Statistical optimization of insulin-loaded Pluronic F-127 gels for buccal delivery of basal insulin

The principle of statistical optimization was employed to fabricate insulin-loaded Pluronic F-127 (PF-127) gel formulations having the potential for buccal delivery of basal insulin. A two-level resolution III fractional factorial design was applied to simultaneously evaluate five independent formulation variables: PF-127 concentration, insulin concentration, sodium sulfate concentration, hydroxypropylmethyl cellulose (HPMC) concentration, and presence of sodium glycocholate. The amount of insulin released and permeated from gels as well as gelation time and mucoadhesion force of gels were measured and used as dependent response variables for formulation optimization. Optimization of a gel formulation was achieved by applying constrained optimization via regression analysis. In vitro permeation flux of insulin from the optimized formulation through procine buccal mucosa was 93.17 (±0.058, n?=?3) μg/cm(2). Plasma insulin levels following buccal administration of the optimized formulation at 10, 25 and 50 IU/kg to healthy rats were found to be dose dependent and basal insulin levels were maintained at least for 8 h. Furthermore, continuous hypoglycemia for at least 8 h was observed with 89%, 51% and 25% of blood glucose reduction, respectively, for these three doses. The results of this investigation conclude the feasibility of development of optimized buccal insulin-loaded Pluronic F-127 gels for basal insulin delivery.     

Pluronic F-127 gels incorporating highly purified unsaturated fatty acids for buccal delivery of insulin

The present study investigated the release profiles of insulin from Pluronic F-127 (PF-127) gel containing unsaturated fatty acids such as oleic acid (18:1), eicosapentaenoic acid (20:5) or docosahexaenoic acid (22:6) and the hypoglycemic effect of insulin following the buccal administration of the gel formulations in normal rats. Insulin release from the gels decreased in the presence of unsaturated fatty acids. Remarkable and continuous hypoglycemia was induced by all PF-127 gels (insulin dose, 25 IU/kg) containing unsaturated fatty acids. PF-127 gels containing oleic acid showed the highest pharmacological availability (15.9+/-7.9%). Our finding demonstrate that 20% PF-127 gels containing unsaturated fatty acids are potential formulations for the buccal delivery of insulin.     

Development and characterization of thermosensitive pluronic-based metronidazole in situ gelling formulations for vaginal application

The purpose of this study was to develop pluronic-based in situ gelling formulations of metronidazole (MTZ) for treatment of bacterial vaginosis, aimed at prolonging the residence time, controlling drug release, enhancing efficacy, decreasing recurrence, and increasing patient compliance. The in situ gel formulations were prepared using different concentrations of pluronic F-127 (PF-127) alone and in combination with pluronic F-68 (PF-68). The prepared formulations were evaluated for their gelation temperature (T(gel)), in vitro drug release, rheological properties, mucoadhesion properties and tolerability by vaginal mucosa in tissue levels. The T(gel) decreased with increasing PF-127 concentration. The T(gel) was modulated by addition of PF-68 to be within the acceptable range of 25-37 °C. With increasing pluronic concentration, the in vitro drug release decreased, viscosity and mucoadhesive force increased. Histopathological examination of rabbit vaginas from the control and treated groups revealed normal histology of the vagina and cervix. Based on the in vitro evaluation of prepared formulations, the in situ gelling liquid formulated with PF-127/PF-68 (20/10 %, m/m) was selected for further clinical evaluation.     

Effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations

The objectives of our study were to evaluate the effect of four terpene enhancers, enhancer lipophilicity, and ethanol concentration using hydroxypropyl cellulose (HPC) and two Pluronic F-127 (PF-127) gel formulations on the percutaneous permeation of ketoprofen. All experiments were conducted using hairless mouse skin in vitro. Data recorded over 24 hr was compared with that for control gels (containing no terpene) using Franz diffusion cells. In the three gel formulations, the highest increase in the ketoprofen permeation was observed using limonene followed by nerolidol, fenchone, and thymol. Relationships were established between terpene lipophilicity, enhancement ratios for ketoprofen flux (ER_flux), and the cumulative amount of ketoprofen after 24 hr (Q₂₄     

Transbuccal permeation, anti-inflammatory activity and clinical efficacy of piroxicam formulated in different gels

