Preparation and characterization of biodegradable urea-loaded microparticles as an approach for transdermal delivery

This work describes the formulation and characterization of urea-loaded microspheres prepared using various polymers such as ethyl cellulose (EC), cellulose acetate phthalate (CAP) and poly (D,L-lactic-co-glycolic acid) (PLGA), along with the utilization of a solvent evaporation technique. The effect of various formulation parameters (i.e. polymer type and concentration, vehicle type, polymer solution/vehicle volume ratio, drug/polymer ratio, homogenizer and stirrer speed, sonication time and speed, type of washing solution, drying and separation method) on the characteristics of microspheres was also evaluated. Results obtained indicated that, in the presence of urea, highest rate of EC microsphere production could be obtained at a drug/polymer ratio of 1:2 and a polymer solution/vehicle volume ratio of 1:50. In some cases, crystallization of urea was observed during the encapsulation process using cellulose derivative polymers. CAP microparticles showed a rough and tortuous surface while EC microparticles had a wider range of particle size. However, with the PLGA polymer, much better desired microparticles with a smaller size range of 1-3 microm were obtained. In general, PLGA microspheres were spherical in shape and possessed smooth surfaces with less pores in comparison with those obtained by the other polymers. The yield of particle production and the extent of urea encapsulation in PLGA particles were measured to be 68.87% +/- 5.3 and 40.5% +/- 3.4, respectively. The release study from PLGA microspheres revealed that up to 70% of the drug was released within a few days, through a four-stage release pattern.     

Preparation and characterization of biodegradable urea-loaded microparticles as an approach for transdermal delivery

This work describes the formulation and characterization of urea-loaded microspheres prepared using various polymers such as ethyl cellulose (EC), cellulose acetate phthalate (CAP) and poly (D,L-lactic-co-glycolic acid) (PLGA), along with the utilization of a solvent evaporation technique. The effect of various formulation parameters (i.e. polymer type and concentration, vehicle type, polymer solution/vehicle volume ratio, drug/polymer ratio, homogenizer and stirrer speed, sonication time and speed, type of washing solution, drying and separation method) on the characteristics of microspheres was also evaluated. Results obtained indicated that, in the presence of urea, highest rate of EC microsphere production could be obtained at a drug/polymer ratio of 1:2 and a polymer solution/vehicle volume ratio of 1:50. In some cases, crystallization of urea was observed during the encapsulation process using cellulose derivative polymers. CAP microparticles showed a rough and tortuous surface while EC microparticles had a wider range of particle size. However, with the PLGA polymer, much better desired microparticles with a smaller size range of 1–3?µm were obtained. In general, PLGA microspheres were spherical in shape and possessed smooth surfaces with less pores in comparison with those obtained by the other polymers. The yield of particle production and the extent of urea encapsulation in PLGA particles were measured to be 68.87%?±?5.3 and 40.5%?±?3.4, respectively. The release study from PLGA microspheres revealed that up to 70% of the drug was released within a few days, through a four-stage release pattern.     

Development and characterization of skin permeation retardants and enhancers: a comparative study of levothyroxine-loaded PNIPAM, PLA, PLGA and EC microparticles

Polymeric microparticles suitable for topical and transdermal delivery systems were studied using poly D,L lactide (PLA), poly D,L lactide co glycoside (PLGA), poly (N-isopropylacrylamide) (PNIPAM) and ethyl cellulose (EC). Drug encapsulation efficacy, microparticle stability and skin permeation studies of levothyroxine loaded microparticles were carried out using excised human skin, and the skin permeation pattern was observed using confocal laser scanning microscopy. It was found that ethyl cellulose microparticles had the highest drug encapsulation and minimal drug leakage during the 14 week storage period. The PNIPAM microparticles had the lowest drug encapsulation efficiency and a fast degradation rate. The PLGA microparticles exhibited a temperature dependent drug leakage. Permeation studies using a flow-through diffusion cell indicated that the polymer transition temperature (T(g)) may influence the skin permeation rate of levothyroxine. Polyesters (PLA and PLGA) and PNIPAM acted as a skin penetration retardant and caused skin accumulation of the drug. These microparticles have potential use in skin formulations containing sunscreens and other active ingredients that are meant to be concentrated on the skin surface. However, skin permeation was observed from EC microparticles, therefore such polymers may be used as carriers in transdermal formulations to help achieve therapeutic concentrations of the drug in the plasma.     

