In Vitro and In Vivo Release of Naltrexone from Biodegradable Depot Systems

ABSTRACT

The aim of this study was to prepare poly(d, l-lactide) (PLA) microspheres containing naltrexone (NTX) by a solvent evaporation method, and to evaluate both in vitro and in vivo release characteristics and histopathological findings of tissue surrounding an implant formulation in rats.

This method enabled the preparation of microspheres of regular shape and relatively narrow particle size distribution. The in vitro release profiles of NTX from PLA microspheres showed the release of NTX did not follow zero-order kinetics. An initial burst release was observed, subsequently followed by a nearly constant rate of 0.4% per day after ten days. The cumulative amount of NTX released at the end of 60 days was 80%. Compressed microspheres showed near zero-order sustained release of NTX for 360 days. The plasma NTX levels in rats showed that for compressed microspheres NTX concentrations were constant and exceeded 2 ng/mL for 28 days. Throughout the 28 days of study, the implantations cause a minor inflammatory response, which can be regarded as a normal defence mechanism. The sustained release performance of NTX from the biodegradable depot systems may provide a reliable, convenient, and safe mechanism for the administration of NTX for the long-term treatment of opioid dependence.     

An Investigation of the Synthesis of Poly(D,L-Lactic Acid) and Preparation of Microspheres Containing Indomethacin

Abstract

Seven batches of poly(D, L-lactic acid) (PLA) were prepared from D, L-lactic acid using tetraphenyltin or zinc acetate as a catalyst. The samples of PLA were characterized by terminal group analysis, gel permeation chromatography, infrared analysis, and differential scanning calorimetry. Polymerization conditions such as the time of reaction and the type of catalyst affected the molecular weight of PLA. Microspheres containing indomethacin were prepared by the oil/water (o/w) solvent evaporation technique using different formulations and process variables. The in vitro release of indornethacin in phosphate buffer was found to be dependent on the molecular weight of PLA and also on the type and amount of adjuvants used. The batch of microspheres containing 5% cholesterol released the drug at a slow controlled rate (29%, 65%. and 85% in 1, 7, and 24 hr, respectively). The results of F test for the microspheres revealed that there is no significant direrence between the Higuchi model and the power law equation. The drug was released by a dimsion mechanism from the microspheres.     

Preparation of Novel Cationic Copolymer Microspheres and Evaluation of Their Function by In Vitro and In Vivo tests as Ph-Sensitive Drug Carrier Systems

ABSTRACT

Novel pH-sensitive copolymer microspheres containing methylacrylic acid and styrene cross-linking with divinylbenzene were synthesized by free radical polymerization. The microspheres that were formed were then characterized by Fourier-Transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), size analysis, and X-ray analysis. The copolymer microspheres showed pulsatile swelling behavior whenthe pH of the media changed. The pH-sensitive microspheres were loaded with diltiazem hydrochloride (DH). The release characteristics of the free drug and the drug-loaded microspheres were studied under both simulated gastric conditions and intestinal pH conditions. The in vivo evaluation of the pulsatile preparation was subsequently carried out using beagle dogs as experimental subjects. The results demonstrated that the drug release exhibited a pulsatile character both in vitro and in vivo.     

Preparation and Characterization of Oil-in-Water Type Poly (D,L-Lactic Acid) Microspheres Containing Testosterone Enanthate

Abstract

Poly (D, L-lactic acid) (PLA) microspheres containing testosterone enanthate (ET) were prepared by using an oil-in-water (O/W) emulsion technique. The size distribution of the microspheres obtained could be explained by a log-normal distribution, and as a result, it was found that ET fully incorporates into microspheres even when the drug is loaded at up to 50%. On the other hand, the dissolution behavior of ET from microspheres was strongly dependent on particle size, suggesting that dissolution of the drug from microspheres can be easily controlled by controlling the preparative conditions.     

