Electroactive controlled release thin films

We present the fabrication of nanoscale electroactive thin films that can be engineered to undergo remotely controlled dissolution in the presence of a small applied voltage (+1.25 V) to release precise quantities of chemical agents. These films, which are assembled by using a nontoxic, FDA-approved, electroactive material known as Prussian Blue, are stable enough to release a fraction of their contents after the application of a voltage and then to restabilize upon its removal. As a result, it is possible to externally trigger agent release, exert control over the relative quantity of agents released from a film, and release multiple doses from one or more films in a single solution. These electroactive systems may be rapidly and conformally coated onto a wide range of substrates without regard to size, shape, or chemical composition, and as such they may find use in a host of new applications in drug delivery as well as the related fields of tissue engineering, medical diagnostics, and chemical detection.     

Synthesis and In Vitro/Ex Vivo Characterizations of Ceftriaxone-Loaded Sodium Alginate/poly(vinyl alcohol) Clay Reinforced Nanocomposites: Possible Applications in Wound Healing

(1) Background: Nanocomposite films are widely applied in the pharmaceutical industry (e.g., nanodrug delivery systems—NDDS). Indeed, these nanomaterials can be produced at a large industrial scale and display valuable properties (e.g., antibacterial, renewability, biodegradability, bioavailability, safety, tissue-specific targeting, and biocompatibility), which can enhance the activity of conventional marketed drugs. (2) Aim: To fabricate and investigate the in vitro properties of the antibiotic ceftriaxone sodium (CTX) once encapsulated into sodium alginate (SA)/poly(vinyl alcohol)PVA-clay reinforced nanocomposite films. (3) Methods: Different ratios of the polymers (i.e., SA, PVA) and CTX drug were used for the synthesis of nanocomposite films by solvent casting technique. Montmorillonite (MMT), modified organically, was added as a nanofiller to increase their thermal and mechanical strength. The prepared samples were physically characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electronic microscopy (SEM), and energy-dispersive X-ray analysis (EDX). The physicochemical behavior (i.e., swelling, erosion, dissolution/drug release behavior and rat skin permeation) was also assessed. Comparisons were made with the currently marketed free CTX dosage form. (4) Results: TGA of the nanoformulation showed increased thermostability. XRD revealed its semi-crystalline nature. SEM depicted a homogeneous drug-loaded SA/PVA nanocomposite with an average size ranging between 300 and 500 nm. EDX confirmed the elemental composition and uniform distribution of mixing components. The water entrapment efficiency study showed that the highest swelling and erosion ratio is encountered with the nanoformulations S100(3) and S100D15(3). Ex vivo permeation revealed a bi-step discharge mode with an early burst liberation chased by continued drug discharge of devised nanoparticles (NPs). The dissolution studies of the drug-loaded polymer nanocomposites elicited sustained pH-dependent drug release. The cumulative drug release was the highest (90.93%) with S100D15(3). (5) Conclusion: S100D15(3) was the finest formulation. To the best of our knowledge, we also pioneered the use of solvent casting for the preparation of such nanoformulations. Polymers and reinforcing agent, concentrations and pH were rate-deterring features for the preparation of the optimized formulation. Thus, CTX-loaded SA/PVA-MMT reinforced nanocomposite appeared as a promising nanodrug delivery system (NDDS) based on its in vitro physicochemical properties.     

Orodispersible Films with Rupatadine Fumarate Enclosed in Ethylcellulose Microparticles as Drug Delivery Platform with Taste-Masking Effect

Orally disintegrating (orodispersible) films provide a versatile tool for drug administration, especially in the pediatric and geriatric population, since they reduce the risk of choking and do not necessitate drinking water during application. By considering their direct contact with the taste buds, palatability is an influential aspect related to patient compliance. The microparticles based on taste-masking polymers containing drugs enclosed inside effectively mask the unpleasant taste of medicines. Ethylcellulose is a hydrophobic polymer widely used as a taste-masking material. Rupatadine fumarate, a second-generation antihistamine drug, is characterised by an intense bitter taste; therefore, it is crucial to achieve a tolerable taste whilst developing orodispersible formulations with its content. The objective of this study was to develop orally disintegrating films with rupatadine fumarate in the form of ethylcellulose-based microparticles obtained from aqueous dispersions of ethylcellulose—Surelease^® or Aquacoat^® ECD. It was a technological challenge to achieve homogenous drug content per dosage unit and sufficient mechanical properties for film operating due to the necessity to suspend the microparticles in the casting solution. Although the process of obtaining films consisted of several steps (mixing, pouring, drying), the particles were homogeneously dispersed, and each film of the desired size contained the proper dose of the drug. The taste-masking effect was also maintained. This parameter was confirmed by three independent methods: in vivo by healthy volunteers, an electronic tongue and a dissolution test. The applied taste-evaluation techniques showed that the films containing Aquacoat^® ECD microparticles have the highest degree of bitter taste reduction, which confirms the results obtained in our previous studies.     