Preparation of ethyl cellulose/methyl cellulose blends by supercritical antisolvent precipitation

The supercritical antisolvent (SAS) technique was used to prepare ethyl cellulose/methyl cellulose blends, two biocompatible polymers commonly used as drug carriers in controlled delivery systems. Ethyl cellulose is widely used as a drug carrier. The drug release of the delivery devices can be controlled to some extent by addition of a water-soluble or water swellable polymer, such as methyl cellulose. This leads to the solubility enhancement of poorly water-soluble molecules. SAS experiments were carried out at different operational conditions and microspheres with mean diameters ranging from 5 to 30 microm were obtained. The effect of CO(2) and liquid flow, temperature and pressure on particle size and particle size distribution was evaluated. The microspheres were precipitated from a mixture of dichloromethane (DCM) and dimethylsulfoxide (DMSO) (4:1 ratio). The best process conditions for this mixture were according to our study 40 degrees C and 80 bar.     

In vitro modified release of acyclovir from ethyl cellulose microspheres

The aim of this study was to demonstrate a sustained-release microparticulate dosage form for acyclovir via an in vitro study. Ethyl cellulose was selected as a model encapsulation material. All of the microspheres were prepared by an oil-in-water solvent evaporation technique. A 2(3) full factorial experiment was applied to study the effects of the viscosity of polymer, polymer/drug ratio, and polymer concentration on the drug encapsulation efficiency and the dissolution characteristics. The encapsulation efficiency of acyclovir in microspheres was in the range of 20.0-56.6%. Increase in the viscosity of ethyl cellulose and the ratio of CH2Cl2/ethyl cellulose increased drug encapsulation efficiency. The drug continuously released from microspheres for at least 12 h, and the release rate depended on the pH of the release medium. The sustained release characteristic was more prominent in the simulated intestine fluid than in the simulated gastric fluid. A faster release of drug was observed when a high viscosity polymer was used. The decomposition of acyclovir significantly decreased when encapsulated by ethyl cellulose, especially when stored at 37 and 50 degrees C.     

Modification of the initial release of a highly water-soluble drug from ethyl cellulose microspheres.

The aim of this study was to develop a microspherical dosage form for a highly water-soluble drug, fenoterol HBr, by using the water insoluble, non-biodegradable polymer, ethyl cellulose. Fenoterol HBr was used as a model drug, based on its pharmacokinetic properties, i.e. the short half-life, incomplete absorption from the gastrointestinal tract due to the first pass effect. Three factors, the initial amount of drug, the volume of non-solvent (petroleum benzin) and the stirring speed of homogenizer, were varied during microsphere preparation. The release of fenoterol HBr from these microparticulate delivery systems was compared, and a possible release mechanism was proposed. The encapsulation efficiency of the drug, the morphology and the particle size of the microspheres were also investigated. The oil-in-oil solvent evaporation method efficiently encapsulated fenoterol HBr in these ethyl cellulose microspheres. A significant increase in the encapsulation efficiency of fenoterol was observed when the drug/polymer ratio was decreased from 15% to 5% (p < 0.05). The particle size of microparticles was in the range of 10-250 microm, and most microspheres had a particle size smaller than 100 microm. Only the volume of petroleum benzin showed a significant effect on the particle size of prepared microspheres (p < 0.05). Both the initial drug loading and the addition of nonsolvent significantly affected the initial release of fenoterol from the ethyl cellulose microspheres. The diffusion-controlled release followed by a constant release was exhibited in these microspheres.     

In vitro modified release of acyclovir from ethyl cellulose microspheres

The aim of this study was to demonstrate a sustained-release microparticulate dosage form for acyclovir via an in vitro study. Ethyl cellulose was selected as a model encapsulation material. All of the microspheres were prepared by an oil-in-water solvent evaporation technique. A 2³ full factorial experiment was applied to study the effects of the viscosity of polymer, polymer/drug ratio, and polymer concentration on the drug encapsulation efficiency and the dissolution characteristics. The encapsulation efficiency of acyclovir in microspheres was in the range of 20.0-56.6%. Increase in the viscosity of ethyl cellulose and the ratio of CH₂Cl₂/ethyl cellulose increased drug encapsulation efficiency. The drug continuously released from microspheres for at least 12 h, and the release rate depended on the pH of the release medium. The sustained release characteristic was more prominent in the simulated intestine fluid than in the simulated gastric fluid. A faster release of drug was observed when a high viscosity polymer was used. The decomposition of acyclovir significantly decreased when encapsulated by ethyl cellulose, especially when stored at 37 and 50 °C.     