In vitro and in vivo release of naltrexone from biodegradable depot systems

The aim of this study was to prepare poly(d, l-lactide) (PLA) microspheres containing naltrexone (NTX) by a solvent evaporation method, and to evaluate both in vitro and in vivo release characteristics and histopathological findings of tissue surrounding an implant formulation in rats.

This method enabled the preparation of microspheres of regular shape and relatively narrow particle size distribution. The in vitro release profiles of NTX from PLA microspheres showed the release of NTX did not follow zero-order kinetics. An initial burst release was observed, subsequently followed by a nearly constant rate of 0.4% per day after ten days. The cumulative amount of NTX released at the end of 60 days was 80%. Compressed microspheres showed near zero-order sustained release of NTX for 360 days. The plasma NTX levels in rats showed that for compressed microspheres NTX concentrations were constant and exceeded 2 ng/mL for 28 days. Throughout the 28 days of study, the implantations cause a minor inflammatory response, which can be regarded as a normal defence mechanism. The sustained release performance of NTX from the biodegradable depot systems may provide a reliable, convenient, and safe mechanism for the administration of NTX for the long-term treatment of opioid dependence.     

Characterisation of Biodegradable Microspheres Containing Dehydro-Iso-Androsterone

Abstract

Poly-DL-lactide (PLA) and poly-DL-lactide-co-glycolide (DL-PGA) micromatrices (PharmazomesTM) containing dehydro-isoandrosterone (DHEA), a weak androgen, were prepared by a solvent evaporation process. Micromatrices with increasing drug loading as well as increasing polymer molecular weight were prepared. The morphology of these systems depended on the drug loading, the polymer molecular weight and polymer composition. Increasing the drug loading or polymer molecular weight resulted in increasingly irregular microparticles being formed. DSC thermograms did not reveal the presence of crystalline DHEA in micromatrices containing 10 to 50% DHEA loading. However crystalline DHEA was observed in microspheres heated to above the glass transition temperature of the polymer. Xray analysis of 30% DHEA micromatrices established the presence of crystalline DHEA in the micromatrices. The percent release of DHEA from the micromatrices, into 40% ethanol at 37°C, increased with increasing DHEA loading. The dissolution of DHEA from drug-polymer compressed discs of constant surface area was proportional to the square root of time indicating matrix controlled release.     

Drug Product Development: A Technical Review of Chemistry,Manufacturing, and Controls Information for the Support of Pharmaceutical Compound Licensing Activities

Abstract

Tolmetin microspheres were prepared by the coacervation process from the ethylcellulose. Microspheres were obtained both in presence and without protecting colloids, such as polyisobutilene (PIB) or ethyl-vinylacetate copolimers (EVA). The effect of these agents on the preparation, drug content, wall thickness, surface morphology, drug dissolution arid release from microspheres, were evaluated. The dissolution rate analysis was carried out also in the presence of a surfactant (Tween 80) at different pH values.

In addition, microspheres containing Tolmetin as a core material were submitted to biological tests, in comparison with the free drug, to evaluate upon experimental models the antipyretic activity and the gastric tolerability.     

In Vitro Evaluation of Albumin Microspheres Containing Actinomycin D

Abstract

Albumin microspheres containing actinomycin D were prepared by the heat stabilization method. The compata-bility of the drug with magnetite and the optimum stability of the drug in different pH were studied. Drug loaded albumin microspheres containing magnetite showed good magnetic response. Release of the drug was slow and continued for 7 days exhibiting sustained release property. The difference as regards to the size, shape, drug content and release rate from freshly prepared and freeze dried drug loaded albumin microspheres was negligible.     

