Controlled dual release of hydrophobic and hydrophilic drugs from electrospun poly(l-lactic acid) fiber mats loaded with chitosan microspheres

This work is to develop novel electrospun poly(l-lactic acid) (PLLA) fiber mats for controllable delivery of hydrophobic and hydrophilic drugs. For this aim, bovine serum albumin (BSA, used as a hydrophilic model drug) was firstly enveloped into chitosan microspheres by spray drying. Benzoin (used as a hydrophobic model drug) was directly dissolved in PLLA solution and then the chitosan microspheres were suspended into the PLLA solution, which was used to prepare PLLA fiber mats by electrospinning. Polyvinylpyrrolidone (PVP) was added into the PLLA solution to tune the drug release behaviors. The results showed that the chitosan microspheres were uniformly distributed in the fibers. BSA had a short-term release while benzoin had a long-term and sustained release in all the dual drug delivery systems, and the release of both hydrophobic and hydrophilic drugs could be adjusted by changing the ratio of PVP/PLLA.     

Control of drug loading efficiency and drug release behavior in preparation of hydrophilic-drug-containing monodisperse PLGA microspheres

We prepared monodisperse poly(lactide-co-glycolide) (PLGA) microspheres containing blue dextran (BLD)—a hydrophilic drug—by membrane emulsification technique. The effects of electrolyte addition to the w₂ phase and significance of the droplet size ratio between primary (w₁/o) and secondary (w₁/o/w₂) emulsions during the preparation of these microspheres was examined. The droplet size ratio was evaluated from the effect of stirring rate of the homogenizer when preparing the primary emulsion. The drug loading efficiency of BLD in these microspheres increased with stirring rate. It increased to approximately 90% when 2.0% NaCl was added to the w₂ phase. Drug release from these microspheres was slower than that when they were prepared without electrolyte addition. Despite the very high efficiency drug release was gradual because BLD was distributed at the microspheres core. Relatively monodisperse hydrophilic-drug-containing PLGA microspheres with controlled drug loading efficiency and drug release behavior were prepared.     

Effect of hydroxyapatite nanoparticles on ibuprofen release from carboxymethyl-hexanoyl chitosan/O-hexanoyl chitosan hydrogel

In order to explore the effect of nanofiller on the regulation of the drug release behavior from microsphere-embedded hydrogel prepared by carboxymethyl-hexanoyl chitosan (HNOCC) and O-hexanoyl chitosan (OHC), the release kinetics was investigated in terms of various amounts of calcium-deficient hydroxyapatite (CDHA) nanoparticles incorporated. HNOCC is a novel chitosan-based hydrophilic matrix with a burst release profile in a highly swollen state. The drug release kinetics of the HNOCC hydrogel can be regulated by incorporation of well-dispersed CDHA nanoparticles. It was found that the release duration of ibuprofen (IBU) from HNOCC was prolonged with increasing amounts of CDHA which acts as a crosslink agent and diffusion barrier. On the contrary, the release duration of the IBU from OHC (hydrophobic phase) was shortened through increasing the CDHA amount over 5%, which is due to the hydrophilic nature of the CDHA nanoparticles destroying the intermolecular hydrophobic interaction and accelerating OHC degradation. Thus, water accessibility and molecular relaxation were enhanced, resulting in a higher release rate. In addition, sustained and sequential release behavior was achieved by embedding the OHC microspheres (hydrophobic phase) into the HNOCC (hydrophilic phase) matrix, which could significantly prolong the release duration of the HNOCC drug-loaded implant.     

Enteric-coated epichlorohydrin crosslinked dextran microspheres for site-specific delivery to colon

Abstract

Enteric-coated epichlorohydrin crosslinked dextran microspheres containing 5-Fluorouracil (5-FU) for colon drug delivery was prepared by emulsification-crosslinking method. The formulation variables studied includes different molecular weights of dextran, volume of crosslinking agent, stirring speed, time and temperature. Dextran microspheres showed mean entrapment efficiencies ranging between 77 and 87% and mean particle size ranging between 10 and 25?µm. About 90% of drug was released from uncoated dextran microspheres within 8?h, suggesting the fast release and indicated the drug loaded in uncoated microspheres, released before they reached colon. Enteric coating (Eudragit-S-100 and Eudragit-L-100) of dextran microspheres was performed by oil-in-oil solvent evaporation method. The release study of 5-FU from coated dextran microspheres was complete retardation in simulated gastric fluid (pH 1.2) and once the coating layer of enteric polymer was dissolved at higher pH (7.4 and 6.8), a controlled release of the drug from the microspheres was observed. Further, the release of drug was found to be higher in the presence of dextranase and rat caecal contents, indicating the susceptibility of dextran microspheres to colonic enzymes. Organ distribution and pharmacokinetic study in albino rats was performed to establish the targeting potential of optimized formulation in the colon.     