In attempts to avoid the systemic side effects of piroxicam (PC) (e.g. gastrotoxicity), several buccal gel formulations containing PC were prepared and their effects on the characteristics of the drug permeation through rabbit buccal mucosa in-vitro were evaluated using a Franz-type diffusion cell. The general rank order of the total flux of 0.5% PC from gels was found to be: hydroxypropylmethylcellulose (HPMC, 2.5%) > hydroxypropylcellulose (HPC, 2.5%) >or= sodium alginate (Na alg., 7%) > methylcellulose (MC, 3%) > hydroxyethylcellulose (HEC, 1.5%) > carbopol 934 (Carb. 934, 1%) >or= sodium carboxymethylcellulose (NaCMC, 2%) > pluronic F-127 (PF-127, 20%) > polyvinyl alcohol (PVA, 10%). The effect of various penetration enhancers 1% sodium lauryl sulphate (NaLS), 3% sodium deoxycholate (NaDC), 3% sodium tauroglycocholate (NaTGC) on the rate of permeation across the excised buccal mucosa (of 0.5% PC in gels prepared using 3% MC, 2.5% HPMC or 7% Na alg. base) and histology of the buccal epithelium was also investigated. Pharmacodynamic evaluation of the anti-inflammatory activity of PC in these gel formulations (containing 3% NaDC as an enhancer) was carried out using the kaolin-induced rat paw oedema method. The results obtained indicated that PC administered in 7% Na alg. or 2.5% HPMC gel bases was significantly more effective than the 3% MC gel and oral drug solution in suppressing oedema formation in rats. Comparative clinical studies were conducted in patients with post-operative dental pain and oedema following maxillofacial operations. The results revealed that 7% Na alg. and 2.5% HPMC gel formulations applied to the buccal mucosa were slightly better than or equally effective to the orally administered commercial product (Feldene Flash) tablet) in reducing pain level, swelling and tenderness within a period of 4 days. These findings suggest that PC (0.5%) administered in the buccal gel may present a potential therapeutical use as a strong anti-inflammatory and analgesic agent.     

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。     

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation,rheological, textural,mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76?±?0.07 and 1.14?±?0.01 (mg/cm²?±?SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (?′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.     

Enhanced rectal absorption of insulin-loaded Pluronic F-127 gels containing unsaturated fatty acids.

The objective of this study was to prepare and to evaluate Pluronic F-127 (PF127) gel containing unsaturated fatty acids such as oleic acid (18:1), eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) as a potential formulation for rectal delivery of insulin. The hypoglycemic effect of insulin was examined following rectal administration of the various formulations in normal rats. Rectal insulin absorption was markedly enhanced, and marked hypoglycemia was induced by all PF127 gels (insulin dose, 5 U/kg) containing different unsaturated fatty acids. PF127 gels containing unsaturated fatty acids presented low tmax mean values indicating that the absorption of insulin occurred very rapidly in the rectum. The relative hypoglycemic efficacy of PF127 gel formulations containing fatty acids such as oleic acid, eicosapentaenoic (EPA) and docosahexaenoic (DHA) were 28.4+/-8.1, 26.8+/-14.3 and 23.1+/-5.7%, respectively. The finding demonstrated that 20% PF127 gels containing unsaturated fatty acids are potential formulations for rectal delivery of insulin.     

In vitro release of lidocaine from pluronic F-127 gels

The release of lidocaine from aqueous, crystal clear and colorless gels of Pluronic F-127 (a polyoxyethylene-polyoxypropylene surface-active block polymer) has been studied in an in vitro release model which did not utilize a membrane. Pluronic F-127 forms micelles in aqueous systems and the gels are believed to be viscous isotropic liquid crystals. Due to their reverse thermal gelation behavior, good solubilization capacity, optical properties and low toxicity, they appear to have potential application as topical drug delivery systems. It has been found that the rate of lidocaine release was inversely proportional to its concentration, the concentration of Pluronic F-127 and electrolyte concentration (sodium chloride). Release of lidocaine was maximal at pH values close to its pK_a; however, release of the more water-soluble benzocaine (included for comparison purposes) was relatively pH-independent over the pH range studied. Since the apparent diffusion coefficient of lidocaine increased with increasing temperature, in spite of increasing macro-viscosity of the gel, it is apparent that drug is released by diffusion through the extramicellar aqueous channels of the gel matrix. Hence, the rate of drug release was determined by the micro-viscosity of the extramicellar fluid, the dimensions of the aqueous channels, and the equilibrium relationship of drug between the micelles and the external aqueous phase.     

