Multiple Emulsion Formulations Research Articles

マルチプルエマルションの調製と特徴

マルチプルエマルションの調製と特徴

Oral multiple w/o/w emulsion formulation of a peptide salmon calcitonin: in vitro-in vivo evaluation.

Salmon calcitonin (sCT) is a polypeptide hormone consisting of 32 amino acid residues (MW approx. 3400 Da), which can be used successfully for the treatment of osteoporosis, Paget's disease and hypercalcaemia. Only nasal and parenteral preparations of sCT are currently available, and as injections are poorly accepted by patients, nonparenteral preparations for oral, rectal and nasal administration are highly desirable. However, oral sCT is poorly bioavailable, being susceptible to enzymatic degradation in the gastrointestinal tract. To design a formulation of sCT suitable for oral use. A water/oil/water (w/o/w) type multiple emulsion formulation was designed for oral application of sCT. sCT was placed in the inner water phase, and a protease inhibitor, aprotinin, was included in the outer water phase of this system to investigate the influence of protease inhibitors in the presence of sCT. The effectiveness of the formulation was evaluated in vitro by placing emulsion samples in a dialysis medium and in vivo by using a rat model. Incorporating sCT in the inner aqueous phase of a w/o/w emulsion appears to protect the peptide from enzymatic degradation. sCT was further protected by incorporating the protease inhibitor, aprotinin, in the outer aqueous phase. w/o/w emulsion formulations appear to be promising carrier systems for peptide-protein drugs.

Concanavalin-A Conjugated Fine-Multiple Emulsion Loaded with 6-Mercaptopurine

Fine-multiple (water-in-oil-in-water) emulsions were prepared by two-step emulsification using sonication. They were coated with concanavalin-A (Con-A) by three methods. The one involving covalent coupling of Con-A to the multiple emulsion incorporated anchor was better compared with lipid derivatized Con-A anchoring or the glutaraldehyde-based cross-linking method, as shown by the faster rate of dextran-induced aggregation. The selected multiple emulsions were characterized by physical properties such as droplet size, encapsulation efficiency, and zeta potential. Stability parameters such as droplet size, creaming, leakage, and aggregation as a function of relative turbidity were monitored over a 1-month period, which revealed good stability of the formulations. The release profile of 6-mercaptopurine followed zero-order kinetics. Pharmacokinetic studies showed an increase in half-life and bioavailability from multiple emulsion formulations administered intravenously. There was prolonged retention of drug in various tissues of rats when treated with Con-A-coated multiple emulsion as compared with uncoated one. Our study demonstrates the suitability of fine-multiple emulsion for intravenous administration and the potential for prolonged retention of drugs and targeting in biological systems.

Peptide vaccination using nonionic block copolymers induces protective anti-viral CTL responses

High molecular weight nonionic block copolymers have been developed as vaccine adjuvants. We employed these adjuvants in water-in-oil emulsion and multiple emulsion formulations with a synthetic peptide-based antigen vaccine to test their ability to prime anti-viral CD8 + T cell responses. Vaccines were made using the H-2 d-restricted immunodominant peptide from lymphocytic choriomeningitis virus (LCMV), NP118–126, and administered to BALB/c ByJ (H-2 d) mice. Peptide-containing emulsions were able to induce NP118–126 specific CTL and IFN-γ secreting CD8 + T cells in the vaccinated mice and these responses were maintained for at least 90 days post immunization. At all times, the responses induced by the copolymer formulations were equal to, or better than, formulations based on incomplete Freund's adjuvant (IFA). In addition, the responses induced by prophylactic vaccination using the multiple emulsion formulation resulted in accelerated viral clearance following infection with a strain of LCMV (clone 13) that causes a persistent infection in naı̈ve adult mice. These results indicate that peptide vaccination using a formulation based on high molecular weight nonionic block copolymer in a simple water-in-oil or a multiple emulsion format can induce virus-specific CD8 + T cell responses and confer protection sufficient enough to prevent the establishment of a persistent infection.