Matrices of water-soluble drug using natural polymer and direct compression method

The objective of this research was to find an optimum Carrageenan matrix formulation with the desired drug release and physical properties prepared by direct compression. In order to achieve this, matrices containing 10% theophylline, different Carrageenan level, and different excipient were prepared and evaluated. A selected matrix containing 40% Carrageenan and lactose fast flo was tested for dissolution in three different dissolution media (distilled water, 0.1 N HCl, and phosphate buffer pH 7.4). The same formulation was also tested for dissolution at 50 rpm, 100 rpm, and 150 rpm, and using different dissolution apparatus (Apparatus 1 and 2).

All matrices showed a decrease in drug release as the polymer level was increased. Only Avicel PH-101 did not show any significant difference between matrices prepared with 30% and 40% polymer. At 10% polymer level, it appears that the type of diluent used controls the drug release. However, at high polymer level, 30% and 40%, it appears that the polymer level controls the drug release. Phosphate buffer pH 7.4 and 0.1 N HCl increase drug release and appear to increase Carrageenan solubility and decrease gel formation. Also, as the rotational speed of the apparatus was increased, the integrity of the gel layer was decreased, and the release of drug was increased. The drug release from Carrageenan matrices appears to follow the diffusion model for inert matrix up to 90 min. After 90 min, the drug release follows a zero-order model.

This study demonstrated that matrices using Carrageenan can be successfully prepared by direct compression.     

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.     

Controlled Transdermal Mucolytic Delivery System

Bromhexine a mucolytic agent was studied to explore for dermal route of administration. The formulations were based on commercial eudragit polymers and polyvinyl pyrrolidone.

Two systems i.e., Matrix and Pseudolatex were studied for their comparative performance evaluation in in vitro. The various combinations of hydrophobic (Eudragit RL-100) and hydrophilic (PVP 40,000) polymers were used to prepare the both matrix and pseudolatex topical systems. The prepared systems were studied for in vitro diffusion using a Franz diffusion cell. Study revealed that the relative concentration of hydrophobic to hydrophilic polymers determines the drug diffusion and across the skin permeation of the drug. Both the systems were noted to be stable, however, the drug release and across the skin permeability of drug from pseudolatex system recorded to be better and uniform. Preliminary studies on bromhexine are indicative of its potentiality for transdermal preparation and establish the need for in vivo evaluation.     

Sustained release characteristics of tablets prepared with mixed matrix of sodium carrageenan and chitosan: effect of polymer weight ratio, dissolution medium, and drug type

The interpolymeric complexation of carrageenan and chitosan was investigated for its effect on drug release from polymeric matrices in comparison to single polymers. For this purpose, matrices with carrageenan: chitosan (CG:CS) ratios of 100%, 75%, 50%, 25%, and 0% were prepared at 1:1 drug to polymer ratio. The effect of dissolution medium and drug type on drug release from the formulations was addressed. Two model drugs were utilized: diltiazem HCl (DZ) as a salt of a basic drug and diclofenac Na (DS) as a salt of an acidic drug. Three dissolution media were used: water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). Some combinations of the two polymers showed remarkable sustained release effect on DZ in comparison to the single polymers in water and SGF. However, no apparent effect for the combination on DZ release was shown in SIF. The medium effect was explained by the necessity of chitosan ionization, which could be attained by the acidic SGF or microacidic environment created by the used acidic salt of DZ in water, but not in SIF. An interaction between the medium type and CG:CS ratio was also found. With DS, the polymer combinations had similar dissolution profiles to those of the single polymers in water and SIF, which was explained by the lack of chitosan ionization by the medium or the drug basic salt. The dissolution profiles could not be obtained in SGF, which was attributed to the conversion of DS into diclofenac free acid. The importance of chitosan ionization for its interaction with CG to have an effect on the release of DS was demonstrated by performing dissolution of SGF presoaked tablets of DS in SIF, which showed an effect of combining the two polymers on sustaining the drug release.     

Control of Drug Release Rate by Use of Mixtures of Polycaprolactone and Cellulose Acetate Butyrate Polymers

Chlorpromazine microspheres were prepared by an emulsion solvent evaporation technique using polycaprolactone and cellulose acetate butyrate as the matrix. The fluidity of the polymer solution was easily adjusted by use of mixtures of two polymers and thus provided a practical means to control the microsphere size. The In Vitro release pattern was easily changed by changing the ratios of these two polymers. An increase in polycaprolactone content of the polymer microsphere matrix brought about an increase in the release rate. Drug loading had no predictable effect on the dissolution rate, but smaller microspheres gave more rapid drug release due to the greater surface area.     