Reduction in burst release after coating poly(D,L-lactide-co-glycolide) (PLGA) microparticles with a drug-free PLGA layer

The high initial burst release of a highly water-soluble drug from poly (D,L-lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) solvent extraction/evaporation method was reduced by coating with an additional polymeric PLGA layer. Coating with high encapsulation efficiency was performed by dispersing the core microparticles in peanut oil and subsequently in an organic polymer solution, followed by emulsification in the aqueous solution. Hardening of an additional polymeric layer occurred by oil/solvent extraction. Peanut oil was used to cover the surface of core microparticles and, therefore, reduced or prevented the rapid erosion of core microparticles surface. A low initial burst was obtained, accompanied by high encapsulation efficiency and continuous sustained release over several weeks. Reduction in burst release after coating was independent of the amount of oil. Either freshly prepared (wet) or dried (dry) core microparticles were used. A significant initial burst was reduced when ethyl acetate was used as a solvent instead of methylene chloride for polymer coating. Multiparticle encapsulation within the polymeric layer increased as the size of the core microparticles decreased (< 50 µm), resulting in lowest the initial burst. The initial burst could be controlled well by the coating level, which could be varied by varying the amount of polymer solution, used for coating.     

Preparation of naproxen–ethyl cellulose microparticles by spray-drying technique and their application to textile materials

Abstract

The objective of this study is to develop a new textile-based drug delivery system containing naproxen (NAP) microparticles and to evaluate the potential of the system as the carrier of NAP for topical delivery. Microparticles were prepared by spray-drying using an aqueous ethyl cellulose dispersion. The drug content and entrapment efficiency, particle size and distribution, particle morphology and in vitro drug release characteristics of microparticles were optimized for the application of microparticles onto the textile fabrics. Microparticles had spherical shape in the range of 10–15?μm and a narrow particle size distribution. NAP encapsulated in microparticles was in the amorphous or partially crystalline nature. Microparticles were tightly fixed onto the textile fabrics. In vitro drug release exhibited biphasic release profile with an initial burst followed by a very slow release. Skin permeation profiles were observed to follow near zero-order release kinetics.     

A burst drug release caused by imperfection of polymeric film-coated microparticles prepared by a fluidized bed coater

The aim of this study was to investigate the drug release from microparticles coated with various polymeric films. Ibuprofen-loaded microparticles with diameter of 250 and 300 microm were prepared by a fluidized bed granulator. Five polymers were used as coating materials, i.e., ethylene vinyl acetate, ethyl cellulose, ethyl cellulose aqueous dispersion, polyethacrylate or Eudragit NE 30D, and carnauba wax. The coating was performed with a fluidized bed coater. Afterwards the coated microparticles were characterized in terms of particle size, morphology, and drug content. The drug dissolution was also investigated in pH 7.4 phosphate buffer. In our attempts for production of extended release ibuprofen microparticles coated with polymeric films, it was shown that the coating process had a significant effect on drug release. The undesired burst release of ibuprofen was observed in all film-coated microparticulate formulations, resulting from the imperfection of coating films.     

Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres

This study is an attempt to prepare microspheres loaded with two antihypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.     

Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres

This study is an attempt to prepare microspheres loaded with two anti-hypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.     

Microencapsulation of mildronate in biodegradable and non-biodegradable polymers

Abstract

The extremely high hygroscopicity (solubility in water ≥2?g/ml) of the pharmaceutical preparation mildronate defines specific requirements to both packaging material and storage conditions. To overcome the above mentioned inconveniences, microencapsulated form of mildronate was developed using polystyrene (PS) and poly (lactic acid) (PLA) as watertight coating materials. Drug/polymer interaction as well as influence of the microencapsulation process variables on microparticle properties was studied in detail. Water-in-oil-in-water double emulsion technique was adapted and applied for the preparation of PS/mildronate microparticles with total drug load up to 77 %wt and PLA/mildronate microparticles with total drug load up to 80 %wt. The repeatability of the microencapsulation process was ±4% and the encapsulation efficiency of the active ingredient reached 60 %wt. The drug release kinetics from the obtained microparticles was evaluated and it was found that drug release in vivo could be successfully sustained if polystyrene matrix has been used.     