Preparation and characterization of hollow Fe3O4/SiO2@PEG–PLA nanoparticles for drug delivery

In this study we present a novel targeted anticancer drug delivery, which was size controlled Fe₃O₄/SiO₂ hollow microspheres (HMS) as magnetic core and poly (ethylene glycol)-poly–(d,l-lactide) (PEG–PLA) surface coating (HMS@PEG–PLA). And investigations were to test a new convenient method, which is one-step precipitation polymerization on HMS, forming magnetic hollow polymer microspheres. The HMS@PEG–PLA which have hollow structure and uniform size were characterized by Transmission Electron Microscopy (TEM). Vibrating Sample Magnetometer (VSM) showed a characteristic of super paramagnetic with saturation magnetization value of about 19.78 emu/g. In vitro cytotoxicity of Fe₃O₄/SiO₂@PEG–PLA (HMS@PEG–PLA) hollow microspheres were of low toxicity, so it can be used as a drug carrier, and cisplatin (CDDP) as the model drug release behavior was researched. The results have exhibited preferable release properties.     

Entrapment Efficiency and Initial Release of Phenylbutazone from Nanocapsules Prepared from Different Polyesters

Abstract

Several formulations of poly(?-caprolactone) (PCL), poly(lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) nanocapsules containing phenylbutazone were prepared according to the interfacial deposition technique. These formulations differed in the type of polymer used to form the shell of the nanocapsules. Analysis of particle size distribution and encapsulation efficiency of the nanocapsules revealed that the type and molecular weight of polyester used were the main factors influencing these properties. PLA had the highest encapsulation efficiency with the best reproducibility. From in vitro release studies, a small amount of drug release was observed at pH 7.4. However, in the gastric medium, an important burst effect occurred and was highest with the PLGAs and lowest with PCL, suggesting that drug release from these systems is affected by the type of polymer and the environmental conditions. The two formulations of phenylbutazone-loaded nanocapsules should be evaluated based on PCL and PLA in vivo in order to determine to what extent they are able to reduce the local side effects of this drug.     

Prolonged Release of Tegafur from S/O/W Multiple Emulsion

Abstract

To develop a prolonged and sustained release preparation, we prepared an albumin microsphere-in-oil-in-water emulsion (S/O/W) and examined sustained release from it in comparison with other control preparations such as water-in-oil (W/O) emulsions and microspheres in vitro and in vivo, respectively. Tegafur was used as a model drug. A microsphere-in-oil emulsion was prepared by adding albumin microspheres to soybean oil containing 20% Span 80. To prepare an S/O/W emulsion, the microsphere-in-oil emulsion was added into an aqueous solution of hydroxypropyl methylcellulose containing Pluronic F68. The mean particle size of the albumin microspheres was 3 µm, and the ratio of entrapment of tegafur into albumin microspheres was about 25%. In an in vitro release test, the t₇₅ of the S/O/W emulsion was fourfold greater and in an in vivo release test the mean residence time of tegafur from the S/O/W emulsion was more than twofold that from a W/O emulsion or microsphere system. The mean residence time of 5-fluorouracil (5-FU) from an S/O/W emulsion was also greater than with other dosage forms. These results suggest the possible usefulness of an S/O/W emulsion for the sustained and prolonged release of tegafur.     

Comparative In Vitro evaluation of cumulative release of the urinary antiseptics Nalidixic acid,Pipemidic acid,Cinoxacin, and norfloxacin from white beeswax Microspheres

Abstract

The in vitro diffusion of nalidixic acid (1), pipemidic acid (2), cinoxacin (3), and norfloxacin (4) was studied. The transfer rate constants (k_d) from simulated gastro-intestinal juices to simulated plasma, throughout artificial wall lipid membranes, were defined. The k_d values suggested that the four drugs are absorbed both in gastric and intestinal environments in similar amounts. To obtain lack of gastric unwanted effects white beeswax microspheres containing 1, 2, 3, and 4 were investigated as a vehicle for the drug intestinal release; they were prepared by the meltable dispersion process using wetting agents. Discrete, reproducible free flowing microspheres were obtained. The drug content increased when the particle size growed; it ranged from 4% to 18%. More than 95% of the isolated microspheres were of particle size range 100–500 μm. The drug release was evaluated in vitro. Dissolution of entrapped active ingredients was greatly retarded allowing absorption only in the intestinal tract as result of microsphere formation.     

