RESUMO
CONTEXT: Ethylcellulose is commonly dissolved in a solvent or formed into an aqueous dispersion and sprayed onto various dosage forms to form a barrier membrane to provide controlled release in pharmaceutical formulations. Due to the variety of solvents utilized in the pharmaceutical industry and the importance solvent can play on film formation and film strength it is critical to understand how solvent can influence these parameters. OBJECTIVE: To systematically study a variety of solvent blends and how these solvent blends influence ethylcellulose film formation, physical and mechanical film properties and solution properties such as clarity and viscosity. MATERIALS AND METHODS: Using high throughput capabilities and evaporation rate modeling, thirty-one different solvent blends composed of ethanol, isopropanol, acetone, methanol, and/or water were formulated, analyzed for viscosity and clarity, and narrowed down to four solvent blends. Brookfield viscosity, film casting, mechanical film testing and water permeation were also completed. RESULTS AND DISCUSSION: High throughput analysis identified isopropanol/water, ethanol, ethanol/water and methanol/acetone/water as solvent blends with unique clarity and viscosity values. Evaporation rate modeling further rank ordered these candidates from excellent to poor interaction with ethylcellulose. Isopropanol/water was identified as the most suitable solvent blend for ethylcellulose due to azeotrope formation during evaporation, which resulted in a solvent-rich phase allowing the ethylcellulose polymer chains to remain maximally extended during film formation. Consequently, the highest clarity and most ductile films were formed. CONCLUSION: Employing high throughput capabilities paired with evaporation rate modeling allowed strong predictions between solvent interaction with ethylcellulose and mechanical film properties.
Assuntos
2-Propanol/química , Celulose/análogos & derivados , Etanol/química , Solventes/química , Água/química , Celulose/química , Química Farmacêutica , Soluções , ViscosidadeRESUMO
This three-part review has been developed following the evaluation of literature where ethylcellulose, methylcellulose, or hypromellose was used to make microcapsules. Parts 1 and 2 of the review are published in separate papers. Part 1 covers the various materials used to formulate microcapsules, and Part 2 covers the various techniques used to make microcapsules. In the current paper, Part 3 covers the end-use applications for which microcapsules are used. Examples of applications to be covered include modified release, improved efficacy and safety, multiparticulate compression, improved processability and stability, and taste- and odor-masking. It is hoped that formulators can use Part 3 to understand the various end-use applications of microcapsules made from these encapsulating polymers. SciFinder was utilized to perform the literature search. SciFinder leverages literature databases, such as Chemical Abstracts Service Registry and Medline. A total of 379 references were identified during the review. The need for a three-part review reflects the extensive amount of literature identified concerning these three encapsulating polymers.
Assuntos
Cápsulas/química , Celulose/análogos & derivados , Preparações de Ação Retardada/química , Metilcelulose/análogos & derivados , Metilcelulose/química , Celulose/química , Composição de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Derivados da Hipromelose , Cinética , Modelos Teóricos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
This review highlights references where ethylcellulose, methylcellulose and hypromellose were used to make microcapsules. The review has been divided into three parts. This first part discusses various materials used to formulate microcapsules, such as the three encapsulating polymers as well as protective colloids, plasticizers and surfactants. The second part covers the various techniques used to make microcapsules, such as temperature-induced phase separation, emulsion solvent evaporation, solvent evaporation, film coating, and others. The third part covers the various applications for which microcapsules are used, such as modified release, improved efficacy and safety, taste- and odor-masking, and others. It is hoped that formulators can use Part 1 as a guide to the literature documenting formulation of microcapsules made from these encapsulating polymers. SciFinder was utilized to identify the pertinent literature. SciFinder leverages literature databases, such as Chemical Abstracts Service Registry and Medline. A total of 379 references were identified during the review. The need for a three-part review reflects the extensive amount of literature identified concerning these three encapsulating polymers.
Assuntos
Cápsulas/química , Celulose/análogos & derivados , Composição de Medicamentos/métodos , Metilcelulose/análogos & derivados , Metilcelulose/química , Celulose/química , Preparações de Ação Retardada , Humanos , Derivados da Hipromelose , Tamanho da PartículaRESUMO
This three-part review has been developed following the evaluation of literature where ethylcellulose, methylcellulose or hypromellose was used to make microcapsules. Parts 1 and 3 of the review are published as separate papers. Part 1 covers the various materials used to formulate microcapsules, and Part 3 covers the various end-use applications for microcapsules. In the current paper, Part 2 covers the techniques used to make microcapsules. Examples of techniques to be covered include temperature-induced phase separation, emulsion solvent evaporation, solvent evaporation, film coating, nonsolvent addition and spray drying. It is hoped that formulators can use Part 2 to understand how to formulate microcapsules using these encapsulating polymers. SciFinder was utilized to perform the literature search. SciFinder leverages literature databases, such as Chemical Abstracts Service Registry and Medline. A total of 379 references were identified during the review. The need for a three-part review reflects the extensive amount of literature identified concerning these three encapsulating polymers.
