Anhydrous Emulsion Research Articles

Formulation and processing of novel non-aqueous polyethylene glycol-in-silicone oil (o/o) phase change emulsions

Oil-in-oil phase change emulsions, composed of phase change materials (PCMs) dispersed in a continuous oily medium, have never been reported in the literature. The current study involves the formulation, stabilisation and characterisation of novel anhydrous emulsions of polyethylene glycol (PEG4000) as PCM in silicone oil. Emulsions with different dispersed phase concentrations were evaluated by analysing the viscous flow properties, optical microscopy and modulated differential scanning calorimetry. The results evidence that the emulsions can be pre-stabilised at 80 °C, under high shear conditions, by selecting an adequate silicone surfactant but undergo a severe destabilisation after a cooling and heating cycle. Nevertheless, a post-processing protocol (low shear agitation at 80 °C for 24 h) leads to thermal cycle resistant and storage stable non-aqueous dispersions. This process gives rise to a reduction of the shear-thinning character of the emulsion, shifts the melting and crystallization temperature of the PEG4000 to lower values and reduce its crystallinity. This is attributed to partial compatibility of the crystalline fraction of PEG4000 with other compounds of the emulsion.

METHOD DEVELOPMENT AND VALIDATION FOR ANALYSIS OF DEOXYARBUTININ ANHYDROUS EMULSION SYSTEM USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY

Objective: The aim of this study is to develop a simple, precise and accurate analytical method of deoxyarbutin in anhydrous emulsion system preparation.
 Methods: The analysis was conducted using high-performance liquid chromatography (HPLC). Chromatographic analysis was carried out using a reversed phase-C18 column. The mobile consists of two phases methanol and water (60: 40 v/v) at a flow rate of 1.0 ml/min. The determinations were performed using UV detector set at 225 nm. All validation procedures were added with hydroquinone as an internal standard.
 Results: The method showed coefficient correlation is 0.9978, relative standard deviation (RSD) smaller than 2%, Limit of Detection (LOD) and Limit of Quantitation (LOQ) are 0.599 µg/ml and 1.817 µg/ml respectively. The total amount deoxyarbutin in anhydrous emulsion preparation is 1.964+0.02 % with 98% recovery percentage.
 Conclusion: The developed HPLC analytical method meets the validation criteria made by International Conference on Harmonisation (ICH).

Topical treatment of experimental cutaneous leishmaniasis in golden hamster (Mesocricetus auratus) with formulations containing pentamidine

ABSTRACT Current treatment of cutaneous leishmaniasis (CL) relies mainly on pentavalent antimonials salts and second-line drugs include pentamidine and amphotericin B, but these therapies have side effects and require parenteral administration. The aim of this work was to evaluate the topical formulations containing pentamidine isethionate (PI) in the experimental treatment of cutaneous leishmaniasis (CL). Golden hamsters (Mesocricetus auratus) were infected in the nose with Leishmania (Leishmania) amazonensis. Six treatment groups received different topical treatments of anhydrous or hydrating emulsions, for a maximum of 10 days, with an application of 50 mg day-1. After treatment tissue samples of lesions were evaluated by histology, transmission electron microscopy and biopsy cultivation. Compared with untreated group, topical treatment with hydrating emulsion with 10% PI and usnic acid (ACE5AU) showed significantly decrease in volume lesion (P= 0.028) on 20th day after the end of the treatment with reduction of 27.37%. Topical treatment with anhydrous emulsion with 10% PI and usnic acid (ACPU) reduces parasite burden in Golden hamsters. This study demonstrated the potential of topical treatment to reduce the number of parasites that could be combined with others drugs and to have a faster and more effective treatment of cutaneous leishmaniasis.

Poly(L-glutamic acid) Microsphere: Preparation and Application in Oral Drug Controlled Release

