Combination of Pluronic/Vitamin E TPGS as a potential inhibitor of drug precipitation

In this study, we screened surfactants and their combinations at low concentrations as potentially potent inhibitors of drug precipitation in an aqueous medium. Nine surfactants (including Pluronic F127, Pluronic F108, and Pluronic F68) were evaluated at concentrations below their critical micelle concentrations (CMCs) using an in vitro precipitation assay. A model compound used in this study showed a sharp pH-dependent solubility profile and was much more soluble in simulated gastric fluid (SGF) (pH 1.2) than in simulated intestinal fluid (SIF) (pH 7.4). The compound was first dissolved in SGF with each surfactant, and the solutions were dispensed into the wells of a 96-well microtiter plate by a TECAN robot and diluted 10-fold with SIF. After a preset incubation time at room temperature, the solutions were filtrated through a 96-well filter plate, and the compound concentration in the filtrate was measured using an HPLC method. At concentrations below their CMCs, Pluronic F127 and Pluronic F108, but not Pluronic F68, inhibited the compound precipitation in SIF. Combinations of Pluronic F127 or Pluronic F108 with Vitamin E TPGS showed significantly stronger inhibition than the individual surfactants, indicating synergistic effects on inhibition of drug precipitation.     

The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment

A non-solubilizing solid dispersion formulation (polyethylene glycol 6000) and two solubilizing solid dispersions (Vitamin E TPGS and a Gelucire 44/14/Vitamin E TPGS blend) containing the antimalarial, Halofantrine (Hf), were formulated for bioavailability assessment in fasted beagles to determine if the oral absorption of Hf can be enhanced by these delivery systems. Solid dispersions comprising varying proportions of drug to carrier were prepared by the fusion method. Whilst the non-solubilizing formulation was assessed according to its dispersion characteristics, the solubilizing solid dispersions were assessed by their ability to form microemulsions upon dispersion. Studies in fasted beagles showed that the solid dispersions afforded a five- to seven-fold improvement in absolute oral bioavailability when compared with the commercially available tablet formulation. The delivery of Hf in either a solubilizing or non-solubilizing solid dispersion did not result in significant differences in oral bioavailability. The physical stability of the solid dispersions was studied using differential scanning calorimetry and X-ray powder diffraction.     

Design and characterization of submicron formulation for a poorly soluble drug: the effect of Vitamin E TPGS and other solubilizers on skin permeability enhancement

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across the skin since the concentrations of the drug dissolved in the matrix have to be high in order to maintain zero order release kinetics. Several attempts have been reported to improve the permeability of poorly soluble drug compounds using supersaturated systems, however, due to thermodynamic challenges, there was a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of drug crystals at the submicron/nano range in presence of different solubilizers to improve the permeation rate. Effect of several solubilizers, e.g. Pluronic F-127, Vitamin E TPGS, propylene glycol were studied on the submicron suspension systems of ibuprofen as a model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were examined to evaluate their crystal inhibitory effects on particle growth of the drug compound at submicron range. The overall permeation enhancement process through the skin seems to be influenced by the presence of solubilizers and also the presence of submicron drug crystal. The most promising stable formulation was developed with Vitamin E TPGS+HPMC submicron suspension, which produced higher permeation rate compared to other vehicles.     

Correlating the Behavior of Polymers in Solution as Precipitation Inhibitor to its Amorphous Stabilization Ability in Solid Dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.     