Assuntos
Celulose/análogos & derivados , Composição de Medicamentos/métodos , Metilcelulose/análogos & derivados , Metilcelulose/química , Cápsulas , Celulose/química , Derivados da Hipromelose , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Controlled precipitation produced aqueous nanoparticle suspensions of a poorly water soluble drug, itraconazole (ITZ), in an amorphous state, despite unusually high potencies (drug weight/total weight) of up to 94%. Adsorption of the amphiphilic stabilizer hydroxypropylmethylcellulose (HPMC) at the particle-aqueous solution interface arrested particle growth, producing surface areas from 13 to 51 m(2)/g. Dissolution of the particles in acidic media yielded high plateau levels in supersaturation up to 90 times the equilibrium solubility. The degree of supersaturation increased with particle curvature, as characterized by the surface area and described qualitatively by the Kelvin equation. A thermodynamic analysis indicated HPMC maintained amorphous ITZ in the solid phase with a fugacity 90 times the crystalline value, while it did not influence the fugacity of ITZ in the aqueous phase. High surface areas led to more rapid and levels of supersaturation higher than those seen for low-surface area solid dispersions, which undergo crystallization during slow dissolution. The rapid generation of high levels of supersaturation with potent amorphous nanoparticles, containing small amounts of stabilizers oriented at the particle surface, offers new opportunities for improving bioavailability of poorly water soluble drugs.
Assuntos
Desenho de Fármacos , Nanopartículas/química , Soluções Tampão , Gases , Microscopia Eletrônica de Varredura , Nanopartículas/ultraestrutura , Pós , Solubilidade , Solventes , Espectrofotometria , Propriedades de Superfície , Fatores de Tempo , Difração de Raios XRESUMO
Rapid dissolution rates of nanocrystal suspensions of the poorly water-soluble drugs, danazol and itraconazole were measured continuously by in-situ turbidimetry. For pre-wetted suspensions of 300 nm particles, dissolution half-lives as short as a few seconds were determined upon adding surfactant to initiate dissolution. A mass transfer model is presented to determine the particle size distribution and dissolution rate in terms of two steps: interfacial reaction, consisting of micelle uptake and desorption, followed by diffusion of the drug-loaded micelles. The interfacial reaction rate constant, k(S), regressed from turbidity versus time data, in conjunction with the Mie theory of light scattering, was independent of particle size. Therefore, dissolution rate data for micron-sized drug particles, which are widely available, may be used to predict the behavior for submicron particle sizes down to 100 nm. The micellar solubility and k(S) are significantly smaller for itraconazole than danazol, consistent with itraconazole's larger molecular size. For particles smaller than 1 mum, the interfacial reaction resistance was dominant. Since this resistance has received little attention in previous studies, further emphasis on the design of drug nanoparticles with more rapid interfacial reaction offers the possibility of improvements in dissolution rates.
Assuntos
Nanopartículas/química , Preparações Farmacêuticas/química , Algoritmos , Ácidos e Sais Biliares , Danazol/química , Difusão , Itraconazol/química , Cinética , Micelas , Modelos Químicos , Nefelometria e Turbidimetria , Tamanho da Partícula , Dodecilsulfato de Sódio , Solubilidade , TensoativosRESUMO
The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.