Filamentous, mixed micelles of triblock copolymers enhance tumor localization of indocyanine green in a murine xenograft model

Polymeric micelles formed by the self-assembly of amphiphilic block copolymers can be used to encapsulate hydrophobic drugs for tumor-delivery applications. Filamentous carriers with high aspect ratios offer potential advantages over spherical carriers, including prolonged circulation times. In this work, mixed micelles composed of poly(ethylene oxide)-poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127 (PF-127) were used to encapsulate a near-infrared fluorophore. The micelle formulations were assessed for tumor accumulation after tail vein injection to xenograft tumor-bearing mice by noninvasive optical imaging. The mixed micelle formulation that facilitated the highest tumor accumulation was shown by cryo-electron microscopy to be filamentous in structure compared to spherical structures of pure PF-127 micelles. In addition, increased dye loading efficiency and dye stability were attained in this mixed micelle formulation compared to pure PEO-PHB-PEO micelles. Therefore, the optimized PEO-PHB-PEO/PF-127 mixed micelle formulation offers advantages for cancer delivery over micelles formed from the individual copolymer components.     

Drug molecules as probes for studying the compatibility between gels and mucous tissue with dielectric spectroscopy

In this interdisciplinary study low-frequency dielectric spectroscopy is used to assess the possibilities of intimate surface contact between a polymer gel and mucous tissue, which is generally considered to be the first step in the mucoadhesion process. The dielectric responses of six different gels, made from Carbopol 934 or Pluronic F-127 and containing 15 mM of a drug compound, either atenolol, alprenolol, or naproxen, were measured together with the responses of freshly excised porcine nasal mucosa and of systems made by combining the two. An analytical procedure is presented, which enables the dielectric response arising from the drug ions to be extracted. The drug ions are used as probes for measuring the ease, in terms of conductivity, with which they can pass the interface between the gel and the mucus layer. The results can be described by a compatibility factor that provides us with an assessment of the likelihood of intimate surface contact. The compatibility factors found in this study were generally higher for the Carbopol 934 gels than for the Pluronic F-127 gels, which is in agreement with the results of a previous study where sodium and chloride ions were used as probes for measuring the compatibility. Naproxen exhibited the largest difference in compatibility factor between the two gels; the highest compatibility factor of all systems was found for the Carbopol 934 gel whereas the gel based on Pluronic F-127 gave a value of approximately zero. This may partly be explained by interactions between the drug ions and the polymers.     

Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes

The aim of the present work was to develop a mucoadhesive controlled-release formulation of danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol-SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs. Increased mucoadhesion was observed for PC-containing tablets compared with HPMC tablets. As the concentration of polymer increased, drug release decreased, and PC-containing tablets gave slower release compared to HPMC tablets. In vivo bioavailability performed in dogs showed that the perorally administered danazol-SBE 7 complex and the danazol-SBE 7 (in PC matrix) buccal tablets had absolute bioavailabilities of 64% and 25%, respectively, that are significantly greater than 1.8% observed for the commercial formulation Danocrine. The increased bioavailability was attributed to the enhanced solubility consequent to complexation, and the possible avoidance of first-pass metabolism upon buccal administration.     

双氯芬酸钠泊洛沙姆凝胶体外释放的影响因素研究

目的:以双氯芬酸钠为模型药,研究泊洛沙姆407(P407)制剂体外释放的影响因素。方法:采用无膜释放法考察不同P407浓度、振荡频率、温度、等渗调节剂、附加剂等对凝胶溶蚀和药物释放的影响。结果:随振荡频率的增加及等渗调节剂PBS,NaC l或葡萄糖的添加,凝胶溶蚀和药物释放增加;P407浓度增加及处方中加入羟甲基纤维素钠(CMC-Na)、羟丙甲纤维素(HPMC)、甲基纤维素(MC)、羧甲基壳聚糖(O-CMC)等抑制了凝胶溶蚀和药物释放;温度升高药物释放加快而对凝胶溶蚀没有明显影响。结论:药物释放主要取决于凝胶溶蚀,可通过调节处方中影响凝胶溶蚀及药物扩散的因素来控制药物从407凝胶中的释放。     

Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems

This study was designed to combine the mucoadhesive property of Noveon and the thermosensitive property of Pluronic F-127 into one gel system. A rheological study of Pluronic aqueous sols (10-35%), Noveon gels (0.5-2%) and of mixed gels containing Pluronic (10-17.5%) and polycarbophil (0.5-2.5%) was conducted at different temperatures (15-35 degrees C). The viscosity of Pluronic sols increased with an increase in temperature and the mixed gels had thermoreversible property. The viscosity of mixed gels was higher than that of the Pluronic sols containing only Pluronic because of the increase in total polymer concentration. No interaction was found between -COOH groups of Noveon and Pluronic molecules at the studied concentrations of polymers; the viscosity of mixed gels containing un-neutralized Noveon was lower than that of the neutralized mixed gels. The effect of Pluronic F-127 on the mucoadhesive property of Noveon was investigated. The mucoadhesive properties of Pluronic and Noveon gels were compared by a force of detachment test. It was found that Pluronic and Noveon gels showed approximately the same mucoadhesive strength. However, there were significant differences in the viscosity of Noveon and Pluronic gels. The adhesive force of the mixed gel was almost same as that of the Noveon gel. The Pluronic did not affect the adhesive power of Noveon and the increased viscosity did not affect the bioadhesive force of the mixed gels. In spite of increasing viscosity of the gel, the percentage of released model material (mannitol) increased with increasing temperature. This is based on the previously reported observation that the interaction between the Pluronic molecules squeezed mannitol molecules out of the polymer chains. The mannitol release obeyed zero-order kinetics and the flux values of mixed gels at 15 and 35 degrees C were very similar. The Noveon chains among Pluronic chains probably hindered the diffusion of mannitol molecules and the release was thus controlled by Noveon. The combination of a thermosensitive polymer like Pluronic and a bioadhesive polymer like Noveon appears promising from a pharmaceutical viewpoint. These gel systems may find use in the development of bioadhesive, thermosensitive and controlled release formulations.     

Formulation and ex vivo evaluation of rofecoxib gel for topical application

The potential gastrointestinal disorders associated with oral administration of rofecoxib can be avoided by delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropylmethylcellulose (HPMC), sodium alginate and Carbopol 940 were used in an attempt to develop topical gel formulations of rofecoxib. The effects of polymer composition on the rate of drug release from the gel formulations were examined through cellulose membrane mounting on a Keshary-Chien diffusion cell. The effects of initial drug concentration and viscosity on the permeation rate of rofecoxib from the gel formulations were evaluated using rat epidermis at 37 +/- 0.5 degrees C. The anti-inflammatory activity of the rofecoxib gel formulation was evaluated using the rat hind paw edema model. The gel formulation consisting of 4% w/w sodium alginate-Carbopol 940 at 3:1 ratio was found to be suitable for topical application based on in vitro evaluation and ex vivo permeation studies. The drug permeation rate increased with an increase of the initial drug concentration in gels up to 25% w/w. An inverse relationship was observed between the in vitro drug release rate/ex vivo permeation rate and viscosity of the gel formulations. The anti-inflammatory activity of 4% w/w sodium alginate-Carbopol 940 gel containing 25% w/w rofecoxib in the rat hind paw edema model reveals that the drug was delivered to the inflammation site at a controlled level over a period of 6 h. These results suggest the feasibility of the topical gel formulation of rofecoxib.     

Thermoreversible mucoadhesive ophthalmic in situ hydrogel: Design and optimization using a combination of polymers

The purpose of the study was to develop an optimized thermoreversible in situ gelling ophthalmic drug delivery system based on Pluronic F 127, containing moxifloxacin hydrochloride as a model drug. A 3(2) full factorial design was employed with two polymers: Pluronic F 68 and Gelrite as independent variables used in combination with Pluronic F 127. Gelation temperature, gel strength, bioadhesion force, viscosity and in vitro drug release after 1 and 10 h were selected as dependent variables. Pluronic F 68 loading with Pluronic F 127 was found to have a significant effect on gelation temperature of the formulation and to be of importance for gel formation at temperatures 33-36 °C. Gelrite loading showed a positive effect on bioadhesion force and gel strength and was also found helpful in controling the release rate of the drug. The quadratic mathematical model developed is applicable to predicting formulations with desired gelation temperature, gel strength, bioadhesion force and drug release properties.     

