Colloidal structures of O/W creams

O/W creams with crystalline gel structures (Water Containing Hydrophilic Ointment DAB 8, Non-ionic Hydrophilic Ointment DAC and a stearate cream) were investigated by means of small angle X-ray diffraction, differential scanning calorimetry, thermogravimetry and freeze fracture technique in combination with Transmission Electron Microscopy (TEM). It was found that these bases are building up two different colloidal gel structures, a hydrophilic gel phase and a lipophilic gel phase, each of them forming a coherent network. The hydrophilic gel phase is characterized by an interlamellar water layer; this interlamellarly fixed water is in a dynamic equilibrium with the bulk water phase. The lipophilic gel phase immobilizes mainly the inner (dispersed) phase. So the O/W creams presented here are supposed to be four-phase systems. The ratio of interlamellarly fixed water and bulk water, which may be determined easily by means of thermogravimetry, is found to be an important quality criterion for these O/W creams. The desired properties of water release of such a cream may be chosen by shifting the ratio of interlamellarly fixed water and bulk water.     

The "bubble point" for validation of drug release or simulated absorption tests for ointments

The aim of the present study was to design a test to ascertain the behaviour and reliability of a membrane used in drug release and simulated absorption tests in order to arrive at useful indications for simulating topical as well as gastro-intestinal absorption. The membrane can be used in two different conditions: a) as a simple porous membrane placed between the ointment and an accepting liquid phase, generally water phase; b) as a membrane soaked in a lipophilic liquid phase to simulate the horny layer between the ointment and accepting water phase. In this study the "bubble point test" was used to test the integrity of the soaking film as well as the membrane, during and after drug release and simulated absorption tests with different types of ointment. In the case of a drug release test from an ointment, the bubble point test may determine the test conditions, that is the ointment applied to either a dry or hydrated membrane. Only the use of a previously hydrated membrane can guarantee constant conditions in the in vitro model. Use of a dry membrane may lead to infiltration of liquid components of the ointment base, thus altering the contact conditions between the two phases of the cutaneous compartment model (lipogel and W/O creams). The use of a hydrated membrane may also lead to interactions between the two phases of the compartment, with osmotic exchanges between the acceptor phase and ointment sample (hydrogel, PEG gel, O/W creams). The hydrated membrane is therefore reliable only for comparison between lipophilic base ointments. In a simulated absorption test, determination of the bubble point makes it possible to ascertain the physical integrity of the lipoid liquid film immobilized by capillary action in the inner microporous structure of the membrane during the test. This condition is essential to maintain a balance between the parameters regulating the diffusion process between the different compartments of the system. The use of a lipoid-soaked membrane makes it possible to avoid interactions between the ointment sample and an aqueous acceptor phase, such as hydrosoluble bases. Since the diffusion across a lipoid film immobilised within a porous membrane depends on the drug release rate from the ointment base, the test allows a contextual evaluation of the release kinetics as well as an indication of the drug absorption possibilities through an in vitro model of the cutaneous compartment.     

Modified water containing hydrophilic ointment with suspended hydrocortisone-21-acetate--the influence of the microstructure of the cream on the in vitro drug release and in vitro percutaneous penetration.

Water containing hydrophilic ointment DAB 1997 was modified by the incorporation of ethanol and the effects of ethanol on the evaporation, the drug liberation and the permeation through human excised stratum corneum were investigated. Creams with 10%, 20%, 30% (v/v) and without ethanol were produced. As a model drug 2% (w/w) hydrocortisone-21-acetate was suspended in the o/w cream. The evaporation of the creams decreased with an increasing amount of ethanol which was unexpected because the vapor pressure of ethanol is higher than that of water. From this result it was concluded that ethanol might be interlamellarly fixed in the mixed crystal of the polyhydrate of the emulsifier to a higher extent than it is distributed within the aqueous bulk phase. In context with the liberation studies, ethanol decreased the drug liberation from the cream. This is in accordance with the above hypothesis of the ethanol partitioning within the cream, because the solubility of the drug in ethanol is higher than that in water. Therefore the interlamellar drug concentration should be higher than the solubility of the drug in the bulk phase, with the assumption that the gel network of the emulsifier polyhydrate is finally responsible for the delay in drug liberation. The permeation through stratum corneum showed no significant differences between the alcohol-free and the alcohol-loaded formulations. Obviously the decrease in drug liberation by ethanol was compensated for by the penetration enhancing effect.     