Assuntos
Composição de Medicamentos/métodos , Nanopartículas , Administração por Inalação , Aerossóis , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Disponibilidade Biológica , Congelamento , Inalação , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Varredura , Pós , Solubilidade , Soluções , Água , Difração de Raios XRESUMO
PURPOSE: Poorly water-soluble compounds are being found with increasing frequency among pharmacologically active new chemical entities, which is a major concern to the pharmaceutical industry. Some particle engineering technologies have been shown to enhance the dissolution of many promising new compounds that perform poorly in formulation and clinical studies (Rogers et. al., Drug Dev Ind Pharm 27:1003-1015). One novel technology, controlled precipitation, shows significant potential for enhancing the dissolution of poorly soluble compounds. In this study, controlled precipitation is introduced; and process variables, such as mixing zone temperature, are investigated. Finally, scale-up of controlled precipitation from milligram or gram to kilogram quantities is demonstrated. METHODS: Dissolution enhancement capabilities were established using two poorly water-soluble model drugs, danazol and naproxen. Stabilized drug particles from controlled precipitation were compared to milled, physical blend, and bulk drug controls using particle size analysis (Coulter), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), dissolution testing (USP Apparatus 2), and residual solvent analysis. RESULTS: Stabilized nano- and microparticles were produced from controlled precipitation. XRD and SEM analyses confirmed that the drug particles were crystalline. Furthermore, the stabilized particles from controlled precipitation exhibited significantly enhanced dissolution properties. Residual solvent levels were below FDA limits. CONCLUSIONS: Controlled precipitation is a viable and scalable technology that can be used to enhance the dissolution of poorly water-soluble pharmaceutical compounds.
Assuntos
Química Farmacêutica/métodos , Preparações Farmacêuticas/química , Cromatografia Líquida de Alta Pressão , Danazol/química , Composição de Medicamentos , Microscopia Eletrônica de Varredura , Microesferas , Naproxeno/química , Tamanho da Partícula , Solubilidade , Solventes , Difração de Raios XRESUMO
PURPOSE: The objective of this study was to investigate the physical stability of micronized powders produced by the spray-freezing into liquid (SFL) particle engineeringtechnology. MATERIALS AND METHODS: Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 to form a cosolvent solution that was SFL processed. The dried micronized SFL powders were sealed in glass vials with desiccant and exposed to 25 degrees C/60% RH for 3 and 6 mo, 40 degrees C/75% RH for 1, 2, 3, and 6 mo, and conditions where the temperature was cycled between -5 and +40 degrees C (6 cycles/24 hr) with constant 75% RH for 1, 2, 3 and 4 wk. The samples were characterized by using Karl-Fisher titration, differential scanning calorimetry, x-ray diffraction, specific surface area, scanning electron microscopy, and dissolution testing. RESULTS: Micronized SFL powders consisting of porous aggregates with small-particle domains were characterized as having high surface areas and consisted of amorphous danazol embedded within a hydrophilic excipient matrix. Karl-Fischer titration revealed no moisture absorption over the duration of the stability studies. Differential scanning calorimetry studies demonstrated high degrees of molecular interactions between danazol, PVA, poloxamer, and PVP. Scanning electron microscopy studies confirmed these interactions, especially those between danazol and poloxamer. These interactions facilitated API dissolution in the aqueous media. Powder surface area remained constant during storage at the various stability conditions, and danazol recrystallization did not occur during the entirety of the stability studies. Micronized SFL powders containing danazol dissolved rapidly and completely within 5 min in aqueous media. No differences were observed in the enhanced dissolution profiles of danazol after exposure to the storage conditions investigated. Physically stable micronized powders produced by the SFL particle engineering technology were produced for the purpose of enhancing the dissolution of an insoluble drug. CONCLUSIONS: The potential of the SFL particle-engineering technology as a micronization technique for enhancing the dissolution of hydrophobic drugs was demonstrated in this study. The robustness of the micronized SFL powders to withstand stressed storage conditions was shown.
Assuntos
Composição de Medicamentos/métodos , Pós/química , Varredura Diferencial de Calorimetria , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Excipientes , Congelamento , Umidade , Solubilidade , Soluções , Temperatura , Difração de Raios XRESUMO
PURPOSE: The purpose of this work was to investigate spray-freezing into liquid (SFL) and atmospheric freeze-drying (ATMFD) as industrial processes for producing micronized SFL powders with enhanced aqueous dissolution. Micronized SFL powders dried by ATMFD were compared with vacuum freeze-dried SFL powders. METHOD: Danazol was formulated with polyvinyl alcohol (MW 22,000), polyvinylpyrrolidone K-15, and poloxamer 407 to produce micronized SFL powders that were freeze-dried under vacuum or dried by ATMFD. The powders were characterized using Karl-Fischer titration, gas chromatography, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, surface area, and dissolution testing (SLS 0.75%/Tris 1.21% buffer media). RESULTS: Micronized SFL powders containing amorphous drug were successfully dried using the ATMFD process. Micronized SFL powders contained less than 5% w/w and 50 ppm of residual water and organic solvent, respectively, which were similar to those contents detected in a co-ground physical mixture of similar composition. Micronized SFL powders dried by ATMFD had lower surface areas than powders produced by vacuum freeze-drying (5.7 vs. 8.9 m2/g) but significantly greater surface areas than the micronized bulk drug (0.5 m2/g) and co-ground physical mixture (1.9 m2/g). Rapid wetting and dissolution occurred when the SFL powders were introduced into the dissolution media. By 5 min, 100% dissolution of danazol from the ATMFD-micronized SFL powder had occurred, which was similar to the dissolution profile of the vacuum freeze-dried SFL powder. CONCLUSIONS: Vacuum freeze-drying is not a preferred technique in the pharmaceutical industry because of scalability and high-cost concerns. The ATMFD process enables commercialization of the SFL particle-engineering technology as a micronization method to enhance dissolution of hydrophobic drugs.