Drug distribution in enteric microparticles

The aim of this study was to assess the distribution of three fluorescent drug or drug-like molecules in enteric microparticles. Microparticles were prepared using the pH-responsive methylmethacrylate polymer Eudragit L by an emulsion solvent evaporation process. In the process drug and polymer are dissolved in ethanol, and dispersed in a liquid paraffin external phase using sorbitan sesquioleate as stabiliser. The incorporation and distribution of riboflavin, dipyridamole and acridine orange into these microparticles were investigated using confocal laser scanning microscopy (CLSM). The influence of the physicochemical properties of the molecules (solubility in the inner phase, partition coefficient [ethanol/paraffin]) on the distribution, encapsulation efficiency and pH-responsive dissolution behaviour of the microparticles were examined. The drug that tended to partition in ethanol rather than liquid paraffin (riboflavin) was efficiently encapsulated and evenly distributed. In contrast, compounds which partitioned in favour of the liquid paraffin localised towards the surface of the microparticles and exhibited lower encapsulation efficiency (dipyridamole and acridine orange). All three sets of drug-loaded microparticles showed a limited release in acid (<10% release); drug distribution appeared to have a minimum effect on drug release. This microparticle technology has the potential to provide effective enteric drug release with a wide variety of molecules.     

Simultaneous production and co-mixing of microparticles of nevirapine with excipients by supercritical antisolvent method for dissolution enhancement

Microparticles of a poorly water-soluble model drug, nevirapine (NEV) were prepared by supercritical antisolvent (SAS) method and simultaneously deposited on the surface of excipients such as lactose and microcrystalline cellulose in a single step to reduce drug–drug particle aggregation. In the proposed method, termed supercritical antisolvent-drug excipient mixing (SAS-DEM), drug particles were precipitated in supercritical CO₂ vessel containing excipient particles in suspended state. Drug/excipient mixtures were characterized for surface morphology, crystallinity, drug–excipient physico-chemical interactions, and molecular state of drug. In addition, the drug content uniformity and dissolution rate were determined. A highly ordered NEV–excipient mixture was produced. The SAS-DEM treatment was effective in overcoming drug–drug particle aggregation and did not affect the crystallinity or physico-chemical properties of NEV. The produced drug/excipient mixture has a significantly faster dissolution rate as compared to SAS drug microparticles alone or when physically mixed with the excipients.     

Sustained-Release Hydromorphone Microparticles Produced by Supercritical Fluid Polymer Encapsulation

Chronic cancer pain remains prevalent and severe for many patients, particularly in those with advanced disease. The effectiveness of analgesic/adjuvant drug treatments in routine practice has changed little in the last 30 years. To address these issues herein, we have developed sustained-release poly(lactic-co-glycolic acid) microparticles of hydromorphone for intrathecal injection aimed at producing prolonged periods of satisfactory analgesia in patients, as a novel strategy for alleviation of intractable cancer-related pain. These hydromorphone-loaded microparticles were produced successfully using organic solvent-free supercritical fluid polymer encapsulation. Drug loading at 9.2% and encapsulation efficacy at 92% were achieved for particles in the desired size range (20-45 μm) with sustained release over a 5-week period in vitro.     

Floating microparticles based on low density foam powder

The aim of this study was to develop a novel multiparticulate gastroretentive drug delivery system and to demonstrate its performance in vitro. Floating microparticles consisting of (i) polypropylene foam powder; (ii) verapamil HCl as model drug; and (iii) Eudragit RS, ethylcellulose (EC) or polymethyl methacrylate (PMMA) as polymers were prepared with an O/W solvent evaporation method. The effect of various formulation and processing parameters on the internal and external particle morphology, drug loading, in vitro floating behavior, in vitro drug release kinetics, particle size distribution and physical state of the incorporated drug was studied. The microparticles were irregular in shape and highly porous. The drug encapsulation efficiency was high and almost independent of the theoretical loading. Encapsulation efficiencies close to 100% could be achieved by varying either the ratio 'amount of ingredients: volume of the organic phase' or the relative amount of polymer. In all cases, good in vitro floating behavior was observed. The release rate increased with increasing drug loading and with decreasing polymer amounts. The type of polymer significantly affected the drug release rate, which increased in the following rank order: PMMA相似文献   

