Investigation of the utility of an in vitro release test for optimizing semisolid dosage forms

Current literature indicates that an in vitro release test (IVRT) can serve as a research tool during the course of developing topical formulations. The purpose of this study was therefore to investigate the ability of an IVRT to select the topical semisolid formulations with the most rapid release rate of the model drug ketoprofen from two closely related hydrogels in a simulated product development process. Two glycols with distinct differences in their physical-chemical properties, Transcutol P (ethoxydiglycol) and propylene glycol, were incorporated into Carbopol 980 and Poloxamer 407 formulations. The release rate of ketoprofen was determined utilizing different receptor media and conditions, i.e., phosphate buffer pH 7.4, isopropyl myristate (IPM), and a combination of an IPM soaked membrane and phosphate buffer (pH 7.4) as receptor fluid. The results indicated that the conditions chosen could affect greatly the conclusions concerning the formulations. The only observable trend was that Transcutol P-containing formulations tended to permit a faster ketoprofen release than propylene glycol-containing formulations when utilizing IPM as a receptor component. This was attributed to the mutual miscibility of Transcutol P in IPM. It can be concluded that, for the purpose of formulation screening in the early phases of product development, an IVRT will only be useful for predicting the amount of drug available for absorption if the receptor medium has properties that closely mimic human skin. These results illustrate the importance of selecting suitable receptor components and indicate that it may be necessary to consider alternatives to the commonly used synthetic membranes.     

In-vitro release of diclofenac diethylammonium from lipid-based formulations

This article presents the preparation and topical performance of some new lipid-based formulations of diclofenac, namely (a) a diclofenac aqueous gel containing mixed micelles (sodium cholate:egg lecithin molar ratio 0.55); (b) diclofenac lotion that contains soya lecithin, ethanol and buffer; and (c) diclofenac lipogel containing egg lecithin, isopropyl myristate, propylene glycol and ethanol. Gel formulations were prepared using Carbomer 934. Release of diclofenac from all formulations was monitored via dialysis through Spectra/por membrane into phosphate buffer (0.2 M pH=7.4) using a Franz cell. Drug release profile and diffusion coefficients were compared with brand formulation (Geigy's Vlotaren Emulgel). Statistical analysis of data show that the diffusion coefficient of the drug from these formulations rank according to the following order: Diclofenac lotion (D=5.308x10(-7) cm(2)/s) >lipogel (D=2.102 x 10(-7) cm(2)/s) >Voltaren Emulgel (1.518 x 10(-7) cm(2)/s) >aqueous gel mixed micelle (0.966 x 10(-7) cm(2)/s). These results show that diclofenac lotion and lipogel maybe more suitable formulations than the conventional topical dosage form.     

Evaluation of creams and ointments as suitable formulations for peldesine

In-vitro studies were conducted to study the efficacy of mixed and self-emulsifying creams and hydrophobic ointment formulations in delivering peldesine (BCX-34) into and across cryopreserved human cadaver skin (HCS). Oil-in-water cream formulations, containing 1% w/w of radiolabeled C(14) BCX-34 and propylene glycol (PG), glycerin (GLY), isopropyl myristate (IPM), oleic acid (OA) and capric-caprylic esters (CE) were prepared. Petrolatum and lanolin based ointments were also prepared with PG. Sections of the HCS, 250 microm thick, were fitted to vertical Franz diffusion chambers containing a receptor medium of pH 7.4 phosphate buffer solution maintained at 37 degrees C. Using the finite dose technique, 4-6 mg of a formulation sample was applied to the epidermal surface of each section and drug diffusion was permitted for 12 and 24 h periods. The distribution of drug into the HCS epidermis, dermis and into the receptor medium was measured by scintillation spectroscopy. The results show good correlation of the calculated in-vitro values for flux and skin-vehicle partition coefficients against the observed amounts of drug detected in the HCS. The mixed emulsion cream formulation containing PG delivered higher amounts of drug into the skin when compared to the same formulation containing GLY cream. The self-emulsifying cream formulation containing IPM had a higher skin-vehicle partition coefficient and delivered more drug into the dermis when compared to those formulations that contained OA and CE. The petrolatum ointment delivered six times more drug into the epidermis than the lanolin ointment, and had higher skin-vehicle partition values. In conclusion, creams containing PG and petrolatum-base formulations would be suitable for BCX-34 dermal delivery.     

