Preparation and characterization of D,L-PLA loaded 17-β-Estradiol valerate by emulsion/evaporation methods

PLA microparticles containing 17-β-estradiol valerate were prepared by an emulsion/evaporation method in order to sustain drug release. This system was characterized concerning particle size, particle morphology and the influence of formulation and processing parameters on drug encapsulation and in vitro drug release. The biodegradation of the microparticles was observed by tissue histological analysis. Scanning electron microscopy and particle size analysis showed that the microparticles were spherical, presenting non-aggregated homogeneous surface and had diameters in the range of 718–880 nm (inert micro-particles) and 3–4 µm (drug loaded microparticles). The encapsulation efficiency was ～80%. Hormone released from microparticles was sustained. An in vivo degradation experiment confirmed that microparticles are biodegradable. The preparation method was shown to be suitable, since the morphological characteristics and efficiency yield were satisfactory. Thus, the method of developed microparticles seems to be a promising system for sustained release of 17-β-estradiol.     

Cetirizine dihydrochloride loaded microparticles design using ionotropic cross-linked chitosan nanoparticles by spray-drying method

To control the release rate and mask the bitter taste, cetirizine dihydrochloride (CedH) was entrapped within chitosan nanoparticles (CS-NPs) using an ionotropic gelation process, followed by microencapsulation to produce CS matrix microparticles using a spray-drying method. The aqueous colloidal CS-NPs dispersions with a drug encapsulation efficiency (EE) of <15%, were then spray dried to produce a powdered nanoparticles-in-microparticles system with an EE of >70%. The resultant spherical CS microparticles had a smooth surface, were free of organic solvent residue and showed a diameter range of 0.5∼5 μm. The in vitro drug release properties of CedH encapsulated microparticles showed an initial burst effect during the first 2 h. Drug release from the matrix CS microparticles could be retarded by the crosslinking agent pentasodium tripolyphosphate or the wall material. The technique of ‘ionotropic gelation’ combined with ‘spray-drying’ could be applicable for preparation of CS nanoparticlesin-microparticles drug delivery systems. CS-NPs based microparticles might provide a potential micro-carrier for oral administration of the freely water-soluble drug — CedH.     

Thrombin receptor agonist peptide entrapped in poly(D,L)-lactide-co-glycolide microparticles: Preparation and characterization

Thrombin receptor agonist peptide (TRAP-6) could advantageously replace thrombin in terms of accelerating wound healing being less expensive and more stable. To promote TRAP-6 pharmacological action as a tissue reconstruction stimulator this study investigated its entrapment within poly(D,L)-lactide-co-glycolide (PLGA) microparticles. Due to its low molecular weight and water solubility, TRAP-6 microencapsulated form is expected to be more useful. This paper reports TRAP-6 microencapsulation by a double (w/o/w) emulsion-evaporation technique. TRAP-6 release kinetics were evaluated by both chemical (HPLC) and biological assays in vitro. The results revealed a high level of TRAP-6 sensitivity to physico-chemical events during the microencapsulation. The surface morphology difference between control microparticles (without TRAP-6) and microparticles with entrapped TRAP-6 during in vitro degradation highlighted a particular role of TRAP-6. The results can allow one to optimize the microencapsulation procedure and to encounter a new promising approach to development of biodegradable polymer drug delivery systems for wound healing.     

Sustained release and pharmacologic evaluation of human glucagon-like peptide-1 and liraglutide from polymeric microparticles

Abstract

The GLP1-receptor agonists exert regulatory key roles in diabetes, obesity and related complications. Here we aimed to develop polymeric microparticles loaded with homologous human GLP1 (7-37) or the analogue liraglutide. Peptide-loaded microparticles were prepared by a double emulsion and solvent evaporation process with a set of eight polymers based on lactide (PLA) or lactide-glycolide (PLGA), and evaluated for particle-size distribution, morphology, in vitro release and pharmacologic activity in mice. The resulting microparticles showed size distribution of about 30–50?μm. The in vitro kinetic release assays showed a sustained release of the peptides extending up to 30–40?days. In vivo evaluation in Swiss male mice revealed a similar extension of glycemic and body weight gain modulation for up to 25?days after a single subcutaneous administration of either hGLP1-microparticles or liraglutide-microparticles. Microparticles-loaded hGLP1 shows equivalent in vivo pharmacologic activity to the microparticles-loaded liraglutide.     