Pharmaceutical evaluation of genistein-loaded pluronic micelles for oral delivery

The purpose of the present study was to determine whether Pluronic F127 polymeric micelles could improve the oral bioavailability of a poor water-soluble drug, such as genistein. Genistein is a phytoestrogen that has estrogenic activity. F127 triblock copolymer consists of PEO100-PPO65-PEO100. Genistein was incorporated in the Pluronic F127 polymeric micelles by a solid dispersion method. The genistein release of genistein-loaded polymeric micelles was studied in vitro (in pH 1.2 and pH 6.8). And the oral bioavailabilities of genistein powder and genistein-loaded micelles were estimated at a dose of 4.0 mg/kg as genistein in rats. Drug loading amount and drug loading efficiency were 11.18% and 97.41%, respectively. The average size of the genistein-loaded polymeric micelles was 27.76 nm. And genistein release of the genistein-loaded polymeric micelles in vitro was 58% (pH 1.2) and 82% (pH 6.8). The bioavailability of genistein-loaded polymeric micelles was better than genistein powder. Consequently, Pluronic F127 polymeric micelles are an effective delivery system for the oral administration of genistein.     

羟丙基甲基纤维素的凝胶特性及其对曲尼司特缓释片释放行为的影响

目的：研究羟丙基甲基纤维素(HPMC)的凝胶特性及其对曲尼司特缓释片释放行为的影响。方法：采用称重法、图像法和体积测量法,研究HPMC辅料片和曲尼司特缓释片在不同pH环境中的水合度和溶胀度。结果：辅料片在SGF和SIF中的水合速率常数分别为0.897 h-1和0.681 h-1;溶胀速率常数分别为1.005 h^-1和0.713 h^-1。曲尼司特缓释片在SGF中,在0.5 h内迅速水合和溶胀,其后呈负增长;而在SIF中,重量和体积都缓慢增加,5 h后重量稍有下降,体积保持不变。结论：HPMC水凝胶的形成速度和形态与介质的pH有关,凝胶层的溶蚀速度控制药物的释放。     

Drug precipitation inhibitors in supersaturable formulations

Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability.     

Design of taste masked enteric orodispersible tablets of diclofenac sodium by applying fluid bed coating technology

Diclofenac sodium (DS) a non-steroidal anti-inflammatory drug has a bitter taste and is a local stomach irritant. The aim of this study was to formulate taste masked DS orally dispersible tablets (ODTs) with targeted drug release in the intestine. Pellets of DS were designed using sugar sphere cores layered with DS followed by an enteric coat of Eudragit L100 and a second coat of Eudragit E100 for taste masking. The produced pellets had a high loading efficiency of 99.52% with diameters ranging from 493.7 to 638.9?µm. The prepared pellets were spherical with smooth surfaces on scanning electron microscopy examination. Pellets with the 12% enteric coat Eudragit L100 followed by 5% Eudragit E 100 resulted in 1.4?±?0.5% DS release in simulated gastric fluid (SGF) and complete dissolution in simulated intestinal fluid (SIF). The pellets were then used to formulate ODTs. In vitro disintegration time of ODTs ranged from 20?±?0.26 to 46?±?0.27?s in simulated saliva fluid (SSF). Dissolution was less than 10% in SGF while complete drug release occurred in SIF. The release rate was higher for the optimized formulation (F12) in SIF than for the marketed product Voltaren® 25?mg tablets. The optimized ODTs formulation had a palatable highly acceptable taste.     

Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties

R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.     

Examination of the impact of a range of Pluronic surfactants on the in-vitro solubilisation behaviour and oral bioavailability of lipidic formulations of atovaquone

Exogenous surfactants are increasingly used to enhance the dispersion properties of lipid-based formulations of poorly water-soluble drugs, yet their possible effects on formulation digestion and oral bioavailability in-vivo are not well documented. In this study, in-vitro dispersion and digestion experiments were conducted using formulations comprising a blend of long-chain glycerides, ethanol, a model poorly water-soluble drug (atovaquone), and a series of surfactants including Cremophor EL and a range of Pluronic surfactants (Pluronics L121, L61, L72, L43 and F68). Inclusion of Cremophor EL, a surfactant with a high hydrophilic-lipophilic balance (HLB), promoted complete digestion of the formulation and effective dispersion and solubilisation of the lipolytic products and co-administered drug. Surprisingly, formulations containing the Pluronic (L121) with the lowest HLB (0.5) equally effectively promoted digestion and drug solubilisation and a trend towards decreased digestion and drug solubilisation was observed with Pluronics of increasing HLB values. All formulations effectively prevented drug precipitation, suggesting possible utility in-vivo, and no correlation was evident between the ability of the formulations to self-emulsify on dispersion and to promote drug solubilisation on digestion. Subsequent assessment of the oral bioavailability of atovaquone after administration of formulations containing Cremophor EL or Pluronic L121 or a simple solution of atovaquone in long-chain glycerides confirmed the utility of lipid-based formulations for enhancing the oral bioavailability of poorly water-soluble drugs such as atovaquone, but also indicated that in some cases microemulsion preconcentrate formulations may not provide additional bioavailability benefits beyond that achievable using simple lipid solutions.     

Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion.

The aim of this study was to investigate the performance of three new solid dispersion formulations of itraconazole in human volunteers in comparison with Sporanox, the marketed form. Solid dispersions made up of itraconazole (40%, w/w) and HPMC 2910, Eudragit E100 or a mixture of Eudragit E100-PVPVA64 were manufactured by hot-stage extrusion and filled in gelatin capsules. The formulations were tested in eight human volunteers in a double blind, single dose, and cross-over study. Concentrations of the drug and its metabolite hydroxyitraconazole in the plasma were determined using HPLC. The in vivo performance was evaluated by comparing the mean area under the plasma concentration-time curves (AUC), the mean maximum plasma concentration (C(max)), and the mean time to reach C(max) (T(max)). The mean bioavailability of itraconazole was comparable after administration of the HPMC solid dispersion, compared to Sporanox, while it was lower after administration of the Eudragit E100 or Eudragit E100-PVPVA64 dispersions. Due to high variability, a significant decrease in AUC and C(max) was only observed for the Eudragit E100-PVPVA formulation. Although the solid dispersions showed different in vitro dissolution behaviour, T(max) values were comparable. The same observations with respect to AUC, C(max) and T(max) could be made for hydroxyitraconazole. The present results indicate that hot-stage extrusion can be considered as a valuable alternative for manufacturing solid dispersions of itraconazole.     

喷昔洛韦眼用温度敏感原位凝胶的制备及评价（英文）

目的研制以普朗尼克F127为主要基质的喷昔洛韦制剂,以提高其眼部生物利用度。方法通过将HPMC K4M或卡波姆934P与普朗尼克F127复合使用,制备了喷昔洛韦的温度敏感原位凝胶。以胶凝温度、流变学、药物释放特性、药代动力学及眼部刺激性等为指标进行筛选,得到最优化处方。结果使用HPMC K4M或者卡波姆934P均能降低凝胶的胶凝温度,略微增加其粘度,延缓体系中药物的释放速率;药物释放为非Fick扩散;所有处方均未表现出眼部刺激或对角膜的损伤;含卡波姆934P和普朗尼克F127的凝胶体系的眼部生物利用度最高。结论含普朗尼克F127的喷昔洛韦制剂能够以滴眼液的形式给药,而达到眼部温度时可形成凝胶;体内外评价结果表明,含有HPMC K4M或卡波姆934P以及低浓度普朗尼克F127（12%）的喷昔洛韦制剂,提高了药物在眼部的生物利用度,是一种很有前景的眼部给药系统。     

Bioavailability enhancement of a COX-2 inhibitor, BMS-347070, from a nanocrystalline dispersion prepared by spray-drying

Spray drying drug with excipients is usually associated with the preparation of microcrystalline or amorphous drug in order to improve bioavailability. It was found that BMS-347070, when spray-dried with Pluronic F127 from acetone or methylene chloride, was dispersed as nanosized crystalline drug within the water-soluble Pluronic matrix. The reduction in drug particle/crystallite size, coupled with wetting by the Pluronic, resulted in a fast-onset formulation with bioavailability comparable to that of a solubilized and a NanoCrystal formulation. For this system, it is theorized that the polyethylene oxide segments of Pluronic crystallize and that the polypropylene oxide segments remain amorphous, providing a size-restricted domain in which the COX-2 drug crystallizes. This results in improved bioavailability while limiting the potential risk of conversion of an amorphous drug to its crystalline state.     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6 microm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