Enhancement of percutaneous absorption of Finasteride by cosolvents,cosurfactant and surfactants

The enhancing effects of routinely used co-solvents, propylene glycol and 2-propanol, anionic and cationic surfactants and a co-surfactant with different concentrations were evaluated on the skin permeation of Finasteride. In vitro permeation experiments with rat skin revealed that the solvent mixture is a very important factor in the penetration of Finasteride through the skin. Unexpectedly, cationic and anionic surfactants in various concentrations did not show any enhancement effect on drug transdermal absorption but co-surfactant Transcutol P increased skin penetration of Finastride significantly. Transcutol P with 0.25% and 1% showed the best enhancement in the initial and final sampling time, respectively. Transcutol P in a concentration of 0.25% increased skin absorption of the drug nearly 3.6 times in the first 15?min. The highest enhancement ratio (ER) was gained in the presence of 1% Transcutol P (ER?=?5.98). In this study, among the different topical Finastride formulations, Transcutol P 1% in combination with water, propylene glycol and 2-propanol (30, 10, and 60) showed the highest enhancement ratio.     

Effect of sucrose fatty acid esters on transdermal permeation of lidocaine and ketoprofen

The effect of sucrose fatty acid esters on transdermal permeation of lidocaine (LC) and ketoprofen was examined. A drug solution was applied to excised hairless mouse skin pretreated with a sugar ester solution to examine the direct effects of the sugar esters on skin permeability. LC was applied with a pH 6 buffer solution (98.8% ionized), pH 10 buffer solution (99.2% unionized), or propylene glycol, while KP was applied with a pH 6 buffer solution (99.1% ionized), pH 2 buffer solution (98.9% unionized), or propylene glycol. Pretreatment with J-1216 (sucrose laurate, HLB = 16) or J-1205 (sucrose laurate, HLB = 5) significantly increased the permeation of LC from the pH 6 solution and KP from propylene glycol, respectively. The permeability coefficients of the ionized and unionized LC and KP were calculated from the permeability data. The ionized LC and KP permeated even through skin not pretreated with sugar esters, although the permeability coefficients were 24 times and 38 times less than those of the unionized LC and KP, respectively. J-1216 pretreatment increased the permeability of ionized LC from aqueous vehicle 2.7 fold. In the next series of experiments, we formulated 1.5% of J-1205 and J-1216 in various vehicles to examine their effect on the permeation of LC applied on the excised hairless mouse skin with no pretreatment. The results coincided with the results of the pretreatment experiment, and the effect of J-1205 in propylene glycol was more remarkable than that observed in the pretreatment study. When these sugar esters were dissolved in propylene glycol at 1.5%, J-1205 increased significantly the KP permeation rate as well as LC permeation rate, suggesting that the combination of J-1205 and propylene glycol would be a potent vehicle for transdermal formulations.     

Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin

The influence of several penetration enhancers alone and/or in various combinations on the percutaneous penetration of nimesulide (NM) from Carbopol 934 based gel formulations was investigated. Skin permeation studies were performed using Franz-type diffusion cells and full-thickness abdominal rat skin. Various types of compounds such as ethanol, isopropyl alcohol, propylene glycol, Transcutol, Tween 80 and oleic acid were employed as penetration enhancers. The steady-state flux, the lag time and permeability coefficients of NM for each formulation were calculated. The results showed that the skin permeability of NM from gels tested was significantly increased (P < 0.05) by isopropyl alcohol (40%) and the combination of oleic acid (3%) with Transcutol (30%) when compared with the control formulation. In conclusion, these substances could be considered as penetration enhancers for NM topical formulations.     

pH-sensitive film coatings: towards a better understanding and facilitated optimization.

The major aims of this study were: (i) to prepare and characterize polymeric film coatings with pH-dependent properties for oral administration; and (ii) to better understand the underlying mass transport mechanisms upon exposure to simulated gastric and intestinal fluids. Propylene glycol alginate (containing free carboxylic groups) was chosen as a pH-sensitive film former, which was blended with different amounts of ethylcellulose (being water-insoluble throughout the gastro-intestinal tract). The water uptake kinetics of thin free films in 0.1M HCl and phosphate buffer pH 7.4 were monitored gravimetrically and quantitatively described using an appropriate analytical solution of Fick's law of diffusion. Interestingly, the addition of only a low percentage (2.5-10%) of propylene glycol alginate to ethylcellulose significantly increased both, the rate and extent of the films' water uptake, irrespective of the pH of the release medium. Importantly, diffusion was found to be the pre-dominant mass transport mechanism for all system compositions and types of release media. The apparent water diffusivity in the polymeric films could quantitatively be determined as a function of the polymer blend ratio. It significantly increased with increasing pH of the release medium, due to the presence of the free carboxylic groups in propylene glycol alginate. Also the dry mass loss of the polymer networks was much more pronounced at high compared to low pH. The differences in both water uptake as well as dry mass loss resulted in a clear pH-dependence of the drug release kinetics from coated pellets. Importantly, desired pH-sensitive release rates can easily be adjusted by varying the propylene glycol alginate content.     

