5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Gelatine enhances drug dispersion in alginate bilayer film via the formation of crystalline microaggregates

In our previous study, a novel alginate-based bilayer film for slow-release wound dressings was successfully developed. We found that alginate alone yielded poor films; however, the addition of gelatine had significantly enhanced the drug dispersion as well as the physical properties. Here, an investigation of the drug–polymer interactions in the bilayer films was carried out. Drug content uniformity test and microscopy observation revealed that the addition of gelatine generated bilayer films with a homogenous drug distribution within the matrix. The FTIR and XRD data showed an increase in film crystallinity which might infer the presence of drug–polymer crystalline microaggregates in the films. DSC confirmed the drug–polymer interaction and indicated that the gelatine has no effect on the thermal behaviour of the microaggregates, suggesting the compatibility of the drug and excipients in the bilayer films. In conclusion, the addition of gelatine can promote homogenous dispersion of hydrophobic drugs in alginate films possibly through the formation of crystalline microaggregates.     

Development of polyvinyl alcohol-sodium alginate gel-matrix-based wound dressing system containing nitrofurazone

Polyvinyl alcohol (PVA)/sodium alginate (SA) hydrogel matrix-based wound dressing systems containing nitrofurazone (NFZ), a topical anti-infective drug, were developed using freeze-thawing method. Aqueous solutions of nitrofurazone and PVA/SA mixtures in different weight ratios were mixed homogeneously, placed in petri dishes, freezed at -20 degrees C for 18h and thawed at room temperature for 6h, for three consecutive cycles, and evaluated for swelling ratio, tensile strength, elongation and thermal stability of the hydrogel. Furthermore, the drug release from this nitrofurazone-loaded hydrogel, in vitro protein adsorption test and in vivo wound healing observations in rats were performed. Increased SA concentration decreased the gelation%, maximum strength and break elongation, but it resulted into an increment in the swelling ability, elasticity and thermal stability of hydrogel film. However, SA had insignificant effect on the release of nitrofurazone. The amounts of proteins adsorbed on hydrogel were increased with increasing sodium alginate ratio, indicating the reduced blood compatibility. In vivo experiments showed that this hydrogel improved the healing rate of artificial wounds in rats. Thus, PVA/SA hydrogel matrix based wound dressing systems containing nitrofurazone could be a novel approach in wound care.     

Wound dressings containing bFGF-impregnated microspheres

The primary objective was to synthesize a novel wound dressing containing basic fibroblast growth factor (bFGF)-loaded microspheres for promoting healing and tissue regeneration. Gelatin sponge was chosen as the underlying layer and elastomeric polyurethane membranes were used as the external layer. To achieve prolonged release, bFGF addition was loaded in microspheres. The microspheres were characterized for particle size, in vitro protein release and bioactivity. The bilayer dressings were tested in in vivo experiments on full-thickness skin defects created on pigs. Average size of the microspheres was 14.36 +/- 3.56 microm and the network sponges were characterized with an average pore size of 80-160 microm. Both the in vitro release efficiency and the protein bioactivity revealed that bFGF was released in a controlled manner and it was biologically active as assessed by its ability to induce the proliferation of fibroblasts. It was observed that sustained release of bFGF provided a higher degree of reduction in the wound areas. Histological investigations showed that the dressings were biocompatible and did not cause any mononuclear cell infiltration or foreign body reaction. The structure of the newly formed dermis was almost the same as that of the normal skin. The application of these novel bilayer wound dressings provided an optimum healing milieu for the proliferating cells and regenerating tissues in pig's skin defect models.     