Assuntos
Pós/química , Solventes/química , Água/química , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Danazol/química , Liofilização , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Solubilidade , Tecnologia Farmacêutica , Temperatura , Difração de Raios XRESUMO
The purpose of this paper is to investigate the influence of the emulsion composition of the feed liquid on physicochemical characteristics of drug-loaded powders produced by spray-freezing into liquid (SFL) micronization, and to compare the SFL emulsion process to the SFL solution process. Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 in a 2:1:1:1 weight ratio (40% active pharmaceutical ingredient (API) potency based on dry weight). Emulsions were formulated in ratios up to 20:1:1:1 (87% API potency based on dry weight). Ethyl acetate/water or dichloromethane/water mixtures were used to produce o/w emulsions for SFL micronization, and a tetrahydrofuran/water mixture was used to formulate the feed solutions. Micronized SFL powders were characterized by X-ray diffraction, surface area, scanning and transmission electron microscopy, contact angle and dissolution. Emulsions containing danazol in the internal oil phase and processed by SFL produced micronized powders containing amorphous drug. The surface area increased as drug and excipient concentrations were increased. Surface areas ranged from 8.9 m(2)/g (SFL powder from solution) to 83.1 m(2)/g (SFL powder from emulsion). Danazol contained in micronized SFL powders from emulsion and solution was 100% dissolved in the dissolution media within 2 min, which was significantly faster than the dissolution of non-SFL processed controls investigated (<50% in 2 min). Micronized SFL powders produced from emulsion had similar dissolution enhancement compared to those produced from solution, but higher quantities could be SFL processed from emulsions. Potencies of up to 87% yielded powders with rapid wetting and dissolution when utilizing feed emulsions instead of solutions. Large-scale SFL product batches were manufactured using lower solvent quantities and higher drug concentrations via emulsion formulations, thus demonstrating the usefulness of the SFL micronization technology in pharmaceutical development.
Assuntos
Preparações Farmacêuticas/química , Pós/química , Danazol/química , Emulsões/química , Excipientes/química , Congelamento , Microscopia Eletrônica , Tamanho da Partícula , Poloxâmero/química , Álcool de Polivinil/química , Povidona/química , Solubilidade , Solventes/química , Tecnologia Farmacêutica , Água/química , Difração de Raios XRESUMO
A novel cryogenic spray-freezing into liquid (SFL) process was developed to produce microparticulate powders consisting of an active pharmaceutical ingredient (API) molecularly embedded within a pharmaceutical excipient matrix. In the SFL process, a feed solution containing the API was atomized beneath the surface of a cryogenic liquid such that the liquid-liquid impingement between the feed and cryogenic liquids resulted in intense atomization into microdroplets, which were frozen instantaneously into microparticles. The SFL micronized powder was obtained following lyophilization of the frozen microparticles. The objective of this study was to develop a particle engineering technology to produce micronized powders of the hydrophobic drug, danazol, complexed with hydroxypropyl-beta-cyclodextrin (HPbetaCD) and to compare these SFL micronized powders to inclusion complex powders produced from other techniques, such as co-grinding of dry powder mixtures and lyophilization of bulk solutions. Danazol and HPbetaCD were dissolved in a water/tetrahydrofuran cosolvent mixture prior to SFL processing or slow freezing. Identical quantities of the API and HPbetaCD used in the solutions were co-ground in a mortar and pestle and blended to produce a co-ground physical mixture for comparison. The powder samples were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy, surface area analysis, and dissolution testing. The results provided by DSC, XRD, and FTIR suggested the formation of inclusion complexes by both slow-freezing and SFL. However, the specific surface area was significantly higher for the latter. Dissolution results suggested that equilibration of the danazol/HPbetaCD solution prior to SFL processing was required to produce the most soluble conformation of the resulting inclusion complex following SFL. SFL micronized powders exhibited better dissolution profiles than the slowly frozen aggregate powder. Results indicated that micronized SFL inclusion complex powders dissolved faster in aqueous dissolution media than inclusion complexes formed by conventional techniques due to higher surface areas and stabilized inclusion complexes obtained by ultra-rapid freezing.
