstract

The aim of this study was to investigate the influence of ultrasound and high-shear mixing on the properties of microparticles obtained by spray congealing. Dispersions containing 10% carbamazepine and 90% carrier Gelucire® 50/13 (w/w) were prepared using magnetic stirring, high-shear mixing, or ultrasound. Each preparation was made using hot-melt mixing spray congealing to obtain the microparticles. All microparticles presented a spherical shape with high encapsulation efficiency (>99%). High-shear mixing and ultrasound promoted a decrease in the size of microparticles (D₉₀) to 62.8?±?4.1?μm and 64.9?±?3.3?μm, respectively, while magnetic stirring produced microparticles with a size of 84.1?±?1.4?µm. The use of ultrasound led to microparticles with increased moisture content as identified through sorption isotherm studies. In addition, rheograms showed distinct rheological behaviour among different dispersion preparations. Therefore, the technique used to prepare dispersions for spray congealing can affect specific characteristics of the microparticles and should be controlled during the preparation.     

New spray congealing atomizer for the microencapsulation of highly concentrated solid and liquid substances

A new pneumatic atomizer for spray congealing, called wide pneumatic nozzle (WPN), was developed. To evaluate its performance, microparticles containing highly concentrated either solid drug (Propafenone hydrochloride, PRF) or liquid nutraceutical (Vitamin E, VE) have been prepared and characterized. The results showed that the spray congealing nozzle enabled the production of spherical and not aggregated microparticles with high yields (95% w/w) and relatively narrow size distributions; moreover, increasing the viscosity of the suspension from 50 to 500 mPa s, the particle size increased. The loading of the drug was high for microspheres (50% for PRF and 30% for VE) and the encapsulation efficiency was good for all formulations. The drug release was easily modified according to the nature of the used excipients, as both lipophilic (carnauba wax, cetearyl and stearyl alcohols) and hydrophilic (PEG 4000) carriers were employed. Moreover the results evidenced that it was possible to encapsulate actives (VE) that are in a liquid form and to enhance their availability. In conclusion the developed spray congealing nozzle was able to nebulize very viscous systems that are usually not processed by conventional apparatus and to produce microspheres with high and uniform drug content.     

Comparison of spray congealing and melt emulsification methods for the incorporation of the water-soluble salbutamol sulphate in lipid microparticles

Context: Salbutamol sulphate is widely used as bronchodilator for the treatment of asthma. Its use is limited by the relatively short duration of action and hence sustained delivery of salbutamol sulphate offers potential benefits to patients.

Objective: This study explores the preparation of lipid microparticles (LMs) as biocompatible carrier for the prolonged release of salbutamol sulphate.

Materials and methods: The LMs were produced using different lipidic materials and surfactants, by classical melt emulsification-based methods (oil-in-water and water-in-oil-in-water emulsions) and the spray congealing technique.

Results: For the LMs obtained by melt emulsification a lack of release modulation was observed. On the other hand, the sustained release of salbutamol sulphate was achieved with glyceryl behenate microparticles prepared by spray congealing. These LMs were characterized by scanning electron microscopy, X-ray diffractometry and differential scanning calorimetry. The drug loading was 4.72% (w/w). The particle size distribution measured by laser diffraction and electrical zone sensing was represented by a volume median diameter (Dv₅₀) of 51.7–71.4 µm. Increasing the atomization air pressure from 4 to 8 bar produced a decrease of the Dv₅₀ to 12.7–17.5 µm.

Conclusions: Incorporation of the hydrophilic salbutamol sulphate into LMs with sustained release characteristics was achieved by spray congealing.     

Evaluation of spray congealing as technique for the preparation of highly loaded solid lipid microparticles containing the sunscreen agent,avobenzone

Solid lipid microparticles (SLMs) loaded with high amounts of the sunscreen agent, butyl methoxydibenzoylmethane (avobenzone) were prepared in order to reduce its photoinstability. The microparticles were produced, using carnauba wax as lipidic material and phosphatidylcholine as the surfactant, by the classical melt dispersion method or the spray congealing technique with pneumatic atomizer. The sunscreen agent loading was 40.1–48.5% (w/w), with no significant differences between the production methods. However, release studies indicated that spray congealing enabled a more efficient modulation of avobenzone release from the SLMs (26% of encapsulated avobenzone released after 2 h as compared to 60% for melt dispersion). The photoprotective efficacy of the SLMs was evaluated after their introduction in a model cream. A statistically significant decrease of the light-induced degradation of avobenzone was obtained by the SLMs prepared by the melt dispersion procedure (the extent of degradation was 38.6 ± 3.6% for nonencapsulated avobenzone and 32.1 ± 4.3% for the microparticle-entrapped sunscreen). On the other hand, the SLMs produced by spray congealing achieved a more marked reduction in avobenzone photodecomposition to 15.4 ± 4.1%. Therefore, the spray congealing technique was superior to the classical melt dispersion method for rapid and solvent free production of SLMs with a high avobenzone loading capacity. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2759–2769, 2009     

Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation.

Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles; (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Fick's second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were used to predict the resulting drug release kinetics as a function of the gamma-irradiation dose. Importantly, the theoretical predictions were confirmed by experimental results.     

Solid lipid microparticles for the stability enhancement of the polar drug N6-cyclopentyladenosine

The objective of this study was to prepare solid lipid microparticles (SLMs) loaded with the polar adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA). The microparticles were produced by the conventional hot emulsion technique, using different lipidic carriers (tristearin, glyceryl behenate and stearic acid) and hydrogenated phosphatidylcholine as the surfactant. The controlled release of CPA was achieved only with stearic acid microparticles. This phenomenon has been attributed to direct acid-base interactions between the basic nitrogen atoms of CPA and stearic acid. These SLMs were characterized by release studies, scanning electron microscopy and powder X-ray diffraction analyses. The obtained particles showed proper features in terms of morphology and size distribution (3.2-10.3microm), with a drug loading of 0.15+/-0.04%. The influence of the SLMs carrier system on CPA stability was investigated in vitro using human whole blood. The degradation kinetic of microparticle-entrapped CPA was significantly lower from that measured for the free CPA. The overall results indicate that it was possible to achieve the encapsulation and controlled release of a polar drug, such as CPA, within a lipid matrix without resorting to the complex methods generally used for the preparation of these systems.     

Microneedle-assisted microparticle delivery by gene guns: experiments and modeling on the effects of particle characteristics

Abstract

Microneedles (MNs) have been shown to enhance the penetration depths of microparticles delivered by gene gun. This study aims to investigate the penetration of model microparticle materials, namely, tungsten (<1?μm diameter) and stainless steel (18 and 30?μm diameters) into a skin mimicking agarose gel to determine the effects of particle characteristics (mainly particle size). A number of experiments have been processed to analyze the passage percentage and the penetration depth of these microparticles in relation to the operating pressures and MN lengths. A comparison between the stainless steel and tungsten microparticles has been discussed, e.g. passage percentage, penetration depth. The passage percentage of tungsten microparticles is found to be less than the stainless steel. It is worth mentioning that the tungsten microparticles present unfavourable results which show that they cannot penetrate into the skin mimicking agarose gel without the help of MN due to insufficient momentum due to the smaller particle size. This condition does not occur for stainless steel microparticles. In order to further understand the penetration of the microparticles, a mathematical model has been built based on the experimental set up. The penetration depth of the microparticles is analyzed in relation to the size, operating pressure and MN length for conditions that cannot be obtained in the experiments. In addition, the penetration depth difference between stainless steel and tungsten microparticles is studied using the developed model to further understand the effect of an increased particle density and size on the penetration depth.     

Diffusion loading and drug delivery characteristics of alginate gel microparticles produced by a novel impinging aerosols method

Microencapsulation of a hydrophilic active (gentamicin sulphate (GS)) and a hydrophobic non-steroidal anti-inflammatory drug (ibuprofen) in alginate gel microparticles was accomplished by molecular diffusion of the drug species into microparticles produced by impinging aerosols of alginate solution and CaCl₂ cross-linking solution. A mean particle size in the range of 30–50 µm was measured using laser light scattering and high drug loadings of around 35 and 29% weight/dry microparticle weight were obtained for GS and ibuprofen respectively. GS release was similar in simulated intestinal fluid (phosphate buffer saline (PBS), pH 7.4, 37°C) and simulated gastric fluid (SGF) (HCl, pH 1.2, 37°C) but was accelerated in PBS following incubation of microparticles in HCl. Ibuprofen release was restricted in SGF but occurred freely on transfer of microparticles into PBS with almost 100% efficiency. GS released in PBS over 7?h, following incubation of microparticles in HCl for 2?h was found to retain at least 80% activity against Staphylococcus epidermidis while Ibuprofen retained around 50% activity against Candida albicans. The impinging aerosols technique shows potential for producing alginate gel microparticles of utility for protection and controlled delivery of a range of therapeutic molecules.     

Characteristic and controlled release of anticancer drug loaded poly (D,L-lactide) microparticles prepared by spray drying technique

Anticancer drug release from polylactic acid microspheres prepared by the spray-drying process was studied. Several process parameters and properties of the polymer solution have been investigated. Normal size distributions with diameters ranging from 5-10 #119 m were obtained by the spray drying technique. The yield of microspheres recovered depended on polymer solution and process conditions employed. Results show that the yield of microspheres could reach 50%, and the experimental drug loading approached the theoretical drug loading. Scanning electron microscopy indicated that microspheres were composed of a dense thin skin layer and porous core. The magnitude of this effect depended on the inlet temperature, feed polymer concentration and airflow rate. Increasing inlet temperature and polymer concentration resulted in an intact particle shape and a slower drug dissolution rate. The in-vitro release of anticancer drug from microspheres was sustained over 7 days. The drug release behaviour depended on inlet temperature, air flow rate, PLA concentration and drug loading. The anticancer drug release rate from polylactic acid microspheres prepared by the spray-drying method was depressed, and the long-acting release could be achieved by appropriate operating parameters.     