A New Mathematical Model Quantifying Drug Release from Bioerodible Microparticles Using Monte Carlo Simulations

Purpose. The major objectives of this study were to 1) develop a new mathematical model describing all phases of drug release from bioerodible microparticles; 2) evaluate the validity of the theory with experimental data; and 3) use the model to elucidate the release mechanisms in poly(lactide-co-glycolide acid)-based microspheres. Methods. 5-Fluorouracil-loaded microparticles were prepared with an oil-in-water solvent extraction technique and characterized in vitro. Monte Carlo simulations and sets of partial differential equations were used to describe the occurring chemical reactions and physical mass transport phenomena during drug release. Results. The new mathematical model considers drug dissolution, diffusion with nonconstant diffusivities and moving boundary conditions, polymer degradation/erosion, time-dependent system porosities, and the three-dimensional geometry of the devices. In contrast with previous theories, this model is able to describe the observed drug release kinetics accurately over the entire period of time, including 1) initial burst effects; 2) subsequent, approximately zero-order drug release phases; and 3) second rapid drug release phases. Important information, such as the evolution of the drug concentration profiles within the microparticles, can be calculated. Conclusions. A new, mechanistic mathematical model was developed that allows further insight into the release mechanisms in bioerodible microparticles.     

Nasal delivery of antisense oligonucleotides: in vitro evaluation of a thiomer/glutathione microparticulate delivery system

Purpose: The aim of this study was to develop a nasal mucoadhesive microparticulate delivery system for phosphorothioate antisense oligonucleotides (PTO-ODNs) utilizing the thiomer technology.

Methods: PTO-ODN microparticles, coated with either the mucoadhesive polymer polycarbophil-cysteine (PCP-Cys) or unmodified PCP and reduced glutathione (GSH) were prepared by the emulsification solvent evaporation technique. Particle size, drug load, decrease in thiol groups on microparticles, swelling properties, release of incorporated PTO-ODN, and mucoadhesive properties were examined. Permeation enhancing effect of the deployed thiomer conjugate was investigated on excised porcine respiratory mucosa of the nasal cavity.

Results: Results demonstrated that microparticles were almost of spherical structure displaying particle diameter up to 30?μm. In addition, a controlled drug release of the incorporated PTO-ODN was achieved from these particles. Mucoadhesion studies revealed that thiolated PCP-Cys microparticles display 3-fold higher mucoadhesive properties than the corresponding unthiolated polycarbophil microparticles. The uptake of PTO-ODN, incubated in thiolated polycarbophil and glutathione microparticles, from the nasal mucosa was 2.2-fold improved.

Conclusions: According to these results, the thiolated polycarbophil/reduced GSH microparticles might be a promising formulation for systemic delivery of PTO-ODNs via the nasal route.     

pH-Triggered Release of Macromolecules from Spray-Dried Polymethacrylate Microparticles

Purpose. pH-triggered microparticles release their therapeutic payloads at acidic pH (e.g., in the phagosome), making intracellular drug delivery more efficient. Here we modify lipid-based microparticles that are safe and efficacious in nerve and brain and are potentially inhalable, making them pH-triggerable by incorporating an acid-soluble polymethacrylate, Eudragit E100 (E100). Methods. Microparticles were produced by spray-drying and characterized by electron microscopy, Coulter counting, density measurement, and release kinetics of fluorescently labeled proteins. In addition, biocompatibility and cellular uptake were observed in rats. Results. Microparticles were spheroids 3 to 5 m in diameter with densities of 0.12 to 0.25 g/L. Microparticles with 20% (w/w) or more E100 demonstrated slow release of fluorescently labeled proteins at pH 7.4 but rapid release at pH 5. pH-triggerability was maintained for over 2 weeks in solution. Protein loadings of 0.2-20% (w/w) were pH-triggerable. Histologic examination of particles in rat connective tissue near nerve and muscle demonstrated biocompatibility aside from muscle edema in the cell layers adjacent to the particles and a localized inflammatory reaction with macrophages laden with microparticles. Conclusions. Microparticles containing E100 were pH-triggerable for many days and were taken up by macrophages, suggesting that they may be useful for intracellular drug delivery.     