Roles of effective stabilizers in improving oral bioavailability of naringenin nanocrystals: Maintenance of supersaturation generated upon dissolution by inhibition of drug dimerization

Nanocrystals (NCs),a colloidal dispersion system formulated with stabilizers,have attracted widespread interest due to their ability to effectively improve the oral bio availability of poorly water-soluble drugs.The stabilizer plays a key role because it can affect the physical stability and even the oral bio availability of NCs.However,how stabilizers affect the bio availability of NCs remains unknown.In this study,F68,F127,HPMC,and PVP were each used as a stabilizer to formulate naringenin NCs...     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6?µm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME)

A precipitation screening method using a 96-well microtiter plate was developed to evaluate in vitro drug precipitation kinetics of liquid formulations for poorly water-soluble compounds, using milligram quantities of compounds and milliliter volumes of biorelevant media. By using this method we identified three formulations showing distinct in vitro precipitation kinetics (fast, slow, and no precipitation) for a model new molecular entity (JNJ-25894934). The in vitro precipitation profiles in simulated intestinal fluid (SIF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) were compared with those measured by a USP dissolution method, and with in vivo absorption at the fasted and fed states in canine pharmacokinetic (PK) studies. The precipitation kinetics of all three formulations in the initial hours measured by the screening method correlated to those determined by the USP method (R(2) = 0.96). The PK results showed that the fast-precipitation formulation had the lowest bioavailability. However, a similar bioavailability was observed for the slow- and no-precipitation formulations. The oral bioavailability of JNJ-25894934 at the fed state was also significantly higher than that at the fasted state for all three formulations (p < 0.05). In addition, the in vitro precipitation profiles in FeSSIF correlated better with in vivo absorption than those in SIF and FaSSIF.     

Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability

A new, supersaturable self-emulsifying drug delivery system (S-SEDDS) of paclitaxel was developed employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC the SEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study was conducted in male Sprague-Dawley rats to assess exposure after an oral paclitaxel dose of 10 mg/kg in the SEDDS formulations with (S-SEDDS) and without HPMC. The paclitaxel S-SEDDS formulation shows approximately 10-fold higher maximum concentration (C(max)) and five-fold higher oral bioavailability (F approximately 9.5%) compared with that of the orally dosed Taxol formulation (F approximately 2.0%) and the SEDDS formulation without HPMC (F approximately 1%). Coadministration of cyclosporin A (CsA), an inhibitor of P-glycoprotein and CYP 3A4 enzyme, at a dose of 5 mg/kg with the S-SEDDS formulation further increased the oral bioavailability (F approximately 22.6%). This assessment demonstrates that the systemic exposure of paclitaxel following oral administration can be substantially improved via the S-SEDDS approach.     

Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs

The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2273–2281, 2013     

Development of novel ibuprofen-loaded solid dispersion with improved bioavailability using aqueous solution

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability, various ibuprofen-loaded solid dispersions were prepared with water, HPMC and poloxamer. The effect of HPMC and poloxamer on aqueous solubility of ibuprofen was investigated. The dissolution and bioavailability of solid dispersion in rats were then evaluated compared to ibuprofen powder. When the amount of carrier increased with a decreased in HPMC/poloxamer ratio, the aqueous solubility of ibuprofen was elevated. The solid dispersion composed of ibuprofen/HPMC/poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and Cmax of drug than did ibuprofen powder in rats. The solid dispersion improved the bioavailability of drug about 4-fold compared to ibuprofen powder. Thus, this ibuprofen-loaded solid dispersion with water, HPMC and poloxamer was a more effective oral dosage form for improving the bioavailability of poor water-soluble ibuprofen.