Wound Dressings Based on Chitosans and Hyaluronic Acid for the Release of Chlorhexidine Diacetate in Skin Ulcer Therapy

In the present work wound dressings, based on chitosan hydrochloride (HCS), 5-methyl-pyrrolidinone chitosan (MPC), and their mixtures with an anionic polymer, hyaluronic acid (HA), were prepared by freeze-drying. Chlorhexidine diacetate (CX) was used as an antimicrobic drug. The mechanical properties of the wound dressings were investigated. In particular, the wound dressings were subjected to dynamic hydration measurements to evaluate their capability to absorb wound exudate and to rheological analysis to investigate their resistance to mechanical stresses on hydration. The wound dressings were also characterized for drug release properties. The antioxidant and antimicrobial activities of medicated and non-medicated wound dressings were also investigated. All the wound dressings are characterized by mechanical resistance suitable for skin application. The addition of hyaluronic acid to chitosans leads to a reduction in wound dressing hydration properties and a modulation of drug release. The wound dressing based on MPC is characterized by the highest elastic properties and by the best scavenger activity. Antimicrobial activity against bacteria and C. albicans is shown by the dressing based on chitosan also in absence of chlorhexidine.     

Wound dressings based on chitosans and hyaluronic acid for the release of chlorhexidine diacetate in skin ulcer therapy

In the present work wound dressings, based on chitosan hydrochloride (HCS), 5-methyl-pyrrolidinone chitosan (MPC), and their mixtures with an anionic polymer, hyaluronic acid (HA), were prepared by freeze-drying. Chlorhexidine diacetate (CX) was used as an antimicrobic drug. The mechanical properties of the wound dressings were investigated. In particular, the wound dressings were subjected to dynamic hydration measurements to evaluate their capability to absorb wound exudate and to rheological analysis to investigate their resistance to mechanical stresses on hydration. The wound dressings were also characterized for drug release properties. The antioxidant and antimicrobial activities of medicated and non-medicated wound dressings were also investigated. All the wound dressings are characterized by mechanical resistance suitable for skin application. The addition of hyaluronic acid to chitosans leads to a reduction in wound dressing hydration properties and a modulation of drug release. The wound dressing based on MPC is characterized by the highest elastic properties and by the best scavenger activity. Antimicrobial activity against bacteria and C. albicans is shown by the dressing based on chitosan also in absence of chlorhexidine.     

奥硝唑缓释膜体内、外释放性的研究

目的:测定奥硝唑缓释膜体内、外释放度。方法:体外释放度试验采用《中国药典》“转篮法”;体内释放度实验取大鼠于牙周袋内置入缓释膜(0.18mg),给药后不同时间测定龈沟液中奥硝唑浓度,并与大鼠腹腔注射奥硝唑溶液(25mg)比较。结果:缓释膜在体外试验中10min释药13.9%,10h后仍有药物释放;腹腔注射给药后龈沟液药物浓度是牙周袋内局部置药的1%~5%。结论:该缓释膜具有良好的缓释功能,能在大鼠牙周袋内较长时间维持有效浓度。     

创面用复方喷雾膜剂的制备及其性质研究

目的 研制创面用复方喷雾膜剂（compound spraying film,CSF）,并进行质量评价.方法 采用物理混合法制备CSF,评价其成膜性能和机械性能;以HPLC法测定其含量和释药行为;建立大鼠创面模型,评价其创面愈合效果.结果 CSF的成膜温度为（30±2）℃,成膜时间为（29±6）s,机械性质良好.CSF含人参皂苷（GRg1） （5.82±0.08）mg/g,体外释药以骨架溶蚀为主,释药动力学符合零级方程和Ritger-Peppas方程特征.CSF用于治疗大鼠背部机械创伤,愈合百分率均显著高于复方水溶液组和空白喷雾膜剂组（P＜0.05）.结论 CSF使用方便,性质优良,促愈效果明显,具有良好的应用前景.     