1-ethyl and 1-propylazacycloalkan-2-one ester prodrugs of ketoprofen. Synthesis,chemical stability,enzymatic hydrolysis,anti-inflammatory activity,and gastrointestinal toxicity

Six ketoprofen (CAS 22071-15-4) alkylazacycloalkan-2-one ester derivatives (I-VI) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities after oral administration. Furthermore these derivatives were assayed to determine in vitro their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility to enzymatic cleavage in rat plasma. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. Esters I-VI showed an anti-inflammatory activity, determined as the percent of inhibition of carrageenan-induced edema, similar to that of ketoprofen, although at higher doses. They were significantly less irritating to the gastric mucosa than the parent drug. In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity.     

Preparation and evaluation of self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin

Atorvastatin is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin have been successfully prepared to improve its bioavailability. SMEDDS is a mixture of lipid, surfactant, and cosurfactant, which are emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo-ternary phase diagrams composed of various excipients were plotted. Droplet size, zeta-potential and long-term physical stability of the formulations were investigated. The release of atorvastatin from SMEDDS capsules was studied using the dialysis bag method in 0.1 M HCl and phosphate buffer (pH 7.4), compared with the release of atorvastatin from a conventional tablet. A pharmacokinetic study was performed in 6 beagle dogs after oral administration of 6 mg kg-1 atorvastatin. The bioavailability of atorvastatin SMEDDS capsules was significantly increased compared with that of the conventional tablet. SMEDDS capsules consisting of Labrafil, propylene glycol and Cremophor RH40 provided the greatest bioavailability. Our studies indicate that the use of SMEDDS for the delivery of atorvastatin can improve its bioavailability.     

Gentamicin release from photopolymerized PEG diacrylate and pHEMA hydrogel discs and their in vitro antimicrobial activities

Hydrogels based on poly(ethylene glycol)-diacrylate (PEG-DA) and 2-hydroxyethyl methacrylate (HEMA) were polymerized with cross-linking agent ethylene glycol diacrylate (EGDMA) under mild photoinitiating conditions. PEG-DA and HEMA concentrations of disks with 1 ± 0.3 mm thickness were 30% and 50% w/w and 40% and 60% w/w, respectively. Gentamicin sulphate was incorporated into the hydrogel during photopolymerization and its release kinetics were tested by spectrophotometric method at 255 nm wavelength in phosphate buffer (pH 7.4) and citrate buffer (pH 2.2). The drug release in citrate buffer was faster compared with to phosphate buffer. The release of drug from 40% HEMA containing hydrogel showed Fickian diffusion mechanisms in phosphate buffer (pH 7.4). Antimicrobial efficiency of the samples was tested by agar diffusion method in two different bacterial cultures (Pseudomonas aeruginosa [ATCC 10145], Staphylococcus aureus [ATCC 25923]). Inhibition zone diameter (mm) surrounding each sample was measured after 24 hr incubation of drug loaded disks onto agar plates at 37°C. Inhibition zone formation also confirms that gentamicin sulphate preserves its antimicrobial activity after subjected to photopolymerization conditions.     

Ex vivo study of transdermal permeation of four diclofenac salts from different vehicles

The ex vivo permeation of diclofenac was studied using four different salts (sodium, potassium, diethylamine, and epolamine) dissolved in four different solvents (water, propylene glycol (PG), Transcutol, and oleic acid (OA)) as donor phases through a human skin membrane. The four salts show different solubility values and different behavior in the four solvents, which are also permeation enhancers and this fact further is connected to the permeation results. The same order of magnitude of fluxes through the membrane as those previously reported for acidic diclofenac released from buffer solutions of pH >7 were found, taking into account differences originated by different membranes and other parameters tested in the experiments. Saturation concentration for the four salts in different solvents, necessary to calculate permeation coefficients, was critically evaluated; a short discussion made it possible to explain that corrections in the solubility values must be considered, related to the complex behavior in solution of these salts. Statistical processing of the experimental data suggests that differences between the four salts in promoting absorption of the drug is unproven; while differences are evident between the solvents, water is the most effective enhancing vehicle. Aqueous formulations containing diclofenac salt with an organic base appear to be the best combination to promote permeation in topical applications.     