Effect of admixture of betamethasone butyrate propionate ointment on preservative efficacy

Twenty percent of dermatologists have experienced a separation of water or deterioration of topical corticosteroids mixed with commercially available ointments and/or creams. However, few investigations of this deterioration of admixtures have been reported. To assess the effects of preservatives in preventing microbial contamination of these admixtures, we attempted to investigate the concentration of preservative agents in admixtures and the microbial contamination of these admixtures with a topical corticosteroid ointment (Antebate). The concentration of parabens was reduced by half using an admixture of corticosteroid ointment with four types of moisturizing creams, Urepearl, Pastaronsoft, Hirudoid, and Hirudoidsoft. After a further 3 months, no decrease in parabens was seen. No microbial contamination was found in any admixture stored at room temperature for 1 week and touched two times daily with a finger. The concentration and ratio of the parabens in the aqueous phase and oil phase were entirely different in the admixtures before being centrifuged. The aqueous phase of the admixtures of the oil/water (O/W)-type emulsions of Urepearl and Hirudoid was not found to have microbial contamination immediately after being centrifuged. All aqueous phases stored at room temperature or in a refrigerator for 1 week and touched with a finger twice daily exhibited microbial contamination. These experiments demonstrated that O/W-type emulsions, in which the water easily separates from the bases, should be thoroughly mixed to prevent microbial contamination.     

In vitro release of diclofenac diethylamine from caprylocaproyl macrogolglycerides based microemulsions

The purpose of the present study was to determine the influence of both formulation parameters and vehicle structure on in vitro release rate of amphiphilic drug diclofenac diethylamine (DDA) from microemulsion vehicles containing PEG-8 caprylic/capric glycerides (surfactant), polyglyceryl-6 dioleate (cosurfactant), isopropyl myristate and water. From the constructed pseudo-ternary phase diagram at surfactant-cosurfactant mass ratio (K(m) 1:1), the optimum oil-to-surfactant-cosurfactant mass ratio values (O/SC 0.67-1.64) for formulation of microemulsions with similar concentrations of hydrophilic, lipophilic and amphiphilic phases (balanced microemulsions) were found. The results of characterization experiments indicated bicontinuous or nonspherical water-continuous internal structure of the selected microemulsion vehicles. Low water/isopropyl myristate apparent partition coefficient for DDA as well as elevated electrical conductivity and apparent viscosity values for the investigated microemulsion formulations containing 1.16% (w/w) of DDA, suggested that the drug molecules was predominantly partitioned in the water phase and most likely selfaggregate and interact with interfacial film. Release of DDA from the selected water-continuous (W/O), oil-continuous (O/W) and balanced microemulsions was investigated using rotating paddle dissolution apparatus modified by addition of enhancer cell. A linear diffusion of DDA through regenerated cellulose membrane was observed for the W/O and O/W formulations with the low content of dispersed phase. Non-linearity of the drug release profile in the case of bicontinuous formulations was related to the more complex distribution of DDA including interactions between the drug and vehicle. The membrane flux value increases from 25.02 microgcm(-2)h(-1) (W/O microemulsion) to 117.94 microgcm(-2)h(-1) (O/W microemulsion) as the water phase concentration increases. Moreover, the obtained flux values for balanced microemulsions (29.38-63.70 microgcm(-2)h(-1)) suggested that bicontinuous microstructure hampers the release of the amphiphilic drug.     