Evaluating tamsulosin hydrochloride-released microparticles prepared using single-step matrix coating

The purpose of the present study was to prepare matrix extended release pellets of diclofenac potassium using low amount of release-modifying agents and, to compare its performance in vivo with coated pellets and matrix tablets. Coated pellets were prepared by extrusion-spheronization, followed by double layer coating using different polymers separately. Matrix pellets with different release rate in vitro were prepared by extrusion-spheronization with different kinds of retarding materials. Bioavailability study of different coated pellets revealed that the drug concentration in plasma of beagle dogs was too low to be detected and, implied that the drug was nearly not released from the preparations before reaching colon due to the appearance of lag time in the dissolution process. The phenomenon indicated that slow-release pellets of diclofenac potassium perhaps should not be developed as double membrane-controlled type. The AUC((0 → 24)) of the immediate release pellets, the two matrix pellets and the reference were 304.4, 87.7, 204.1 and 179.1 μg h/ml, respectively. The C(max) of the formulations mentioned above were 46.3, 13.0, 33.6 and 32.1 μg/ml, respectively. All the matrix formulations, including the reference, exhibited incomplete absorption due to the short small intestine transit time and termination of the drug release in the colon because of its limited solubility. The matrix pellets were bioequivalent with the commercially available tablet (Voltaren(?)) although the drug release in vitro of the former was much faster, while the bioavailability of the matrix pellets with similar in vitro drug release to the reference (Voltaren(?)) was much lower than the latter. The results perhaps was caused by lacking of physical robustness in the waxy tablet formulation, resulted in low wet strength and easily destroyed by the mechanical destructive forces and finally introduced faster drug release rate in vivo. It is apparent that preparations with similar performance in vitro may differ a lot in vivo because of the differences in drug release rate in vivo owing to various wet strengths of excipients contained, especially for sustained release products.     

In vivo wound healing performance of drug loaded electrospun composite nanofibers transdermal patch

Acute injuries or wound is required the fast delivery of drug to control infections without any side effect. In this direction in the present investigation, antibiotic ciprofloxacin loaded hydrophilic biodegradable poly vinyl alcohol (PVA) and sodium alginate (NaAlg) electrospun composite nanofiber based transdermal patch was developed for local delivery of antibiotic drug. The antibiotic drug ciprofloxacin was loaded in it by active loading. The drug entrapped in the composite nanofibers was confirmed by the scanning electron microscopy and swelling behavior. The in vivo studies were carried on male rabbits by using the drug loaded and unloaded composite nanofibers transdermal patch and marketed one. It is observed that, in vitro activity provides a sustained and controlled release pattern of the drug from transdermal patch. The mechanism of drug release was also studied using different models. The nanofiber transdermal patch follows the Higuchi and Korsmeyer–Peppas model for drug release. The in vivo studies demonstrate that, wound healing takes place in less time as compared drug unloaded patch. Hydroxyproline produced in wound bed with time shows that it content is maximum in case drug loaded PAV-NaAlg patch. This demonstrates that wound healing rate is higher in case drug loaded PVA-NaAlg transdermal patch.     

Design of a gastroretentive mucoadhesive dosage form of furosemide for controlled release

The aim of the present study was to develop and characterize a gastroretentive dosage form suitable for controlled drug release. It consists of a drug loaded polymeric film made up of a bilayer of immediate (IR) and controlled release (CR) layers folded into a hard gelatin capsule. Gastroretention results from unfolding and swelling of the film and its bioadhesion to the gastric mucosa. Furosemide, a drug with a narrow absorption window, was selected as the model drug. Inclusion of hydroxypropyl β-cyclodextrin in both layers and Carbopol^® 971P NF in the CR layer of the bilayer film resulted in optimum drug release, bioadhesion and mechanical properties. The film with zig-zag folding in the capsule was shown to unfold and swell under acidic conditions and provide IR of drug over 1 h and CR for up to 12 h in acidic medium. X-ray diffraction, differential scanning calorimetry and scanning electron microscopy revealed uniform dispersion of furosemide in the polymeric matrices. The results indicate the dosage form is gastroretentive and can provide controlled release of drugs with narrow therapeutic windows.     