Pharmaceutical Evaluation of Gas-Filled Microparticles as Gene Delivery System

Purpose. To produce and characterize a nonviral ultrasound-controlled release system of plasmid DNA (pDNA) encapsulated in gas-filled poly(D,L-lactide-co-glycolide) microparticles (PLGA-MPs). Methods. Different cationic polymers were used to form pDNA/polymer complexes to enhance the stability of pDNA during microparticle preparation. The physico-acoustical properties of the microparticles, particle size, pDNA integrity, encapsulation efficiency and pDNA release behavior were studied in vitro. Results. The microparticles had an average particle size of around 5 m. More than 50% of all microparticles contained a gas core, and when exposed to pulsed ultrasound as used for color Doppler imaging create a signal that yields typical color patterns (stimulated acoustic emission) as a result of the ultrasound-induced destruction of the microparticles. Thirty percent of the pDNA used was successfully encapsulated and approximately 10% of the encapsulated pDNA was released by ultrasound within 10 min. Conclusions. Plasmid DNA can be encapsulated in biodegradable gas-filled PLGA-MPs without hints for a structural disintegration. A pDNA release by ultrasound-induced microparticle-destruction could be shown in vitro.     

In vivo and in vitro characteristics for insulin-loaded PLA microparticles prepared by w/o/w solvent evaporation method with electrolytes in the continuous phase

Insulin-loaded poly(lactide) (PLA) microparticles were successfully prepared by 6% w/v PLA in the organic phase, 10% w/v PVP and varied types of 5%w/v electrolytes in the continuous phase, by using a water-in-oil-in-water emulsion/solvent extraction technique. Addition of electrolytes such as NaCl, CaCl₂ into the external phase significantly improved insulin entrapment efficiency compared to the case of no additives. NaCl was the most effective for obtaining high entrapment efficiency, with microparticle yield 81.2%, trapping efficiencies 49%, insulin-loading level 5.5% w/w and mean particle size 14.8?µm. The distribution (%) of insulin on the PLA microparticles surface, outer layer and core were 8, 37 and 43%, respectively. The cumulative release of insulin had an upper limit of ～24% of the insulin load at 24 days. A steady release rate was 0.5?µg insulin/mg microparticles/day of insulin release maintained for 24 days. Total protein-leaking amount was reduced after addition of electrolytes in the continuous aqueous phase. Rabbit glucose levels were evaluated after subcutaneous 20?mg insulin-loaded PLA microparticles or PLA blank microparticles. Study results show that the insulin-loaded PLA microparticles significantly reduced the glucose level than PLA blank microparticles. The insulin-loaded PLA microparticles, physicochemical characterization data and the animal result obtained in this study may be relevant in optimizing the PLA microparticle formulation incorporation and delivery insulin carriers.     

In vitro and in vivo evaluation of single-unit commercial immediate-and sustained-release capsules compared with multiple-unit polystyrene microparticles dosage forms of indomethacin

The objective of this study is to select a multiple-unit sustained-release formulation and to compare it with both commercial immediate and single unit sustained-release capsules and also to determine whether an in vitro-in vivo correlation exists for single- and multiple- unit formulations. Indomethacin (20-60% w/w)-loaded, multiple-unit polystyrene microparticles were prepared by emulsion-solvent evaporation method from an aqueous system. The in vitro release profiles obtained in phosphate buffer of pH 6.8 for drug-loaded polystyrene microparticles and for commercial sustained-release capsules (Indocap-SR, 75 mg) were compared. As the microparticles with 50% indomethacin load showed a release profile comparable to that of the Indocap-SR release profile, the microparticles with this drug load was considered as optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in human volunteers. In spite of significantly higher C(max), Ka, and Ke, and lower T(max), t1/2a, t1/2e and AUC(0 --> infinity)) values observed with commercial Microcid immediate-release capsules, there was no sign of difference among the listed parameters between optimized microparticles and Indocap-SR capsules. Indeed, the values of retard quotient (Rdelta) calculated from half-value duration analysis did not show any statistical difference, indicating the occurrence of an almost same degree of retardation of drug release from the optimized microparticles and the Indocap-SR capsules. Furthermore, linear relationship obtained between the percentages dissolved and absorbed suggests a means to predict in vivo absorption by measuring in vitro dissolution. The results suggest that the optimized polystyrene microparticles could provide an alternative controlled-release drug delivery system for indomethacin.     