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.     

Dissolution Characteristics of Polycaprolactone-Polylactide Microspheres of Chlorpromazine

Abstract

Studies were conducted on the preparation of controlled release polycaprolactone-polylactide microcapsules of chlorpromazine and on release of the drug from the microcapsules in pH 7.0 buffer medium. A wide range of release rates of the drug was obtained by simple change in the polymer system. Chlorpromazine was released from the microspheres in a biphasic manner consisting of an initial fast release phase followed by a slow-release phase. Increasing the drug content increased the initial drug release rate but no significant drug loading effect on the second stage dissolution rate was noted. There was no significant effect of particle size on the drug release rate from the microspheres. The swelling property of the microspheres and the agglomerate nature of the sieve fractions may complicate the drug release kinetics and obscure the particle size effect on dissolution rate.     

Preparation and Evaluation of Controlled Release Indomethacin Microspheres

Abstract

Microspheres containing indomethacin were prepared with various combinations of polymers Eudragit RS and Eudragit L. The effects of different ratios of polymers, solvent-polymer ratio, polymer-drug ratio and evaporation temperature on the physical characteristics of the microspheres as well as the in vitro release rate of the drug were investigated. All the factors studied had an influence on the physical characteristics of the microspheres. In vitro dissolution results showed that all formulations gave prolonged release of indomethacin and the release followed apparent zero order kinetics until 80% of drug had been released.     

Controlled Release of Cyclosporine from Microspheres

Abstract

A controlled release microsphere formulation of cyclosporine is reported for the first time. Ethylene-vinyl acetate copolymer was utilized to prepare microspheres containing cyclosporine. The polymer was dissolved in methylene chloride (10% w/v) to which different quantities of cyclosporine was added to give drug loadings of 5, 25 and 50% in the microspheres. The polymer-drug solution was extruded into ethanol, where gelling of the polymer was achieved at ?78°C in an ethanol-liquid nitrogen bath. Microspheres containing 25% of cyclosporine retained their shape and gave optimum results. Lower drug loadings (5% cyclosporine) resulted in deformed microspheres, whereas high drug loadings (50 % cyclosporine) produced tear drop shaped microspheres. This method used to prepare microspheres is simple, quick and inexpensive and can be used for drugs that are unstable to heat. Furthermore, the polymer used is bio-compatible and can be used to design formulations such as films containing cyclosporine which can then be used as subcutaneous implants.     

Microspheres for the oral delivery of insulin: preparation,evaluation and hypoglycaemic effect in streptozotocin-induced diabetic rats

Insulin-loaded microspheres were prepared by alternating deposition film layers that were composed of insulin and poly(vinyl sulfate) potassium on the surface of poly(lactic acid) (PLA) microspheres. The preparation of the insulin-loaded microspheres was optimized by an orthogonal test design, and the relationship between drug loading (DL) and film layers was studied. The particle size, DL and encapsulation efficiency of the obtained insulin-loaded microspheres with 10 films were 5.25?±?0.15?µm, 111.33?±?1.15?mg/g and 33.7?±?0.19%, respectively. Following this, the physical characteristics of the insulin-loaded microspheres were investigated. The results from scanning electron microscopy and a laser particle size analyzer (LPSA) indicated the spherical morphology, rough surface and increasing particle sizes of the insulin-loaded microspheres, which were compared to those of PLA microspheres. An in vitro release study showed that the insulin-loaded microspheres were stable in HCl solution (pH 1.0) and released insulin slowly in phosphate-buffered solution (pH 6.8). Finally, the drug efficacy of the prepared insulin-loaded microspheres via oral administration was evaluated in rats with diabetes induced by streptozotocin, and an obvious dose-dependent hypoglycemic effect was observed. This preliminary data could illustrate the prospect of using microspheres for the oral delivery of insulin.     