Wound healing evaluation of benzalkonium chloride-loaded hydrocolloid in the wound infection model

An adequate environment for wound healing improves cell proliferation and cell activity, rearranges fibroblasts, and suppresses the multiplication of bacteria. The aim of this study was to evaluate the wound-healing effects of a semi-occlusive hydrocolloid wound dressing (HWD) containing a topical antiseptic drug, benzalkonium chloride (BKC) in an infectious wound model. In vivo wound-healing profiles in rats exhibited that BKC-loaded HWD successfully promoted epithelialization rate, compared with gauze control or HWD without BKC. Furthermore, the significant decrease in desquamated epithelial regions, numbers of microvessels and inflammatory cells infiltrated in granulation tissues and granulation tissue areas were observed in the histopathological and histomorphometrical profiles of BKC-loaded HWD. In conclusion, these results suggest that BKC-loaded HWD facilitates wound healing and re-epithelization, and has promising effects for the treatment of infected wounds, as compared to HWD without BKC.     

正交试验优化复方奥硝唑阴道生物黏附膜处方

目的:优化复方奥硝唑阴道生物黏附膜的处方。方法:以辅料酸性壳聚糖浓度、明胶浓度、聚乙烯醇(PVA)浓度及主药浓度为考察因素,以生物黏附力为考察指标,采用正交试验设计优化处方,并测定优化处方的生物黏附力和体外释放度。结果:优化的处方组成是酸性壳聚糖浓度为2.0%,明胶浓度为1.0%,PVA浓度为1.0%,主药浓度为2.0%。优化处方所制3批膜剂的平均生物黏附力为2.1N·cm-2,12h时平均体外累积释放率大于89%。结论:按照优化处方制备的复方奥硝唑阴道生物黏附膜具有较好的生物黏附力和缓释性。     

Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes

The aim of this work is to improve the ocular bioavailability of ciprofloxacin hydrochloride (CPX) through the preparation of ocular mucoadhesive chitosan (CS)-coated liposomes. Liposomes were prepared by the thin film hydration technique, using different molar ratios of L-α-phosphatidylcholine (PC), cholesterol (CH), stearylamine (SA) and dicetyl phosphate (DP). CS was used to coat the optimal liposomal formulae. The prepared formulae were characterized regarding encapsulation efficiency (%EE), particle size, physical morphology and in vitro drug release. The in vivo characterization of the prepared formulae was performed through evaluating the level of CPX in the external eye tissue of nine albino rabbits. Results showed an alteration in release rate and %EE of CPX from liposomal formulae upon varying the molar ratios of the lipid bilayer composition. The optimal liposomal formulae F1 (10:0, PC:CH), F12 (10:0:0.5, PC:CH:SA) and F15 (10:0:1, PC:CH:DP), showed % EE of 38.5?±?2.10, 39.65?±?1.85 and 30.05?±?0.75 and % in vitro release after 8 hours (Q_8h) of 78.15?±?2.4, 54.07?±?2.3 and 62.14?±?2.9, respectively. In vitro drug release and in vivo results confirmed that CS-coated liposomal formulae have exhibited a higher retention of CPX. Consequently, CS-coated liposomes could be a promising approach to increase the ocular bioavailability of CPX.     

新型氨基酸修饰羟基磷灰石纳米复合缓释材料的制备与释药特性研究

目的：本文设计并合成了新型聚氨基酸纳米羟基磷灰石缓释材料,并以替莫唑胺为模型药物,对所合成材料的体外释药性能进行研究。方法：采用微乳液法制备多孔羟基磷灰石,以天冬氨酸单体为原料,合成聚氨基酸高分子材料,利用高分子化合物水溶液中的蜷缩成膜性能与羟基磷灰石组成复合缓释纳米材料。以替莫唑胺为模型药物,对所制备的复合纳米缓释制剂的体外释放性能进行研究。结果：所制备的替莫唑胺-纳米复合羟基磷灰石缓释制剂为光滑的纳米球制剂,体外释放实验显示,可起到长约200 h的缓释效果。结论：本文制备的替莫唑胺复合纳米羟基磷灰石缓释制剂具有长期的缓释性能,可潜在适用于体内植入给药。     

Formulation and evaluation of sustained release floating capsules of nicardipine hydrochloride