PLA/PEG-PPG-PEG/Dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices,part 2: in vivo evaluation

Abstract

Hot-melt extrusion (HME) plays an important role in preparing implants as local drug delivery systems in pharmaceutical fields. Here, a new PLA/PEG-PPG-PEG/Dexamethasone (PLA/F68/Dex) implant prepared by HME has been developed. Importantly, the implant was successfully achieved to control release of immunosuppressive drug to an implanted device. In particular, this implant has not been reported previously in pharmaceutical fields. FTIR and XRD were adopted to investigate the properties of the samples. The in vivo release study showed that the maximum value of Dex release from the implants was approximately 50% at 1 month. The in vivo degradation behavior was determined by UV spectrophotometer and scanning electron microscopy studies, and the weight loss rate of the implants were up to 25% at 1 month. Furthermore, complete blood count (CBC) test, serum chemistry and major organs were performed, and there is no significant lesion and side effects observed in these results. Therefore, the results elucidated that the new PLA/F68/Dex implant prepared by HME could deliver an immunosuppressive drug to control the inflammatory reaction at the implant site.     

Assessment of formulated amodiaquine microparticles in Leishmania donovani infected rats

The aim of this study was to formulate, characterise and evaluate the activity of amodiaquine microparticles against Leishmania donovani. Microparticles were formulated by encapsulating the drug in bovine serum albumin using the spray-dryer method. The microparticles were evaluated for size, zeta potential, drug content, encapsulation efficiency and in vitro release profile. The size range of the microparticles formulated was between 1.9 and 10?μm with an average zeta potential of ?25.5?mV. Of the expected 20% drug loading, an average of 18.27% was obtained giving an encapsulation efficiency of 91.35%. Pharmacokinetic profile of amodiaquine improved with microencapsulation of the drug with C_max, AUC_0→48 and t_1//2 all significantly higher than amodiaquine solution. Amodiaquine microparticles showed an overall higher bioavailability and hence were more effective in eliminating intra-tissue parasites than the drug solution. It would therefore be expected that the formulated microparticles will be more effective in treating visceral leishmaniasis.     

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.     

Surface modification of poly (l-lactic acid) microspheres for site-specific delivery of ketoprofen for chronic inflammatory disease

The purpose of this research was to investigate the potential of surface modified Poly (l-lactic acid) (PLA) microspheres as a carrier for site-specific delivery of anti-inflammatory drug, ketoprofen, for the treatment of rheumatoid arthritis. Microspheres were prepared by solvent evaporation method using 20% w/w PLA in methylene chloride and 100 mL of a 2.5% poly vinyl alcohol (PVA) solution. Formulations were optimized for several processing parameters like drug to polymer ratio, stirring rate and volume of preparation medium etc. The surface of PLA microspheres was modified with gelatin to impart fibronectin recognition. The microspheres were characterized by surface morphology, size distribution, encapsulation efficiency, and by in vitro drug release studies. The prepared microspheres were light yellow, discrete, and spherical. Formulation with optimum drug to polymer ratio exhibited smallest vesicle size (43.02), high drug encapsulation efficiency (81.11) and better process yield (83.45). The release of drug was extended up to 24 h with Higuchi pattern of drug release. The in vivo results showed that the gelatin modified formulation reduced paw edema at greater extent than pure drug and PLA microspheres and it could be a promising carrier system for controlled and site-specific delivery of ketoprofen with possible clinical applications.     