In vitro availability of kaempferol glycosides from cream formulations of methanolic extract of the leaves of Melilotus elegans.

In Ethiopian traditional medicine, Melilotus elegans Salzm. ex Ser. (Leguminosae) is used for the treatment of haemorrhoids and lacerated wounds. In view of its wide spread use and proven anti-inflammatory activity, 80% methanolic extract of the leaves was formulated into creams. HPLC/UV and MS studies revealed the presence of flavonoids, of which kaempferol was the major aglycone. Quantitative estimation of kaempferol in the hydrolyzed extract as determined by HPLC/UV was found to be 16.3+/-0.93 microg/mg (n=6, range) of extract. The in vitro release profiles of kaempferol glycosides (quantified as kaempferol equivalent) from the cream formulations in a multilayer membrane system indicated that a lipophilic cream of the extract provides higher release of kaempferol glycosides than hydrophilic and amphiphilic ones. Over a study period of 4h, the lipophilic cream released 66+/-5.70% of kaempferol glycosides, while the hydrophilic and amphiphilic creams resulted in 55+/-2.77 and 38+/-2.30% release, respectively.     

Topical delivery of urea encapsulated in biodegradable PLGA microparticles: O/W and W/O creams

This study describes the formulation and characterization of O/W and W/O creams containing urea-loaded microparticles prepared with poly (D, L-lactic-co-glycolic acid) (PLGA) in order to encapsulate and stabilize urea. The solvent evaporation method was used for preparing PLGA microparticles containing urea. The microparticles size was evaluated by laser light diffractometry. The resulting microparticles were then incorporated in O/W and W/O creams and stability and the release pattern from the creams was evaluated by UV-spectrophotometry. The particle size of PLGA microparticles was in the range of 1-5 microm and most microparticles had a particle size smaller than 3 microm. The encapsulation efficiency was calculated as 40.5% +/- 3.4. This study also examined release pattern of urea which varied among different formulations. The results showed that the release from O/W creams followed Higuchi kinetics while the release from W/O creams showed the zero order kinetics and the creams containing microparticulated urea had slower release than free urea creams.     

Topical delivery of urea encapsulated in biodegradable PLGA microparticles: O/W and W/O creams

This study describes the formulation and characterization of O/W and W/O creams containing urea-loaded microparticles prepared with poly (D, L-lactic-co-glycolic acid) (PLGA) in order to encapsulate and stabilize urea. The solvent evaporation method was used for preparing PLGA microparticles containing urea. The microparticles size was evaluated by laser light diffractometry. The resulting microparticles were then incorporated in O/W and W/O creams and stability and the release pattern from the creams was evaluated by UV-spectrophotometry. The particle size of PLGA microparticles was in the range of 1–5 µm and most microparticles had a particle size smaller than 3 µm. The encapsulation efficiency was calculated as 40.5%?±?3.4. This study also examined release pattern of urea which varied among different formulations. The results showed that the release from O/W creams followed Higuchi kinetics while the release from W/O creams showed the zero order kinetics and the creams containing microparticulated urea had slower release than free urea creams.     

Water-in-oil-in-water double emulsions loaded with chlorogenic acid: release mechanisms and oxidative stability