Oral-based controlled release formulations using poly(acrylic acid) microgels

Aim: To investigate the release of hydrophobic and hydrophilic substances from tablets containing Pemulen and Carbopol as excipients. Method: The dissolution patterns of a hydrophobic (diazepam) and a hydrophilic active substance (midodrine-HCl) from different tablet formulations containing a nonmodified polyacrylic microgel (Carbopol 981 F) or a hydrophobically modified polyacrylic microgel (Pemulen®) have been studied. Possible differences in dissolution in phosphate buffer (pH 6.8) and in 0.1 M HCl between tablets produced using wet granulation and direct compression were also investigated. Results: Tablets produced by wet granulation had a greater effect on the release of active substance from the tablets. No major differences were observed in the release patterns of the hydrophilic substance midodrine-HCl from wet granulated tablets based on Carbopol and Pemulen. However, the release pattern of the more hydrophobic drug substance, diazepam, differed considerably between the two polymers. Wet granulation gave reproducible release patterns. The release patterns from the polymers differed considerably at pH 6.8 but were similar at low pH. Conclusions: The release of the diazepam from the hydrophobic polymer Pemulen was very slow, and the release was close to zero order.     

Double-walled microspheres loaded with meglumine antimoniate: preparation,characterization and in vitro release study

Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate.

Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy.

Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs.

Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics.     

Soybean Lecithin‐Mediated Nanoporous PLGA Microspheres with Highly Entrapped and Controlled Released BMP‐2 as a Stem Cell Platform

Injectable polymer microsphere‐based stem cell delivery systems have a severe problem that they do not offer a desirable environment for stem cell adhesion, proliferation, and differentiation because it is difficult to entrap a large number of hydrophilic functional protein molecules into the core of hydrophobic polymer microspheres. In this work, soybean lecithin (SL) is applied to entrap hydrophilic bone morphogenic protein‐2 (BMP‐2) into nanoporous poly(lactide‐co‐glycolide) (PLGA)‐based microspheres by a two‐step method: SL/BMP‐2 complexes preparation and PLGA/SL/BMP‐2 microsphere preparation. The measurements of their physicochemical properties show that PLGA/SL/BMP‐2 microspheres had significantly higher BMP‐2 entrapment efficiency and controlled triphasic BMP‐2 release behavior compared with PLGA/BMP‐2 microspheres. Furthermore, the in vitro and in vivo stem cell behaviors on PLGA/SL/BMP‐2 microspheres are analyzed. Compared with PLGA/BMP‐2 microspheres, PLGA/SL/BMP‐2 microspheres have significantly higher in vitro and in vivo stem cell attachment, proliferation, differentiation, and matrix mineralization abilities. Therefore, injectable nanoporous PLGA/SL/BMP‐2 microspheres can be potentially used as a stem cell platform for bone tissue regeneration. In addition, SL can be potentially used to prepare hydrophilic protein‐loaded hydrophobic polymer microspheres with highly entrapped and controlled release of proteins.     

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.     

Sustained Release Tablets of Theophylline

Sustained release tablets of theophylline (anhydrous) were prepared using hydrophilic polymers (Methyl Cellulose, Methocel K₄M and K₁₅M) and hydrophobic polymers (ethyl cellulose, cellulose acetate). In addition water soluble adjuvants were used to modify release rate. With methocel, rapid gelling was observed and release was near zero-order, whereas with hydrophobic polymers release followed Fickian law of diffusion.     

Control of Drug Release Rate by Use of Mixtures of Polycaprolactone and Cellulose Acetate Butyrate Polymers

Abstract

Chlorpromazine microspheres were prepared by an emulsion solvent evaporation technique using polycaprolactone and cellulose acetate butyrate as the matrix. The fluidity of the polymer solution was easily adjusted by use of mixtures of two polymers and thus provided a practical means to control the microsphere size. The In Vitro release pattern was easily changed by changing the ratios of these two polymers. An increase in polycaprolactone content of the polymer microsphere matrix brought about an increase in the release rate. Drug loading had no predictable effect on the dissolution rate, but smaller microspheres gave more rapid drug release due to the greater surface area.     