Assuntos
Pós/química , Tecnologia Farmacêutica/métodos , Água/química , Congelamento , SolubilidadeRESUMO
PURPOSE: To develop and demonstrate a novel particle engineering technology, spray freezing into liquid (SFL), to enhance the dissolution rates of poorly water-soluble active pharmaceutical ingredients (APIs). METHODS: Model APIs, danazol or carbamazepine with or without excipients, were dissolved in a tetrahydrofuran/water cosolvent system and atomized through a nozzle beneath the surface of liquid nitrogen to produce small frozen droplets, which were subsequently lyophilized. The physicochemical properties of the SFL powders and controls were characterized by X-ray diffraction, scanning electron microscopy (SEM), particle size distribution, surface area analysis, contact angle measurement, and dissolution. RESULTS: The X-ray diffraction pattern indicated that SFL powders containing either danazol or carbamazepine were amorphous. SEM micrographs indicated that SFL particles were highly porous. The mean particle diameter of SFL carbamazepine/SLS powder was about 7 microm. The surface area of SFL danazol/poloxamer 407 powder was 11.04 m2/g. The dissolution of SFL danazol/poloxamer 407 powder at 10 min was about 99%. The SFL powders were free flowing and had good physical and chemical stability after being stored at 25 degrees C/60%RH for 2 months. CONCLUSIONS: The novel SFL technology was demonstrated to produce nanostructured amorphous highly porous particles of poorly water soluble APIs with significantly enhanced wetting and dissolution rates.
Assuntos
Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Água/química , Composição de Medicamentos , Congelamento , Tamanho da Partícula , Solubilidade , Tecnologia Farmacêutica/instrumentaçãoRESUMO
Spray-freezing into liquid (SFL) is a novel particle engineering technology where a feed solution containing an active pharmaceutical ingredient (API) and pharmaceutical excipient(s) is atomized beneath the surface of a cryogenic liquid, such as liquid nitrogen. Intense atomization results from the impingement that occurs between the liquid feed and the cryogenic liquid. The atomized feed droplets instantly solidify within the liquid nitrogen continuous phase to form a suspension. The frozen microparticles are then collected and lyophilized to obtain the dry SFL micronized powder. The novel SFL process has been used in this study to enhance the dissolution rates of two poorly water soluble APIs, carbamazepine and danazol. The SFL process has also been used to produce stable peptide particles of insulin.
Assuntos
Composição de Medicamentos/métodos , Microesferas , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Danazol/administração & dosagem , Danazol/química , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/química , Excipientes , Congelamento , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Insulina/administração & dosagem , Insulina/química , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Pós , SolubilidadeRESUMO
The objective of this study is to evaluate excipient type on the physicochemical properties of insulin microparticles produced by spray freezing into liquid (SFL). A novel process was developed to produce microparticles containing bioactive peptides and proteins. The microparticles were formed by atomization of an aqueous feed solution containing insulin beneath the surface of a cryogenic liquid (e.g. liquid nitrogen). In this study, bovine insulin was dissolved in deionized water alone or with tyloxapol, lactose or trehalose. The aqueous solution was sprayed directly into liquid nitrogen through a polyetheretherketone capillary nozzle under high pressure to form frozen microparticles. Lyophilization was used to sublime the ice. The SFL insulin powder was characterized by different techniques, including X-ray diffraction, reverse-phase high pressure liquid chromatography, size exclusion chromatography, scanning electron microscopy (SEM), particle size distribution and surface area. The mean diameter of the insulin microparticles was 5-7 microm. SEM revealed that the microparticles were highly porous, and the morphology of the microparticles was influenced by the excipient type. The total surface area of the insulin microparticles ranged from 20 to 40 m(2)/g, and the magnitude depended on the specific composition and total solids content of the aqueous feed solution. X-ray diffraction results indicated lack of crystallinity. No change in the level of the degradation product, A-21 desamido insulin, was found in the SFL insulin samples processed alone or with trehalose or tyloxapol. Similarly, no change in formation of high molecular weight transformation products (e.g. covalent insulin dimer) was detected in the samples processed with excipients. The results demonstrated that SFL is a feasible technique for forming porous microparticles containing insulin. The physicochemical properties of insulin were preserved by the SFL technique.