Abstract

Chlorogenic acid (CA) is a natural compound used as an antioxidant in the preparation of food, drugs, and cosmetics. Due to their low stability and bioavailability, many researchers have studied the encapsulation of CA in various delivery colloidal systems. The aim of this study was to evaluate the stability of water-in-oil-in-water (W/O/W) double emulsions loaded with CA and its antioxidant capacity. For this purpose, CA-W/O/W double emulsions were prepared using Span 80 and lecithin as lipophilic emulsifiers, and Tween 20 as a hydrophilic emulsifier. The influence of nature of lipophilic emulsifiers, the presence of chitosan (CH) in the internal and external aqueous phases, pH, temperature and the storage time of W/O/W double emulsions were also investigated. Depending on the preparation conditions, the W/O/W double emulsions showed the droplet size in the range 9.13?±?0.55?μm–38.21?±?1.87?μm, the creaming index 34%–78% and the efficiency encapsulation 79.45?±?1.5%–88.13?±?1.9%. Zeta potential values were negative for the W/O/W double emulsion without CH (?36.8?±?2.02mV; ?27.3?±?1.75mV) and positive for the W/O/W double emulsions with CH in the external aqueous phase (+6.5?±?0.42mV; 28.6?±?0.92mV). The study of the release of CA from W/O/W double emulsions has highlighted two mechanisms: one based on the coalescence between the water inner droplets or between the oil globules as well as a diffusion releasing mechanism. The oxidative stability parameters of the W/O/W double emulsions, such as the peroxide value (POV) and the conjugated diene content (CD) were measured.     

莫匹罗星软膏体外透皮吸收率的测定及质量评价

目的 评价莫匹罗星软膏原研制剂和5家仿制企业市售制剂体外透皮吸收及皮内滞留情况。方法 采用单室Franz池,以KM种小鼠背部皮作为体外透皮吸收皮肤,分别以0.1mol/L磷酸二氢钠(pH6.3)和30%乙醇0.1mol/L磷酸二氢钠(pH6.3)缓冲溶液作为亲水性和亲脂性释放液,采用HPLC法测定不同时间点释放液中莫匹罗星的浓度,计算累积透皮量,并测定取样末点皮内滞留的莫匹罗星量。结果 不同企业生产的莫匹罗星软膏在亲水性释放液中8h的透皮吸收百分比范围为0.01%~0.05%,皮内滞留百分比范围为0.51%~1.79%;在亲脂性释放液中8h透皮吸收和皮内滞留百分比范围分别为0.01%~1.04%和0.69%~2.59%。结论 莫匹罗星软膏原研制剂与5家仿制制剂在体外透皮的释药趋势一致,仿制药与原研药在亲脂性释放液中透皮吸收及在两种释放液种的皮内滞留量差异较大。本研究可为莫匹罗星软膏仿制药的一致性评价提供参考依据。     

Rheology and stability of water-in-oil-in-water multiple emulsions containing Span 83 and Tween 80

Multiple emulsions are often stabilized using a combination of hydrophilic and hydrophobic surfactants. The ratio of these surfactants is important in achieving stable multiple emulsions. The objective of this study was to evaluate the long-term stability of water-in-oil-in-water (W/O/W) multiple emulsions with respect to the concentrations of Span 83 and Tween 80. In addition, the effect of surfactant and electrolyte concentration on emulsion bulk rheological properties was investigated. Light microscopy, creaming volume, and rheological properties were used to assess emulsion stability. It was observed that the optimal surfactant concentrations for W/O/W emulsion long-term stability were 20% wt/vol Span 83 in the oil phase and 0.1% wt/vol Tween 80 in the continuous phase. Higher concentrations of Tween 80 had a destructive effect on W/O/W emulsion stability, which correlated with the observation that interfacial film strength at the oil/water interface decreased as the Tween 80 concentration increased. High Span 83 concentrations increased the storage modulus G′ (solidlike) values and hence enhanced multiple emulsion stability. However, when 30% wt/vol Span 83 was incorporated, the viscosity of the primary W/O emulsion increased considerably and the emulsion droplets lost their shape. Salt added to the inner aqueous phase exerted an osmotic pressure that caused diffusion of water into the inner aqueous phase and increased W/O/W emulsion viscosity through an increase in the volume fraction of the primary W/O emulsion. This type of viscosity increase imposed a destabilizing effect because of the likelihood of rupture of the inner and multiple droplets.     