Formulation and pharmacodynamic evaluation of captopril sustained release microparticles

Cellulose propionate (CP) microparticles containing captopril (CAP) were prepared by solvent evaporation technique. The effects of polymer molecular weight, polymer composition and drug:polymer ratios on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared captopril microparticles were examined. The anti-hypertensive effect of the selected CAP formulation in comparison with aqueous drug solution was also evaluated in vivo using hypertensive rats. The formulation containing drug:polymer blend ratio 1:1.5 (1:1 low:high molecular weight CP), namely F7, was chosen as the selected formulation with regard to the encapsulation efficiency (75.1%), flow properties (theta=24 degrees, Carr index=5%, Hausner ratio=1.1, packing rate=0.535) and release characteristics. Initial burst effect was observed in the release profile of all examined formulations. DSC and SEM results indicated that the initial burst effect could be attributed to dissolution of CAP crystals present on the surface or embedded in the superficial layer of the matrix. The release kinetics of CAP from most microparticle formulations followed diffusion mechanism. After oral administration of the selected microparticle formulation (F7) to hypertensive rats, systolic blood pressure decreased gradually over 24 h compared to reference drug solution. These results may suggest the potential application of cellulose propionate microparticles as a suitable sustained release drug delivery system for captopril.     

Multiunit floating drug delivery system of acyclovir: development,characterization and in vitro-in vivo evaluation of spray-dried hollow microspheres

Acyclovir, anti-herpes virus drug, was loaded in hollow microspheres to improve bioavailability and patient compliance by prolonging the residence time in the gastrointestinal tract. The hollow microspheres of acyclovir were prepared by spray-drying method using ethyl cellulose as a drug-controlled release polymer. We found that the selected process parameters of spray-drying method like inlet temperature, outlet temperature, spray flow rate and vacuum pressure can give rise to hollow microspheres with good yields of production, high drug content and buoyancy, narrow size distribution and good encapsulation efficiency. The size of the microspheres prepared from different ratios of acyclovir and ethyl cellulose was 1.1-2.7 μm. When the drug:polymer ratio was increased, the size and percent drug content increased. The hollow microspheres having higher polymer concentrations were less buoyant than those with lower polymer concentrations. The formulation HSF1 showed the highest buoyancy of 94.18 ± 4.4 %. Dissolution profiles indicate that when drug:polymer ratio increased from 1:2 to 1:6, a decrease in release rate was observed. The highest correlation coefficient was obtained in first-order release model as compared to zero-order followed by Higuchi model. From the Higuchi plot it was found that drug release from the microspheres was diffusion type. The ‘n’ values from Korsmeyer-peppas model indicated that all three formulations follow Fickian diffusion controlled release. The AUC values for oral administration of selected formulation and conventional tablet (Zovirax) clearly indicated two- to three-fold improvement in the bioavailability of acyclovir from prepared formulation when compared to conventional commercial tablet.     

Formulation and pharmacodynamic evaluation of captopril sustained release microparticles

Cellulose propionate (CP) microparticles containing captopril (CAP) were prepared by solvent evaporation technique. The effects of polymer molecular weight, polymer composition and drug?:?polymer ratios on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared captopril microparticles were examined. The anti-hypertensive effect of the selected CAP formulation in comparison with aqueous drug solution was also evaluated in vivo using hypertensive rats. The formulation containing drug?:?polymer blend ratio 1?:?1.5 (1?:?1 low?:?high molecular weight CP), namely F7, was chosen as the selected formulation with regard to the encapsulation efficiency (75.1%), flow properties (θ?=?24°, Carr index?=?5%, Hausner ratio?=?1.1, packing rate?=?0.535) and release characteristics. Initial burst effect was observed in the release profile of all examined formulations. DSC and SEM results indicated that the initial burst effect could be attributed to dissolution of CAP crystals present on the surface or embedded in the superficial layer of the matrix. The release kinetics of CAP from most microparticle formulations followed diffusion mechanism. After oral administration of the selected microparticle formulation (F7) to hypertensive rats, systolic blood pressure decreased gradually over 24?h compared to reference drug solution. These results may suggest the potential application of cellulose propionate microparticles as a suitable sustained release drug delivery system for captopril