Hydrogels Formed by Cross-Linked Polyvinylalcohol as Colon-Specific Drug Delivery Systems

Polyvinylalcohol (PVA) of different molecular weights was cross-linked with succinyl, adipoyl, or sebacoyl chloride to obtain hydrogel-forming polymers and to determine their suitability as colon-specific drug delivery systems. Diclofenac sodium, propranolol hydrochloride, and vitamin B6 hydrochloride were used as hydrophilic model drugs with colon-specific release that should yield high concentrations in the large intestine, minimizing release in the upper part of the gastrointestinal tract. Spray-dried mixtures of the drugs and the polymer (at a 1 : 2 w/w ratio) were prepared, and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, and 7.4. The results indicated the ability of the cross-linked polymers to slow the release of the drugs analyzed with respect to the pure drug dissolution at each pH. The lengthening of the cross-linker acyl chain was noted to decrease drug release further.     

Effect of hydrophobic octadecyl groups on pH-sensitive aggregation behavior of imidazole-containing polyaspartammide derivatives

The effect of hydrophobic octadecyl groups on pH-dependent aggregation behavior of polyaspartammide derivatives was studied. A series of pH-sensitive amphiphilic polymers with different degrees of octaceylamine (C18) substitution were synthesized through a successive graft reaction of octaceylamine, O-(2-aminoethyl)-O'-methylpolyethylene glycol, and 1-(3-aminopropyl)imidazole on polysuccinimide. Micelle-like nano-aggregates were formed in aqueous solution at pH > 6.8 and they showed different pH dependent aggregation behavior according to degree of substitution (DS) of the hydrophobic C18 chains. These polymers will have a potential application as carriers for pH-sensitive drug release in anticancer or intracellular delivery systems.     

Preparation of alginate microspheres by water-in-oil emulsion method for drug delivery: Effect of Ca2+ post-cross-linking

Alginate microspheres were prepared by a water-in-oil emulsion solvent diffusion method. The alginate microspheres were post-cross-linked with Ca²⁺ ions. Influence of Ca²⁺ concentration on the characteristics and drug release behaviors of alginate microspheres was evaluated. Blue dextran was used as a water-soluble model drug. The non-cross-linked alginate microspheres were less than 100 μm in size and had a spherical shape. The cross-linked alginate microspheres were also spherical in shape with a rougher surface but their particle sizes were larger than 100 μm. The drug encapsulation efficiency of the non-cross-linked alginate microspheres was very high (82%). The drug encapsulation efficiency of alginate microspheres cross-linked with 5% and 10% Ca²⁺ concentrations were similar to the non-cross-linked microspheres. The in vitro drug releases of the cross-linked alginate microspheres showed prolong release profiles. The cumulative release of blue dextran decreased as the Ca²⁺ concentration increased. Thus, Ca²⁺-post-cross-linked alginate microspheres show possibility for use as controlled-release drug carriers.     

Effect of Microsphere Size and Formulation Factors on Drug Release from Controlled-Release Furosemide Microspheres

Controlled-release furosemide microspheres were prepared with various combinations of Eudragit L: Eudragit RS and Eudragit S: Eudragit RS and release of drug from microspheres containing these polymers in different ratios was studied. A wide range of release rates of drug can obtained by a simple change in the ratio of polymers. An increase in Eudragit RS content of polymer microsphere matrix brought about a decrease in the release rate.

On the other hand, the effect of particle size on the drug release rate from furosemide microspheres was also investigated. The effect of microsphere sizes on release rate depends on the type of Eudragit. The decrease in release rates of small microspheres may be due to agglomerate formation. Dissolution data indicated that the release followed Higuchi's matrix model kinetics.     

Effect of heat on characteristics of chitosan film coated on theophylline tablets

The effect of heat on the characteristics of chitosan film coated on theophylline tablets was studied. Chitosan of high viscosity grade with molecular weight in the range of 800,000-1,000,000, 80-85% degree of deacetylation was used as a film former by dissolving in 1% v/v acetic acid solution. The coated tablets had been cured at 40, 60, and 100°C for 6, 12, and 24 hr. The morphology of the film at the edge and surface of coated tablets was investigated using scanning electron microscopy. Film cracking was increased and clearly observed in the coated tablets cured at 100°C for 24 hr. As a result, more water could be absorbed into the tablets, followed by faster disintegration and faster drug release. The evidence of partial conversion of chitosonium acetate to chitin in the ¹³C nuclear magnetic resonance (NMR) spectra of chitosan films cured at 40, 60, and 100°C was observed, but it had no effect on drug release behavior. Theophylline tablets coated with chitosan films gave sustained release behavior in various media, i.e., distilled water, 0.1 N hydrochloric acid, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. In addition, the film coating temperature at 55-60°C and curing process at 40 and 60°C had no effect on the drug release from theophylline tablets coated with chitosan polymer. Finally, it might be concluded that both the physical and chemical properties of chitosan films were affected by heat.