Characterization of the mechanical properties of a water/oil/water multiple emulsion oily membrane by a micropipette aspiration technique

The main goal of this paper was to apply to water/oil/water (w/o/w) multiple emulsions the micropipette aspiration method, which is known as one of the most adopted techniques to study globule or cell deformability. It consists in aspirating, step by step, an individual oily globule into a cylindrical glass tube under well-controlled conditions of aspiration. This method provides some physical parameters of the oily membrane. This micromanipulation technique was applied to various multiple emulsion formulations in order to evaluate both the elastic properties and the interfacial tension of the oily membrane as a function of the lipophilic surfactant concentration. It was shown that the elastic shear modulus and the interfacial tension of the oily membrane increased with the lipophilic surfactant concentration. The analysis of the behavior of the multiple emulsion during a swelling-breakdown and release kinetics confirmed these results. This rigidification of the membrane could be produced during the second step of the preparation of the multiple emulsion, by a migration of the lipophilic surfactant to the interface between the oily and the external aqueous phases.

Kinetics of swelling–breakdown of a W/O/W multiple emulsion: possible mechanisms for the lipophilic surfactant effect

The properties and behavior of a W/O/W multiple emulsion formulation were analyzed during a swelling–breakdown process. Various experimental analyses, such as granulometry, rheology and conductimetry were performed, as well as a micropipette aspiration method. The predominant role of the lipophilic surfactant during the swelling phase was confirmed. Two different mechanisms can be proposed. Both imply the migration of the lipophilic surfactant from one interface to another and probably take place successively. The lipophilic surfactant could diffuse from the first to the second interface, thus rigidifying the membrane, or from the oily phase to the first interface, resulting in delayed coalescence of the aqueous droplets during swelling.

Effects of Drug Concentration in Inner Aqueous Phase and Additives in Oleaginous Phase on Release and Bioavailability of Isoniazid from Multiple Emulsion

The effects of drug concentration in internal aqueous phase of stabilized w/o/w emulsion and additives in oleaginous phase on release characteristics of isoniazid were investigated. The release was significantly effected by both of the formulation variables. The release was enhanced initially with increasing concentration of drug in internal aqueous phase followed by a steady release at high concentration of isoniazid. The release declined substantially in the presence of aluminum tristearate, cetostearyl alcohol, and cholesterol, and it increased with egg lecithin and oleic acid in oily phase. The bioavailability was increased with a multiple-emulsion formulation.

EFFECT OF FORMULATION VARIABLES OF MULTIPLE EMULSION ON THE STABILITY AND ANTITREMOR ACTIVITY OF CHLORPHENOXAMINE HYDROCHLORIDE

W/O/W multiple emulsion formulations of chlorphenoxamine hydrochloride were prepared. The results of dissolution indicate that the release of the drug from w/o/w multiple emulsion was significantly sustained.. The incorporation of the additives into the external aqueous phase of w/o/w multiple emulsions based on liquid paraffin increased the release of the drug in the following order: sodium chloride >' Polyvinyl alcohol > hydroxypropyl methylcellulose > polyvinylpyrrolidone. Stability studies of differentemulsion samples were conducted at various temperatures and, evaluated by using the conductivity method. The obtained data indicated that the emulsions were stable during the storage for 3 months at 25°C. The formula (Fm) of the multiple emulsion which contained castor oil with Span 60 possessed a more efficient prolonged antitremor effect and lowered of spontaneous locomotor activity (SLMA) in mice than that of the drug solution. The statistical analysis also revealed that this formula produced a greater sedative effect compared with that of the drug solution.

Causes of weight loss in HIV infection

High molecular weight nonionic block copolymers have been developed as vaccine adjuvants. We employed these adjuvants in water-in-oil emulsion and multiple emulsion formulations with a synthetic peptide-based antigen vaccine to test their ability to prime anti-viral CD8+ T cell responses. Vaccines were made using the H-2d-restricted immunodominant peptide from lymphocytic choriomeningitis virus (LCMV), NP118–126, and administered to BALB/c ByJ (H-2d) mice. Peptide-containing emulsions were able to induce NP118–126 specific CTL and IFN-γ secreting CD8+ T cells in the vaccinated mice and these responses were maintained for at least 90 days post immunization. At all times, the responses induced by the copolymer formulations were equal to, or better than, formulations based on incomplete Freund's adjuvant (IFA). In addition, the responses induced by prophylactic vaccination using the multiple emulsion formulation resulted in accelerated viral clearance following infection with a strain of LCMV (clone 13) that causes a persistent infection in naı̈ve adult mice. These results indicate that peptide vaccination using a formulation based on high molecular weight nonionic block copolymer in a simple water-in-oil or a multiple emulsion format can induce virus-specific CD8+ T cell responses and confer protection sufficient enough to prevent the establishment of a persistent infection.