Nicardipine hydrochloride, a calcium channel blocker with significant vasodilating and antihypertensive activities, was formulated in this work as sustained release floating capsules. A hydrocolloid of high viscosity grade was used for the floating systems. The inclusion of sodium bicarbonate to allow evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release were included as coprecipitates with the drug and/or as additives in the formulated capsules. Both simple powder mixing of the ingredients and granule preparation via wet granulation were used. Seven capsule formulae were prepared. The prepared capsules were evaluated in vitro by testing drug dissolution, floating time and the kinetics of drug release. In vitro evaluation of a commercially available conventional 20 mg capsule of nicardipine hydrochloride, "Micard", was carried out for comparison. The hydrocolloid used succeeded in effecting capsule buoyancy. Floating time increased with increasing the proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. All of the seven floating capsule formulae prepared proved efficient in controlling drug release. The sustained release floating capsule formulation of choice was evaluated in vivo in comparison to "Micard" capsules using rabbits. Reversed phase HPLC with UV detection was used for drug determination in rabbit plasma. Plasma concentration time curves revealed a longer drug duration for administration in the sustained release formula than the conventional "Micard" capsule being 16 h in the former versus 8 h for the latter.     

Niosomes: a controlled and novel drug delivery system

During the past decade formulation of vesicles as a tool to improve drug delivery, has created a lot of interest amongst the scientist working in the area of drug delivery systems. Vesicular system such as liposomes, niosomes, transferosomes, pharmacosomes and ethosomes provide an alternative to improve the drug delivery. Niosomes play an important role owing to their nonionic properties, in such drug delivery system. Design and development of novel drug delivery system (NDDS) has two prerequisites. First, it should deliver the drug in accordance with a predetermined rate and second it should release therapeutically effective amount of drug at the site of action. Conventional dosage forms are unable to meet these requisites. Niosomes are essentially non-ionic surfactant based multilamellar or unilamellar vesicles in which an aqueous solution of solute is entirely enclosed by a membrane resulting from the organization of surfactant macromolecules as bilayer. Niosomes are formed on hydration of non-ionic surfactant film which eventually hydrates imbibing or encapsulating the hydrating aqueous solution. The main aim of development of niosomes is to control the release of drug in a sustained way, modification of distribution profile of drug and for targeting the drug to the specific body site. This paper deals with composition, characterization/evaluation, merits, demerits and applications of niosomes.     

骨载异烟肼缓释微球的制备及其在动物模型中的释放研究

目的：观察探讨骨载异烟肼聚乳酸微球的设计和制备方法及其在动物模型中的释放效果。方法：选择24只雄性新西兰大白兔作为实验动物模型,采用复乳法制备缓释微球,对微球进行形态学观察、粒径分布观察、体内释药和体外释药观察。结果：平均微球粒径（10.59±0.3）μm,平均包封率（44.9±0.9）%,平均载药率（13.0±0.6）%。在24h、72h、1w、3w微球组滑膜药物浓度明显高于口服组和原药组,P＜0.05。与口服组和原药组对比,微球组0～24h药物波动差值明显更低,P＜0.05。结论：本研究制备的骨载异烟肼缓释微球具有良好的缓释性,能够在抗结核治疗中置入骨结核病灶对术后病灶发挥持久的疗效。     

Oral mucosal bioadhesive tablets of pectin and HPMC: in vitro and in vivo evaluation

The potential of tablets containing 1:4, 1:1 and 4:1 weight ratios of pectin and hydroxypropyl methylcellulose (HPMC) for the sustained release of diltiazem by sublingual administration has been investigated. Measurements of maximum adhesive force to rat peritoneal membrane indicated a satisfactory bioadhesive strength. An in vitro sustained release of diltiazem over 5 h was achieved with bilayer tablets composed of a drug-free ethylcellulose layer in addition to the pectin/HPMC layer containing drug. Plasma concentration-time curves obtained following sublingual administration to rabbits of single and bilayer tablets with 1:1 weight ratios of pectin and HPMC showed evidence of sustained release of diltiazem. Bioavailability of diltiazem was 2.5 times that achieved by oral administration for single layer tablets and 1.8 times for the bilayered tablets.