Preparation of Biodegradable,Surface Engineered PLGA Nanospheres with Enhanced Lymphatic Drainage and Lymph Node Uptake

Purpose. Nanospheres can be utilised for the targeting of drugs and diagnostic agents to the regional lymph nodes. The surface modification of model polystyrene, (PS), and poly(lactide-co-glycolide),(PLGA), nanospheres by poly(lactide)-poly(ethylene glycol), (PLA:PEG), copolymers has been assessed by in vitro characterisation and in vivobiodistribution studies following subcutaneous administration of the nanospheres to the rat. Methods. Three PLA: PEG copolymers were investigated, with PEG chain lengths of 750, 2000 and 5000 Da. The PLA:PEG copolymers were either coated onto the surface of PS and PLGA nanospheres or used as a co-precipitate in the formation of PLGA-PLA:PEG nanospheres. Coating of the nanospheres was confirmed by an increase in their particle size and a corresponding decrease in the surface potential. The kinetics of injection site drainage and lymph node retention was determined over a 24 hour time course for naked, coated and co-precipitated nanosphere systems. Results. Dependent on the surface characteristics, the distribution of the nanospheres can be significantly modified and the lymph node localisation dramatically enhanced by coating their surfaces with PLA:PEG copolymers or by producing co-precipitate nanospheres of PLGA and PLA:PEG. Conclusions. A fully biodegradable nanosphere system has been developed with excellent lymph node targeting characteristics.     

Ciclosporin-loaded poly(lactide) microparticles: Effect of TPGS

Abstract

The properties of spray dried PLA microparticles were affected by the choice of solvents, amount of ciclosporin and TPGS added. Ethyl acetate formed microparticle with smooth surface when compared to those produced by dichloromethane. The results of FTIR have not shown chemical interaction amongst PLA, ciclosporin and TPGS while thermal analysis showed physical interactions amongst these components. TPGS was found to lower Tg value of PLA by exerting a plasticizing effect while ciclosporin reverted this effect. When the content of TPGS increased from 2% (w/w) to 10% (w/w), the microparticles tended to agglomerate due to the lowering of the polymer Tg values at the employed spray drying temperature. In addition, a lesser amount of ciclosporin was found at the surface of the microparticle and resulted in smaller initial release of ciclosporin. When 2% (w/w) TPGS was used, the initial release of ciclosporin was enhanced and the microparticles formed were not agglomerated.     

Ligand-Specific Targeting of Microspheres to Phagocytes by Surface Modification with Poly(L-Lysine)-Grafted Poly(Ethylene Glycol) Conjugate

Purpose. The purpose of this study was to demonstrate specific receptor-mediated targeting of phagocytes by functional surface coatings of microparticles, shielding from nonspecific phagocytosis and allowing ligand-specific interactions via molecular recognition. Methods. Coatings of the comb polymer poly(L-lysine)-g-poly(ethylene glycol) (PLL-g-PEG) were investigated for potential to inhibit 1) nonspecific spreading of human blood-derived macrophages (MOs) and dendritic cells (DCs) on glass and 2) nonspecific phagocytosis of PLL-g-PEG-coated, carboxylated polystyrene (PS) or biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres. Coating was performed by adsorption of positively charged PLL-g-PEG on negatively charged microparticles or plasma-cleaned glass through electrostatic interaction. The feasibility of ligand-specific interactions was tested with a model ligand, RGD, conjugated to PEG chains of PLL-g-PEG to form PLL-g-PEG-RGD and compared with inactive ligand conjugate, PLL-g-PEG-RDG. Results. Coatings with PLL-g-PEG largely impaired the adherence and spreading of MOs and DCs on glass. The repellent character of PLL-g-PEG coatings drastically reduced phagocytosis of coated PS and PLGA microparticles to 10% in presence of serum. With both MOs and DCs, we observed ligand-specific interactions with PLL-g-PEG-RGD coatings on glass and PS and PLGA microspheres. Ligand specificity was abolished when using inactive ligand conjugate PLL-g-PEG-RDG, whereas repellency of coating was maintained. Conclusions. Coatings of PLL-g-PEG-ligand conjugates provide a novel technology for ligand specific targeting of microspheres to MOs and DCs while reducing nonspecific phagocytosis.     