Preparation and in vitro evaluation of an ilomastat microemulsion gel by a self-microemulsifying system

The purpose of this study was to construct a microemulsion gel formulation by a self-microemulsifying system for transdermal topical delivery of ilomastat. The optimum formulations were screened by penetration evaluation in vitro. Ilomastat microemulsion gel was prepared by drawing a ternary phase diagram and Pluronic F127 was added as gel matrix for the formulation. The optimal formulations had wide microemulsion existent field and good self-microemulsifying efficiency. The droplet size was within 100 nm. Statistical comparison of the permeation throughout 24 h showed that the two microemulsion gel preparations of ilomastat provided higher permeation than that of the normal gel which had only a low cumulative amount of ilomastat (6.03 microg x cm(-2)) 24 h after application. Cumulative amount of ilomastat from microemulsion gels A and B was 2.2 times and 1.8 times that of the normal gel at 24 h respectively. These results indicate that the microemulsion gel may be a promising vehicle for topical delivery of ilomastat.     

In vivo studies on nasal preparations of ciprofloxacin hydrochloride

Gel formulations of ciprofloxacin hydrochloride (CPH) were prepared with bioadhesive polymers such as hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC) and methylcellulose (MC). They were administered into the nasal cavity of rabbits. A nasal aqueous suspension of CPH with glycerol was also applied. In addition, the effect of Tween 80 as penetration enhancer was examined. The agar plate diffusion technique was applied for the assay of CPH. The results were compared with oral and intravenous administrations. The bioavailability of the CPH gel formulation prepared with HPMC was almost identical to that of the oral route. Other nasal formulations with HEC and MC had bioavailabilities lower than oral preparations. The relative bioavailabilities for the formulation containing HEC and MC were 48.7 and 45.54%, respectively. To increase the bioavailabilities, 1% (w/w) of Tween 80 was added. The bioavailability of these gel formulations increased to 63.54 and 55.72%, respectively. Experiments carried out on rabbits showed that the nasal administration of CPH bioadhesive gel formulation containing HPMC may be an alternative to the oral route.     

Absorption of insulin from pluronic F-127 gels following subcutaneous administration in rats.

The main objective of this work was to evaluate the use of Pluronic (PF127) gels, polylactic-co-glycolic acid (PLGA) nanoparticles and their combination for parenteral delivery of peptides and proteins having short half-lives using insulin as a model drug. The in vitro insulin release profiles of various PF127 formulations were evaluated at 37 degrees C using a membraneless in vitro model. In vivo evaluation of the serum glucose and insulin levels was performed following subcutaneous administration of various insulin formulations in normal rats. The in vitro results demonstrated that the higher the concentration of PF127 in the gel, the slower the release of insulin from the matrices, independent of the vehicle used. The acute hypoglycemic peak resulting from administration of an insulin solution between 0.5 and 2.0 h after administration (peak at 1 h) is replaced after administration of insulin-PLGA nanoparticles by an almost constant hypoglycemic effect with a slower recovery of the serum glucose levels at about 2 h after administration. By loading insulin into PF127 gels, a slower and more prolonged hypoglycemic effect of insulin was obtained in inverse proportion to the polymer concentration. PF127 gel formulations containing insulin-PLGA nanoparticles had the most long-lasting hypoglycemic effects of all formulations. From the current in vitro and in vivo study, we concluded that PF127 gel formulations containing either drug or drug-nanoparticles could be useful for the preparation of a controlled delivery system for peptides and proteins having short half-lives. Copyright     

Development and characterization of micellar systems for application as insect repellents

N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent due to its high efficacy. In this work, micellar systems based on poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) triblock copolymer were developed and studied for the purpose of controlling the release and cutaneous permeation of DEET, using concentrated solutions of the copolymer Pluronic F127 to form thermoreversible gels. The formulations presented thermoreversible gelation above 5 °C and altered rheological behavior at 15 and 25 °C. The presence of the drug drastically changed the sol–gel transition temperatures. The micrographs suggest that DEET induced the formation of anisotropic structures, and Maltese Crosses were observed. The formulation containing 10 wt% DEET and 15 wt% Pluronic F127 presented sustained drug release for up to 7 h. DEET release profile followed the Higuchi kinetics model. There was a reduction of approximately 35% in the amount of DEET absorbed through the skin after 6 h. About 62% of DEET from the formulation consisting of Pluronic F127 and DEET remain retained on the skin. The anisotropic structure may constitute a barrier to diffusion and thereby controlling the drug release effectively. These tests suggest that the tested samples exhibit safety profile greater than some commercially available products.