Polymeric surfactants based on polysiloxanes—graft-poly (oxyethylene) for stabilization of multiple emulsions

Abstract Polymers consisting of hydrophilic and hydrophobic segments have been suggested as emulsifiers for stabilization of multiple emulsions. Attempts have been made to produce and use new polymeric surfactants based on polysiloxane—graft-poly(oxyethylene) for stabilization of water-in-oil-in-water (W/O/W) multiple emulsions. Hydrophobic comb-grafted copolymers have been used at the inner interface to obtain stable small droplet size water-in-oil emulsions. Hydrophilic comb-grafted copolymers with similar structures but with high density grafting and long poly(oxyethylene) chains have been used to stabilize the outer interface of the W/O/W emulsion. Stable multiple emulsion formulations with very slow release rates can be obtained when using the two types of silicone emulsifier.

Future developments in cosmetic formulations

Synopsis In recent years, there have been a great deal of interest in applications of microemulsions, liposomes (vesicles) and multiple emulsions in cosmetic formulations. These systems will provide the cosmetic industry with new types of formulations which are easier to apply, better functional benefit and potentially safer formulations. Microemulsions are thermodynamically stable systems and hence shelf life is no problem. Many cosmetic ingredients can be adequately solubilized in the swollen micelles of the microemulsions. Such solubilized systems may enhance transport and diffusion through various barriers, eg., the skin, thus enhancing the efficacy of the formulations. However, microemulsions may cause skin irritation by disrupting the liquid crystalline structure of the stratum corneum. This problem may be overcome by formulating microemulsions, which on evaporation produce lamellar liquid crystalline structures. The problem of skin irritation is certainly reduced or eliminated using liposomes or vesicles, which offer an alternative to microemulsions. The principles for formation and stabilization of vesicles are discussed in this paper and research work is needed to produce nanocapsules from liposomes, using polymerizable surfactants. Multiple emulsions of the water/oil/water (w/o/w) or oil/water/oil (o/w/o) types are also valuable systems for formulating cosmetics. In the first place, they offer a means of sustained release of the various ingredients. Secondly, they allow one to separate the various ingredients in the formulation, thus preventing their possible interaction. The basic principles required for preparation of stable multiple emulsions are summarised. Developments of polymeric surfactants led to the formulation of stable multiple emulsions. An example of a recently formulated stable w/o/w multiple emulsion is given in this paper The stability of the system was investigated using optical microscopy. Creaming occurred on storage, particularly at high temperature (40 degrees C) and this was significantly reduced by addition of Kelzan (a polysaccharide with high molecular weight). The final formulation was studied rheological techniques.

Stabilisation of w/o/w multiple emulsions by interfacial complexation of macromolecules and nonionic surfactants

A new approach to obtain stable w/o/w multiple emulsions has been developed; the basis is the interfacial interaction between a macromolecule, e.g. albumin or polyacrylic acid in the internal aqueous, and a lipophilic poloxamer surfactant in the dispersed oil phase. Lipophilic poloxamer surfactants of high molecular weight, e.g. Poloxamer 331, were preferable in forming a stable w/o and the subsequent w/o/w emulsions. Similarly, hydrophilic poloxamer surfactants of high molecular weight could enhance the stability of the w/o/w multiple emulsions when used to emulsify the initial w/o emulsions, e.g. poloxamer 403. A water soluble, internal marker, Sulphane Blue, was encapsulated within the emulsion droplets and the release rate studies were carried out. The results revealed that both the mass transfer rate and stability of the oil membrane could be influenced by the combination of external (secondary) hydrophilic surfactants used. The secondary surfactant affected release rate primarily by control of mass transfer through the oil liquid membrane. In optimising a stable multiple emulsion formulation, both the HLB (hydrophilic-lipophilic balance) values and surface activities of the surfactants have to be considered.