阿替洛尔非pH依赖型缓释片的制备及处方优化

以羟丙甲纤维素为缓释材料,琥珀酸为pH缓冲剂制备非pH依赖型阿替洛尔缓释片.考察以不同用量的羟丙甲纤维素和琥珀酸配制成不同处方缓释片,测定各个处方在0.1mol/L盐酸和pH7.4磷酸盐缓冲液中的释放度,采用多指标同步优化筛选处方.结果表明,优化处方在不同pH介质中均有较好的缓释效果.     

Gentamicin Release from Photopolymerized PEG Diacrylate and pHEMA Hydrogel Discs and Their In Vitro Antimicrobial Activities

Hydrogels based on poly(ethylene glycol)-diacrylate (PEG-DA) and 2-hydroxyethyl methacrylate (HEMA) were polymerized with cross-linking agent ethylene glycol diacrylate (EGDMA) under mild photoinitiating conditions. PEG-DA and HEMA concentrations of disks with 1 ± 0.3 mm thickness were 30% and 50% w/w and 40% and 60% w/w, respectively. Gentamicin sulphate was incorporated into the hydrogel during photopolymerization and its release kinetics were tested by spectrophotometric method at 255 nm wavelength in phosphate buffer (pH 7.4) and citrate buffer (pH 2.2). The drug release in citrate buffer was faster compared with to phosphate buffer. The release of drug from 40% HEMA containing hydrogel showed Fickian diffusion mechanisms in phosphate buffer (pH 7.4). Antimicrobial efficiency of the samples was tested by agar diffusion method in two different bacterial cultures (Pseudomonas aeruginosa [ATCC 10145], Staphylococcus aureus [ATCC 25923]). Inhibition zone diameter (mm) surrounding each sample was measured after 24 hr incubation of drug loaded disks onto agar plates at 37°C. Inhibition zone formation also confirms that gentamicin sulphate preserves its antimicrobial activity after subjected to photopolymerization conditions.     

Film drying and complexation effects in the simultaneous skin permeation of ketoprofen and propylene glycol from simple gel formulations

This work investigated the simultaneous permeation of ketoprofen and propylene glycol (PG) across pig ear skin from simple gel formulations administered under simulated in-use conditions. The aims were to quantify rates of permeation of both solvent and active, probe the effects of formulation drying and gain insight into drag/complexation interactions. Simple 3-component gels were formulated using a fixed amount of ketoprofen and hydroxypropyl cellulose thickener with decreasing content of solvent propylene glycol. Multiple finite (5 mg x 15 mg) doses were massaged over 24h into full thickness pig ear skin in vertical Franz-type diffusion cells. The permeation of ketoprofen was inversely proportional to the content of PG, whereas the permeation of PG was directly proportional, although the amount of PG permeated was always greater than ketoprofen, even from the driest gel practically achievable. In this state, the molar ratio of PG/ketoprofen was approximately 12, suggesting that this number of PG molecules constitutes the solvation cage of ketoprofen. Dragging/pulling effect extends throughout the skin and into the receptor compartment and probably the system, in an in vivo situation. Although PG may represent a worse case scenario given its well-documented skin permeation enhancement properties, it is probable that other solvents exert a similar effect on solutes across skin. A drying film will behave in different ways depending on the nature of both the thickener and solvent, where the outcomes are not readily predictable. It is important to account for the fate of all species administered from a topical formulation.     

Doxorubicin skin penetration from monoolein-containing propylene glycol formulations

Topical chemotherapy with the antineoplastic doxorubicin (DXR) could be an alternative to treat skin cancer, however its poor skin penetration often limits the efficacy of topical formulations. The aim of this work was to study the effect of monoolein (MO), a penetration enhancer, on the in vitro skin permeation and retention of DXR. DXR was incorporated in a propylene glycol preparation containing 0-20% of MO. DXR release rate and topical delivery were evaluated in vitro using acetate cellulose membrane and porcine skin, respectively, mounted in a Franz diffusion cell. At 5%, MO did not significantly change DXR release rate, but MO concentrations larger than 10% decreased almost twice its release. In vitro skin penetration studies showed that the presence of MO in the propylene glycol formulations markedly increased DXR presence in the stratum corneum (SC). At 5%, MO significantly increased the amount of DXR in the SC already in the first hours, attained a maximum in 6h. Comparing propylene glycol formulations containing more than 10% MO with that containing 5%, the former took the double of the time (12h) to reach the same amount of DXR in the skin, result that is in agreement with in vitro release studies. Interesting, despite the fact that MO significantly increased the amount of DXR in the SC, drug transdermal delivery did not change. These findings suggest a cutaneous delivery of DXR that is an important condition for topical treatment of skin tumors. Further in vivo experiments can show DXR delivery to deeper skin layers.     