Carnauba Wax Microspheres Loaded with Valproic Acid: Preparation and Evaluation of Drug Release

Abstract

To minimize unwanted toxic effects of valproic acid (1) by the kinetic control of drug release, gastroresistant carnauba wax microspheres loaded with the antiepileptic agent were prepared. The preparation was based on a technique involving melting and dispersion of drug-containing wax in an aqueous medium. The resulting emulsion after cooling under rapid stirring produced solid, discrete, reproducible free flowing microspheres which converted the liquid drug droplets into solid material. About 94% of the isolated microspheres were of particle size range 200-425 μm. The microspheres were analyzed to determine the drug content in various particle size range and to characterize the in vitro release profile. The average drug content was 26% w/w. The intestinal drug discharge of 1 from the carnauba wax microspheres was studied and compared with the release patterns observed for white beeswax and hexadecanol microspheres previously described. The drug release performance was greatly affected by the material used in the microencapsulation process. In the intestinal environment carnauba wax microspheres exhibited more rapid initial rate of release and about 80% of the entrapped drug was discharged in 120 min while complete release occurred in about 8 h.     

Preparation and evaluation of insulin-loaded polylactide microspheres using factorial design

The aim of this work was to study the influence of the concentration and molecular weight of poly(DL-lactide) (PLA) on the characteristics and in vivo biological activity of protein-loaded microspheres. At the same time, an attempt was made to achieve further optimization of the formulation. In the study, insulin was chosen as a model of protein drugs. Nine formulations of injectable insulin-loaded PLA microspheres were prepared using an emulsification and solvent evaporation process according to a factorial design. The trapping efficiency, drug loading, and the drop percentages of blood glucose levels at 24 hr and 72 hr in mice were used to evaluate the formulations. The results showed that PLA molecular weight and, especially, PLA concentration exerted influences on the characteristics and in vivo biological activity of insulin-loaded microspheres. The drug-trapping efficiency increased with the increase of the polymer concentration. The drug loading decreased with the increase of the polymer concentration and was not obviously affected by PLA molecular weight. The drop percentage of blood glucose level at 24 hr increased with the increase of polymer concentration and molecular weight. At 72 hr, the drop percentages of blood glucose levels were slightly increased with the increase of PLA concentration and then significantly decreased after the PLA concentration was above 150 mg/ml. An optimized formulation was prepared with PLA-10k at a concentration of 200 mg/ml. The experimental values of the response variables were close to the predicted values. The results suggest that the in vivo release behavior should be taken into consideration in the design of protein-loaded PLA microspheres.     

Preparation and Evaluation of Insulin-Loaded Polylactide Microspheres Using Factorial Design

The aim of this work was to study the influence of the concentration and molecular weight of poly(DL-lactide) (PLA) on the characteristics and in vivo biological activity of protein-loaded microspheres. At the same time, an attempt was made to achieve further optimization of the formulation. In the study, insulin was chosen as a model of protein drugs. Nine formulations of injectable insulin-loaded PLA microspheres were prepared using an emulsification and solvent evaporation process according to a factorial design. The trapping efficiency, drug loading, and the drop percentages of blood glucose levels at 24 hr and 72 hr in mice were used to evaluate the formulations. The results showed that PLA molecular weight and, especially, PLA concentration exerted influences on the characteristics and in vivo biological activity of insulin-loaded microspheres. The drug-trapping efficiency increased with the increase of the polymer concentration. The drug loading decreased with the increase of the polymer concentration and was not obviously affected by PLA molecular weight. The drop percentage of blood glucose level at 24 hr increased with the increase of polymer concentration and molecular weight. At 72 hr, the drop percentages of blood glucose levels were slightly increased with the increase of PLA concentration and then significantly decreased after the PLA concentration was above 150 mg/ml. An optimized formulation was prepared with PLA-10k at a concentration of 200 mg/ml. The experimental values of the response variables were close to the predicted values. The results suggest that the in vivo release behavior should be taken into consideration in the design of protein-loaded PLA microspheres.