Poly(L-glutamic acid) (PLG) and its derivatives, which are biodegradable and biocompatible, are one kind of the most widely investigated synthetic polypeptides as biomedical materials benefited from their pH-responsive property (pKa~ 4.1) and modifiable side carboxyl group. In this work, PLG was synthesized via a two-step procedure. Poly(γ-benzyl-L-glutamate) (PBLG) was first synthesized by the ring-opening polymerization of γ-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA) using n-hexylamine as initiator, and then PLG was prepared by the deprotection of benzyl groups in PBLG. PLG microsphere was prepared by the oil-in-oil (O/O) anhydrous emulsion method utilizing N,N-dimetylformamide as an inner oil phase and corn oil as an outer oil phase. Rifampicin, a model drug, was load- ed into the PLG microsphere, and the drug loading capacity and entrapment efficiency were revealed. The scanning electron microscopy micrograph indicated that the drug-loaded microsphere exhibited spherical morphology with narrow size distri- bution and average diameter at about 9.0 μm. To investigate the application of PLG microsphere in oral drug delivery (espe- cially for enteric-coated drugs), the in vitro rifampicin release experiments in simulated gastric or intestinal fluid were per- formed. In vitro release results revealed that the release of rifampicin from microsphere was highly dependent on pH. In de- tail, less amount of rifampicin was released in simulated gastric fluid, while the quicker release of rifampicin occurred in simulated intestinal fluid. It was because that the deprotonation of carboxyl groups in PLG caused the loose, expansion, and even disintegration of PLG microsphere in simulated intestinal fluid. Moreover, the morphology of microsphere in simulated gastric fluid was different from that in simulated intestinal fluid, which further confirmed the pH-sensitive property of mi- crosphere. Additionally, in vitro methyl thiazolyl tetrazolium assays demonstrated that the PLG microsphere was biocompat- ible. Therefore, the biocompatible PLG microsphere with the intelligent pH-triggered drug release should be promising for application in oral drug delivery. Keywords enteric carrier; poly(L-glutamic acid); oral administration; microsphere; drug delivery

Potential application of Non Aqueous Emulsion for drug delivery

Conventional emulsions are heterogeneous system in which one immiscible liquid is dispersed as droplets in another liquid. That may be water-in-oil or oil-in-water emulsions. However emulsion can be formulated waterless or without an aqueous phase to produce anhydrous or non-aqueous or oil-in-oil emulsions may be used as reservoirs to deliver lipophilic or hydrolytically unstable drugs, could be considered as depot formulations for sustained release drug delivery. Such systems, presence of water to be avoided. Some drugs are unstable or not soluble in water, formulation of such drug for oral administration has more difficult. Oral drug delivery vehicles must be capable of maintaining sufficient drug concentration in a bioavailable form that will enable expected absorption and biological activity. Such drug delivery vehicles must also be capable of maintaining the drug in its dissolved state and maintain stability of drug. This can be achieved by formulating the non aqueous emulsion. Most important factor considering formulation of stable anhydrous emulsion for oral delivery is concentration of surfactant. At high surfactant concentration may inhibit lipolysis and is disadvantageous to the intestinal mucous and has potential of causing local irritation side effects. So there is a need for such vehicle that will not comprise high and significant portion of surfactants that are irritating to the gastro intestinal mucous.

Water-dispersible non-aqueous emulsions stabilized by a poly(butadiene)-b-poly(2-vinylpyridine) block copolymer

Submicron non-aqueous emulsions, of interest for biomedical and cosmetic formulations, were developed for the system comprising poly(ethylene glycol) (PEG) 400 and Miglyol 812, an enzymatic degradable liquid glycerine ester. These emulsions, with PEG 400 as continuous phase and Miglyol 812 droplets, in the size range of 200 nm, were stabilized by a poly(butadiene)-b-poly(2-vinylpyridine) (PBut-b-P2VP) block copolymer with a composition close to 50/50 wt%. The droplet size, stability and the rheological characteristics were examined as a function of the copolymer concentration. An original aspect of these anhydrous emulsions, with a water miscible continuous phase, is their water dispersibility without additional surfactant. In fact, the initial anhydrous emulsion is sterically stabilized and after water addition at low pH, the protonated P2VP sequence of the copolymer provides the electro-steric stabilization. This oil-in-water emulsion is characterized by sub micron sized Miglyol 812 droplets in an aqueous phase of PEG 400 and water at pH 1. Des émulsions submicroniques non aqueuses, ayant des applications biomédicales et cosmétiques, ont été préparées pour le système poly(éthylène glycol) (PEG) 400/Miglyol 812, un triglycéride biocompatible. Ces émulsions, avec une phase continue PEG 400 et des gouttes dispersées de Miglyol 812 de 200 nm, sont stabilisées par un copolymère à blocs poly(butadiène)-b-poly(2vinylepyridine) (PBut-b-P2VP) ayant une composition massique proche de 50/50 wt%. La taille des gouttelettes, la stabilité et les caractéristiques viscoélastiques de ces émulsions ont été déterminées en fonction du taux en copolymère. Un aspect original de ces émulsions anhydres, ayant une phase continue miscible à l’eau, est de pouvoir les diluer, sans émulsifiant supplémentaire, par adjonction d’eau à pH 1. L’émulsion non aqueuse initiale est stabilisée stériquement par le copolymère, lequel, par protonation de la séquence P2VP à pH 1, assure la stabilisation électro-stérique de l’émulsion aqueuse comportant des gouttes submicroniques de Miglyol 812 dispersées dans une phase PEG 400/eau.