Studies on the drug release properties of nano-encapsulated indomethacin microparticles

Indomethacin micro-crystals sized approximately 2 microm have been encapsulated with polyelectrolyte multi-layers for the purpose of controlled release. Charged linear poly (dimethyldiallyl ammonium chloride) (PDDA) and poly (styrene sulphonate) (PSS) were alternatively deposited on approximately 2 microm drug micro-crystals. The release of indomethacin from coated micro-crystals was measured in aqueous solutions of pH 1.4 and 6.8. The polyelectrolyte multi-layer capsule thickness was proved to control. The results provided a method of achieving prolonged drug release through self-assembly of polymeric shells on drug microcrystals.     

Effects of the type of release medium on drug release from PLGA-based microparticles: experiment and theory

The major objectives of the present study were: (i) to prepare 5-fluorouracil (5-FU)-loaded, poly(lactic-co-glycolic acid) (PLGA)-based microparticles, which can be used for the treatment of brain tumors, (ii) to study the effects of the type of release medium on the resulting drug release kinetics, and (iii) to get further insight into the underlying drug release mechanisms. Spherical microparticles were prepared by a solvent extraction method and characterized using different techniques, including size exclusion chromatography (SEC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and particle size analysis before and upon exposure to various release media. Interestingly, very different drug release patterns (including mono-, bi- and tri-phasic ones) were observed, depending on the pH, osmolarity and temperature of the release medium. An adequate mathematical theory was used to quantitatively describe the experimentally measured 5-FU release patterns. The model considers the limited solubility of the drug, polymer degradation as well as drug diffusion and allowed to determine system and release medium specific parameters, such as the diffusion coefficient of the drug. In particular, the pH and temperature of the release medium were found to be of major importance for the resulting release patterns. Based on the obtained knowledge the selection of an appropriate release medium for in vitro tests simulating in vivo conditions can be facilitated, and "stress tests" can be developed allowing to get rapid feedback on the release characteristics of a specific batch.     

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.     

Characteristic and controlled release of anticancer drug loaded poly (D,L-lactide) microparticles prepared by spray drying technique.

Anticancer drug release from polylactic acid microspheres prepared by the spray-drying process was studied. Several process parameters and properties of the polymer solution have been investigated. Normal size distributions with diameters ranging from 5-10 microm were obtained by the spray drying technique. The yield of microspheres recovered depended on polymer solution and process conditions employed. Results show that the yield of microspheres could reach 50%, and the experimental drug loading approached the theoretical drug loading. Scanning electron microscopy indicated that microspheres were composed of a dense thin skin layer and porous core. The magnitude of this effect depended on the inlet temperature, feed polymer concentration and air flow rate. Increasing inlet temperature and polymer concentration resulted in an intact particle shape and a slower drug dissolution rate. The in-vitro release of anticancer drug from microspheres was sustained over 7 days. The drug release behaviour depended on inlet temperature, air flow rate, PLA concentration and drug loading. The anticancer drug release rate from polylactic acid microspheres prepared by the spray-drying method was depressed, and the long-acting release could be achieved by appropriate operating parameters.     

Wet granulation fine particle ethylcellulose tablets: Effect of production variables and mathematical modeling of drug release

In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of various formulation and process variables, such as FPEC content, hardness of the tablet, and solubility of the drug, on the release of drug from these tablets was examined. Tablets were prepared by wet granulation of drug and FPEC in an appropriate mass ratio. Theophylline, caffeine, and dyphylline were selected as nonionizable model drugs with solubilities from 8.3 to 330 mg/mL at 25°C. Ibuprofen, phenylpropanolamine hydrochloride, and pseudoephedrine hydrochloride were selected as ionizable drugs with solubilities from 0.1 to 2000 mg/mL at 25°C. Drug release studies were conducted in 37°C water with UV detection. As the FPEC content and the hardness of the tablets increased, the release rate of the drug decreased. The drug release rate increased with an increase in the solubility of the drug. Model equations, intended to elucidate the drug release mechanism, were fitted to the release data. Parameters were generated and data presented by SAS software. The Akaike Information Criterion was also considered to ascertain the best-fit equation. Fickian diffusion and polymer relaxation were the release mechanisms for nonionizable and ionizable drugs.