Effect of various vehicles on diclofenac sodium and indomethacin pharmaceutical availability

The aim of the study was to determine the pharmaceutical availability of various ointment systems containing antirheumatic substances and to establish an optimal system for cutaneous application. Topical application permits elimination or at least reduction of side effects connected with oral administration. Three systems were evaluated: emulsion W/O (ointment), emulsion O/W (cream) and gel, all of them containing diclofenac sodium or indomethacin. The investigated systems are characterized by proper rheological parameters and long physicochemical stability. Studies on diclofenac and indomethacin pharmaceutical availability show a good release of the substances from cream and hydrogel bases, but a very poor release from the ointment base.     

Water distribution in creams prepared using cetostearyl alcohol and cetrimide

The water distribution in an antiseptic cream formulation prepared using cetostearyl alcohol and cetrimide has been studied using thermogravimetric analysis, differential scanning calorimetry, ultracentrifugation and scanning electron microscopy. In addition to a free water phase two types of interlamellarly fixed water were found, one associated with the liquid crystalline network around the oil droplets and one associated with the liquid crystalline network of the bulk. The latter was in equilibrium with the free water and can be classed as freely drainable.     

Evaluation of the release profiles of flavonoids from topical formulations of the crude extract of the leaves of Dodonea viscosa (Sapindaceae)

Quercetin and isorhamnetin are found in adequately large concentrations in the plant Dodonea viscosa (Sapindaceae). Plants that contain flavonoids are effective in the topical treatment of skin or mucous membrane inflammation. In this study, the release profiles of quercetin and isorhamnetin from hydrophilic, amphiphilic and lipophilic creams of the crude extract of Dodonea viscosa were determined using a multilayer membrane system. The results revealed that the hydrophilic cream provided the highest rate of release of both flavonoids while there was practically no release from the lipophilic cream. The hydrophilic cream may, therefore, serve most in delivering flavonoids to a diseased skin.     

Vehicle effects on in vitro release of tiaprofenic acid from different topical formulations

The aim of the present study was to investigate the in vitro release properties of tiaprofenic acid (TA) from different topical vehicles. Carbopol 940 gel, chitosan gel, two types of emulsion-based ointment formulations (o/w and w/o) and hydrophilic petrolatum USP were prepared with 2% drug content. Drug release from all vehicles through a standard cellophane membrane was evaluated by using Franz-type diffusion cells. In vitro release study results showed that the diffusion coefficients of the drug from vehicles rank according to the following order: Carbopol 940 gel (D = 3.11 x 10(-7) +/- 0.54 cm(2)/s) > chitosan gel (D = 0.27 x 10(-7) +/- 0.08 cm(2)/s) > emulsion-based ointment (o/w) (D = 0.18 x 10(-7) +/- 0.05 cm(2)/s) > emulsion-based ointment (w/o) (D = 0.13 x 10(-7) +/- 0.02 cm(2)/s) > hydrophilic petrolatum USP (D = 0.02 x 10(-7) +/- 0.01 cm(2)/s). Carbopol 940 gel base showed significantly higher drug release than other vehicles (P < 0.001). These results indicated that Carbopol 940 gel base is a good candidate for the topical delivery of TA, giving significantly higher drug release than the other vehicles.     

Texture Optimization of Water‐in‐Oil Emulsions

The aim of this research is to demonstrate the effect of variations in certain parameters of the oily phase (OP) in water‐in‐oil (W/O) emulsions on rheological and texture properties of finished products. The formulated emulsions were selected according to an optimal experimental procedure. The applied variations were nature of the OP, its volume fraction, the hydrophilic‐lipophilic balance (HLB) value, and the surfactant proportion. Results are presented for the followed tests carried out on the emulsions: texture analysis, rheology, and particle size analysis. The oils used in the study were sweet almond oil, liquid paraffin, maize oil, cyclomethicone, dimethicone, and wheat germ oil. The resulting data demonstrate a notable influence of the volume fraction oil on hardness, viscosity, adhesiveness, and cohesiveness of W/O emulsions. Emulsion hardness and viscosity increased as the OP percentage increased; this effect being even more pronounced for the vegetable oils. In contrast, emulsion adhesiveness and cohesiveness decreased as the volume fraction oil increased. The HLB value of the surfactant mixture of the emulsion also influenced hardness, adhesiveness, and elasticity, increasing or decreasing as HLB value did.     