Optimized Artemether-loaded Anhydrous Emulsion

Objective: The objectives of this study were to identify stable anhydrous emulsions via pseudo ternary phase diagram, optimize artemether-loaded batches using factorial design and subsequently evaluate the antimalarial activity. Methodology: Using labrasol®, triacetin® and lauroglycol 90® as the surfactant, oil and co-surfactant respectively, pseudo ternary phase diagram was generated from the quantitative titration of water with the anhydrous emulsion. Stable combinations from the phase diagram were subjected to a 23 full factorial experimental design. The 22 software-generated formulations were experimentally formulated and characterized for droplet size, polydispersity index, viscosity and thermodynamic stability. Droplet size was chosen and subsequently fitted into the Response column of the software, thus prompting the generation of graphs and Desirability table of 125 predicted formulations. Out of the 125 predictions, three with the least droplet sizes (less than 100 nm) were adjudged as optimized batches. Subsequently, they were formulated, converted to powder by adsorption on magnesium aluminum metasilicate and evaluated. Antimalarial effectiveness of the drug-loaded formulation was also investigated. Results: Triacetin® most significantly (P<0.05) contributed to droplet size variation. The droplet size of the experimental formulations approximated that of the statistical predictions. The anhydrous emulsions (AEs) were powderable and the granulations rated fair and passable according to Carr’s scale. Artemether-loaded anhydrous emulsion (AE) demonstrated highest antimalarial activity. Conclusion: We therefore conclude that optimization proved a useful tool for the identification of excipient proportions with optimal effects.

Study on the Stability of DeoxyArbutin in an Anhydrous Emulsion Systemy

The skin-whitening agent, deoxyArbutin, is a potent tyrosinase inhibitor that is safer than hydroquinone and arbutin. However, it is thermolabile in aqueous solutions, where it decomposes to hydroquinone. Pharmaceutical and cosmetic emulsions are normally oil-in-water (o/w) or water-in-oil (w/o) systems; however, emulsions can be formulated with no aqueous phase to produce an anhydrous emulsion system. An anhydrous emulsion system could offer a stable vehicle for compounds that are sensitive to hydrolysis or oxidation. Therefore, to enhance the stability of deoxyArbutin in formulations, we chose the polyol-in-silicone, anhydrous emulsion system as the basic formulation for investigation. The quantity of deoxyArbutin and the accumulation of hydroquinone in both hydrous and anhydrous emulsions at various temperatures were analyzed through an established high performance liquid chromatographic (HPLC) method. The results indicated that water increased the decomposition of deoxyArbutin in the formulations and that the polyol-in-silicone, oil-based, anhydrous emulsion system provided a relatively stable surrounding for the deoxyArbutin that delayed its degradation at 25 °C and 45 °C. Moreover, the composition of the inner hydrophilic phase, containing different amounts of glycerin and propylene glycol, affected the stability of deoxyArbutin. Thus, these results will be beneficial when using deoxyArbutin in cosmetics and medicines in the future.

Novel anhydrous emulsions: Formulation as controlled release vehicles

Novel anhydrous emulsions, which may offer some advantages as depot or reservoir vehicles for lipophilic drugs in controlled delivery systems, were formulated using castor oil as the disperse phase and dimethicone or cyclopentasiloxane as the continuous phase. Among the emulsifiers studied only silicone surfactants (cyclomethicone/dimethicone copolyols) which were miscible in silicone oil stabilized the emulsions. Cyclomethicone/PEG/PPG-18/18 Dimethicone and Cyclopentasiloxane/PEG/PPG-18/18 Dimethicone were more effective in lowering the interfacial tension between castor oil and both dimethicone and cyclopentasiloxane. Emulsions formulated using either of these two surfactants were found to be stable against phase separation and exhibited least globule growth over 168 h. The average particle size was found to be 2–6 μm in these systems formed by probe sonication. Slow release patterns of 3H-dehydroepiandrosterone (DHEA) and 3H-dexamethasone solubilized in the disperse castor oil phase into an aqueous dialyzing medium were observed over 48 h.