Characterization and skin permeation of ketoprofen-loaded vesicular systems

PurposeTo determine the effect of elasticity on the skin permeation of ketoprofen from surfactant-based vesicular formulations and elastic liposomes.MethodsKetoprofen-loaded surfactant-based vesicles and elastic liposomes were prepared by sonication. Citric buffer (at pH 3.0) was used as rehydration buffer. Characterization studies of the prepared liposomal formulations were performed by dynamic light scattering, extrusion, and ¹H and ³¹P nuclear magnetic resonance (NMR) spectroscopy. Ketoprofen transport studies across human skin were performed for all formulations.ResultsStable ketoprofen-loaded formulations were prepared. Addition of an edge activator, in the absence of the drug, increased the elasticity of the vesicles and liposomes. Ketoprofen loading reduced the elasticity of the liposomes and surfactant-based-vesicles. However, at saturation, the elasticity was still higher than that in the absence of the edge activator and ketoprofen, except for ketoprofen-loaded liposomes with Span 80. NMR studies revealed that the ketoprofen molecules were entrapped in a vesicle bilayer in all vesicular formulations and that the ketoprofen molecules affected the phosphate mobility in the liposomal formulations. Ketoprofen transport studies across human skin clearly showed that the surfactant-based vesicular formulations were superior to the elastic liposomal formulations.ConclusionSurfactant-based vesicles enhance ketoprofen transport across human skin, while no enhancement of ketoprofen was observed when loaded in elastic liposomes.     

Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.     

Synthesis and hydrolytic behaviour of 2-mercaptoethyl ibuprofenate-polyethylene glycol conjugate as a novel transdermal prodrug

Thiolated derivatives of ibuprofen and its polyethylene glycol ester were synthesized via condensation of 2-mercaptoethyl ibuprofenate with carboxy-terminated polyethylene glycol. The release of ibuprofen from this polymeric prodrug has been studied under conditions simulating those encountered in the skin. The polymeric prodrug of ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 4 to 23.9% hydrolysis at pH 8.5 (15% at pH 7.4) after 48 h at 37 degrees C. The polymer-drug conjugate was subjected to enzymatic hydrolysis in human plasma. The polymer showed considerable enzymatic hydrolysis (68% after 48 h). The results showed that the polymeric prodrug model of non-steroidal anti-inflammatory drugs (NSAIDs) described here can be used in topical formulations of NSAIDs. It is expected that the novel thiol derivative will have both enhanced transdermal penetration and stability to oxidation which make it a suitable candidate for transdermal formulations.     

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.     

Self-nanoemulsifying drug delivery system for enhanced bioavailability and improved hepatoprotective activity of biphenyl dimethyl dicarboxylate

Biphenyl Dimethyl Dicarboxylate (BDD) is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-nanoemulsifying drug delivery system (SNEDDS) containing BDD has been successfully prepared using carefully selected ingredients which are less affected by pH and ionic strength changes to improve its bioavailability. SNEDDS is an isotropic mixture of lipid, surfactant, and cosurfactant which are spontaneously emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo ternary phase diagrams composed of various excipients were plotted to identify self -nano -emulsifying area. Droplet size changes upon dilution with aqueous media and in vitro release of BDD from SNEDDS in 0.1N HCl and phosphate buffer (pH 7.4) were studied and compared with commercial chinese pilules and Pennel capsules. The hepatoprotective activity upon oral administration of SNEDDS against carbon tetrachloride-induced oxidative stress in albino rats was assessed by measuring biochemical parameters like serum glutamic oxalacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). Results showed that using a proper ratio of Tween 80 to Transcutol as surfactant and co-surfactant respectively and Miglyol 812 as oil to surfactants mixture resulted in production of infinitely diluted formulations in nano droplet size range. BDD self nano emulsified formula composed of 20% Miglyol 812, 60% Tween 80 and 20% Transcutol released 99% of the drug very rapidly within 10-15 minutes regardless of the pH condition. The oral absorption and bioavailability of BDD self nano emulsified formula in albino rats were significantly enhanced (P<0.01) with an average improvement of 1.7 and 6-folds that of commercial chinese pilules and Pennel capsules respectively. This improvement was also confirmed histopathologically in chemically injured rats and by the significant decrease in elevated liver enzymes level.