Synthesis of a macromolecular camptothecin conjugate with dual phase drug release

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.     

The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds

The design of the novel O/W microemulsion formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds was examined. Using medium chain fatty acid triglyceride (MCT), diglyceryl monooleate (DGMO-C), polyoxyethylene hydrogenated castor oil 40 (HCO-40), ethanol and PBS (pH 6.8) as an oil phase, a lipophilic surfactant, a hydrophilic surfactant, a solubilizer and an aqueous phase, at the mixture ratio of 5%/1%/9%/5%/80% (w/w), respectively, the O/W microemulsion with an average particle diameter of 20 nm or less was prepared. Moreover, for nine kinds of poorly water soluble compounds, such as Ibuprofen, Ketoprofen, Tamoxifen, Testosterone, Tolbutamide and other new compounds, the solubility to water was increased from 60 to 20,000 times by this O/W microemulsion formulation. The AUCs in plasma concentration of Ibuprofen and a new compound, ER-1039, following single oral administration of these compounds as the O/W microemulsion to fasted rats were equivalent to that of solution administration or increased by nine and two times that of suspension administration, respectively. Accordingly, this novel O/W microemulsion is a useful formulation, which enhances the oral bioavailability by raising the solubility of poorly water soluble compounds.     

Study of the structure of coherent emulsions

The object of the study was to analyse relationship between the rheological properties, thermogravimetric behaviour, physical stability, and the wetting contact angle of the lipophilic and aqueous phase of 300 creams of different compositions with a high water content (60-80%, w/w). The starting point was Junginger's theory: water is found in the cream structure in energetic (interlamellar) and steric forms (bulk water). Based on our investigations, an exponential function was found to exist between the contact angle of wetting and the slope of the TG-curves, between the contact angle of wetting and the viscosity of the creams, and between the contact angle of wetting and the evaporation rate of water. A linear relationship was found between the contact angle of wetting and the quantity of water separable by centrifugation.     

Effect of HLB of additives on the properties and drug release from the glyceryl monooleate matrices.

Glyceryl monooleate (GMO) is an amphiphilic surfactant, which as such can solubilize hydrophilic, lipophilic and amphiphilic drug molecules in its different polarity regions. Addition of additives with different polarities in GMO leads to change in phase behavior and related properties of GMO. Effect of the additives with different hydrophilic lipophilic balance (HLB; 1.5, 3, 4, 5, 7, 10 and 11) in GMO matrices on its phase transformation, rheological properties, mechanical properties, wetting and release behavior was investigated. Polarizing light microscopy showed that the GMO matrices incorporated with lower HLB additive (1.5, 3, 4 and 5) form cubic phase at higher rate while lamellar phase was prominent for matrices with additive of HLB 7, 10 and 11. The diametrical crushing strength and viscosity was decreased with increased HLB of additive. Lower HLB additives enhanced contact angle as compared to plain matrices and high HLB additives induced change in solid-liquid interface from hydrophobic to hydrophilic leading to decline in contact angle. Percent swelling of matrices was increased linearly with increase in HLB of additives. Tensiometric method was used for determination of bioadhesive strength of hydrated matrices and it was observed that matrices with additives of HLB 10 presented highest bioadhesion due to higher rate of hydration and formation of lamellar phase. As the HLB of additives in matrix increased, release was shifted from anomalous (non-Fickian) diffusion and/or partially erosion-controlled release to Fickian diffusion. Initial lag was observed for drug released from matrices with additive of HLB 1.5, 3, 4 and 5. Thus incorporation of the additives of different HLB changed molecular packing, which significantly affected drug release pattern.