In vitro and in vivo release properties of brilliant blue and tumour necrosis factor-alpha (TNF-alpha) from poly(D,L-lacticco-glycolic acid) multiphase microspheres

The dissolution properties of twomodel compounds, brilliant blue and tumour necrosis factor (TNF-alpha), from poly(D,L- .lactic-co-glycolic acid) (PLGA) multiphasemicrospheres wereinvestigated. In addition, the invivo releaseof TNF-alpha from the microspheres, in mice, was studied. The microspheres were prepared by an anhydrous multiple emulsion solvent evaporation method. Multiphase microspheres containing brilliant blue exhibited athree phase release profile in vitro, and displayed a significantly lower level of dye released during the initial phase compared to conventional matrix-type microspheres. Slow release of the dye was observed during the second phase, which was followed by a disintegration of the polymer wall during the third phase of the release process. In vitro dissolution profiles of TNF-alpha were calculated by compensation for the simultaneous degradation of the protein in the dissolution medium. The initial burst release of TNF-alpha was significantly reduced with the multiphase microspheres. The three phase release profile, as seen with the dye, was not observed for the microspheres containing the TNF-alpha. The rate of release of the protein from the microspheres was determined in vivo by analysing the residual level of TNF-alpha remaining in the particles following intraperitoneal administration of the microspheres to mice. The release of the protein from the microspheres in vivo was significantly faster than predicted from the results of the in vitro studies. The absence of an initial burst release of TNF-alpha from the multiphase microspheres was reflected in a significant reduction in the plasma level of TNF-alpha when compared to the matrix-type microspheres and a solution of the protein. The controlled release property of the multiphase microspheres is expected to overcome the adverse reactions due to dose dumping that occurs following the local administration of TNF-alpha.

Particle size and loading efficiency of poly(D,L-lactic-coglycolic acid) multiphase microspheres containing water soluble substances prepared by the hydrous and anhydrous solvent evaporation methods

PLGA multiphase microspheres were prepared by the multiple emulsion solvent evaporation method using acetonitrile as the polymer solvent and mineral oil as the evaporation medium. The preparation process was further developed in the present study to reduce the particle size and to increase the loading capacity of brilliant blue, bovine serum albumin (BSA) and tumour necrosis factor-alpha (TNF-alpha) which were used as water soluble model drug substances. Sorbitan sesqui-oleate (SO-15EX), present at the 1% w/w level in the evaporation medium, prevented agglomeration of the microspheres containing a solid-in-oil (S/O) suspension as the core phase. This S/O suspension core provided significantly higher loading efficiency of the proteins to the W/O emulsion core. The W/O emulsion system resulted in agglomeration of the protein-loaded microspheres and the loading efficiency decreased significantly. When brilliant blue was included as the model compound, the loading efficiencies were not influenced by the core type. Heavy mineral oil was employed to stabilize the dispersed unhardened microspheres rather than light mineral oil that was reported previously. This anhydrous emulsion system employing the S/O suspension core and containing a dispersion of TNF-alpha enabled the encapsulation of this protein without loss of activity. It was concluded that the anhydrous emulsion system is asuitable approach toprepare multiple microspheres as an alternative to the W/O emulsion system, especially when solvent sensitive proteins are incorporated into the microspheres.

Mould release agent for PU foams

Oil-in-oil phase change emulsions, composed of phase change materials (PCMs) dispersed in a continuous oily medium, have never been reported in the literature. The current study involves the formulation, stabilisation and characterisation of novel anhydrous emulsions of polyethylene glycol (PEG4000) as PCM in silicone oil. Emulsions with different dispersed phase concentrations were evaluated by analysing the viscous flow properties, optical microscopy and modulated differential scanning calorimetry. The results evidence that the emulsions can be pre-stabilised at 80 °C, under high shear conditions, by selecting an adequate silicone surfactant but undergo a severe destabilisation after a cooling and heating cycle. Nevertheless, a post-processing protocol (low shear agitation at 80 °C for 24 h) leads to thermal cycle resistant and storage stable non-aqueous dispersions. This process gives rise to a reduction of the shear-thinning character of the emulsion, shifts the melting and crystallization temperature of the PEG4000 to lower values and reduce its crystallinity. This is attributed to partial compatibility of the crystalline fraction of PEG4000 with other compounds of the emulsion.

A stable, radioactive substrate emulsion for assay of lipoprotein lipase

A method is described for the assay of lipoprotein lipase, using a stable, radioactive substrate emulsion. Fatty acid-labeled trioleoylglycerol was emulsified by homogenization in glycerol with lecithin as detergent. This anhydrous emulsion was stable for at least six weeks. Substrate solutions for enzyme assay were prepared by diluting the emulsion with buffer containing serum and albumin. The fatty acid produced on hydrolysis was isolated in a one-step liquid-liquid partition system. Incubations with extracts of acetone powders from adipose tissue displayed characteristics of lipoprotein lipase activity, i.e., serum dependence and inhibition by NaCl and protamine. The method is rapid (less than 1 hour), sensitive and reproducible, and suitable for routine use.