The preparation of sustained release erythropoietin microparticle

Purpose: Protein microencapsulation in biodegradable polymers is a promising route to provide for sustained release. The erythropoietin (EPO) microparticles are using human serum albumin (HSA) and poly-L-lysine (PK) as the protection complex to increased EPO integrity, entrapped efficiency and active EPO release by w/o/w solvent evaporation techniques. The optimum formulation development process was also reported by using FITC-OVA as a model protein.

Methods: The model protein FITC-ovalbumin and EPO are protected by human serum albumin and poly-L-lysine complex and encapsulated in 50:50 poly(DL-lactide-co-glycolide) by a w/o/w solvent evaporation method. Protein active integrity and degradation compound is measured by size-exclusion chromatography. Protein-loaded microparticle physical properties and in vitro active and degradation compounds release profile are characterized.

Results: High active integrity protein loading efficiency and particle yield of EPO or OVA-HSA/PK-loaded PLG microparticles are successfully produced by a w/o/w solvent evaporation method. Varied protection protein complex formulations and encapsulation processes are investigated. The high OVA model protein loading efficiency (80.2%), FITC-OVA content (0.24?µg?mg^?1) and yield (72.4%) are obtained by adding 100?µg?mL^?1 FITC-OVA complex with 10% HSA/0.05% PK (Mw 1.5–3?kD) in the initial solution to protect the model protein. In vitro release profiles show more active OVA release from HSA/PK OVA-loaded than OVA-loaded only microparticles and also the amount of degraded protein that comes out after 3 weeks incubated in the PBS medium for OVA-loaded only microparticles is observed. The same formulation and preparation process resulted in EPO loading efficiency (68.4%), EPO content (0.23?µg?mg^?1) and yield (76.1%) for HSA/PK EPO-loaded microparticles. In vitro release profiles show active EPO sustained release over 7 days. Using HSA/PK as carried in the primary emulsion of EPO-loaded microparticles resulted in less burst release% than EPO-loaded only microparticles.     

Chitosan microparticle preparation for controlled drug release by response surface methodology

The objectives were to investigate the effects of formulation variables on the release of drug and to optimize the formulation of chitosan microparticles loaded with drug for controlled release using response surface methodology. Chitosan microparticles were prepared by dropping a chitosan solution into sodium tripolyphosphate (TPP) through ionic cross-linking. The release behaviour of felodipine as a model drug was affected by preparation variables. A central composite design was used to evaluate and optimize the effect of preparation variables, chitosan concentration (X₁), the pH of the TPP solution (X₂) and cross-linking time (X₃) on the cumulative per cent drug release (Y) in 24 h. Chitosan concentration and cross-linking time affected negatively the release of felodipine, while the pH of the TPP did so positively and was the highest influential factor. The optimum rate of drug release, 100% in 24 h, was achieved at 1.8% chitosan concentration, a pH 8.7 for the TPP solution and 9.7 min cross-linking time.     

A novel in situ forming drug delivery system for controlled parenteral drug delivery

The objective of this study was to investigate the in vitro drug (diltiazem hydrochloride and buserelin acetate) release from different in situ forming biodegradable drug delivery systems, namely polymer solutions (in situ implants) and in situ microparticle (ISM) systems. The drug release from ISM systems [poly(d,l-lactide) (PLA) or poly(d,l-lactide-co-glycolide) (PLGA)-solution dispersed into an external oil phase] was investigated as a function of the type of solvent and polymer, polymer concentration and internal polymer phase:external oil phase ratio and was compared to the drug release from in situ implant systems and microparticles prepared by conventional methods (solvent evaporation or film grinding). Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles. The initial drug release from ISM systems decreased with increasing polymer concentration and decreasing polymer phase:external oil phase ratio. The type of biocompatible solvent also affected the drug release. It decreased in the rank order DMSO>NMP>2-pyrrolidone. In contrast to the release of the low molecular weight diltiazem hydrochloride, the peptide release (buserelin acetate) was strongly dependent on the polymer degradation/erosion. One advantage of the ISM system when compared to in situ implant systems was the significantly reduced burst effect because of the presence of an external oil phase. ISM systems resulted in drug release profiles comparable to the drug release of microparticles prepared by the solvent evaporation method. Therefore, the ISM systems are an attractive alternative to existing complicated microencapsulation methods.