Temperature-Responsive Polysaccharide Microparticles Containing Nanoparticles: Release of Multiple Cationic/Anionic Compounds

Most drug carriers used in pulmonary administration are microparticles with diameters over 1 µm. Only a few examples involving nanoparticles have been reported because such small particles are readily exhaled. Consequently, the development of microparticles capable of encapsulating nanoparticles and a wide range of compounds for pulmonary drug-delivery applications is an important objective. In this study, we investigated the development of polysaccharide microparticles containing nanoparticles for the temperature-responsive and two-step release of inclusions. The prepared microparticles containing nanoparticles can release two differently charged compounds in a stepwise manner. The particles have two different drug release pathways: one is the release of nanoparticle inclusions from the nanoparticles and the other is the release of microparticle inclusions during microparticle collapse. The nanoparticles can be efficiently delivered deep into the lungs and a wide range of compounds are released in a charge-independent manner, owing to the suitable roughness of the microparticle surface. These polysaccharide microparticles containing nanoparticles are expected to be used as temperature-responsive drug carriers, not only for pulmonary administration but also for various administration routes, including transpulmonary, intramuscular, and transdermal routes, that can release multiple drugs in a controlled manner.     

依那普利口颊黏膜给药系统:制备和表征

目的探讨依那普利的口颊黏膜给药系统的制备。方法使用粘膜粘附性多聚物、通过溶剂涂布技术,将依那普利配制成口腔贴膜的形式,同时在体外释放研究和透过性研究中评价了其多种理化特点。结果所有配方均显示有高的药物百分含量(96.45%至98.49%)。有良好膨胀特性的配方显示有良好的驻留时间。在体外,发现包括贴膜(F2)在内的高粘性羧甲纤维素钠(SCMC-HV)的药物释放率最高(药物释放很快,在1.5小时内释放92.24%)、其次是贴膜F4(含有聚乙烯吡咯烷酮K-90 1%w/v个SCMC(HV)1%w/v)。研究发现,在10小时结束时,F2和F4的活体外药物穿透率分别为82.24%和89.90%。结论根据最高的膨胀度、最高的驻留时间和最长体外驻留时间选择将配方F4用于构建口颊贴膜,可用于对心血管病的治疗。     

Optimization of Hyaluronate-Based Liposomes to Augment the Oral Delivery and the Bioavailability of Berberine

Various perspectives had been utilized to enhance the poor intestinal permeability and bioavailability of drugs with low water solubility. Berberine (Brb) is a unique molecule that possesses multiple therapeutic activities such as antimicrobial, anti-inflammatory, antioxidant and anti-hyperglycemic effects. To improve Brb permeability and bioavailability, this study presents a newly developed formulation, namely Brb hyaluronate-based liposomes, prepared by using film hydration method and characterized by dynamic light scattering measurements, entrapment efficiency percentage (EE%), transmission electron microscope (TEM), in vitro drug release and physical stability. The bioavailability of the selected formulations was assessed in vivo after oral administration to rats. The results revealed an enhanced effect of hyaluronic acid on the entrapment efficiency, reaching 78.1 ± 0.1% with mean size 520.7 ± 19.9 nm. Sustained release of Brb was recorded up to 24 h in comparison to Brb solution. Physical stability was maintained for three months at refrigeration temperature. Results of pharmacokinetics studies indicated the potential of the liposomal formulation to increase the oral bioavailability of Brb and to accelerate its entry into the bloodstream. The obtained results are accredited to the lipophilic nature of the prepared system, resembling the structural features of bio-membrane, in addition to their small size that enhances intestinal penetration.     

The course of cryptococcal capsular polysaccharide antigenemia/human cryptococcal polysaccharide elimination kinetics

The detection of cryptococcal polysaccharides in the serum is diagnostic of cryptococcosis in the absence of rheumatoid factor. The significance of the continued detection of this antigen in the serum during antifungal therapy is not known. Prolonged antigenemia might indicate ongoing active infection, delayed clearance of the polysaccharides from the blood, or continued release of the polysaccharide antigens from a reservoir of nonviable organisms. In seven cases the cryptococcosis with prolonged and high levels of cryptococcal polysaccharide antigenemia, the courses of antigenemia were determined. During the convalescent phase, the T 1/2's were approximately 48 hours for the antigen clearance in all the cases studied. The polysaccharide antigens recovered from the serum of one patient had molecular weights of greater than 200,000 daltons. In rabbits, a single intravenous injection of cryptococcal capsular polysaccharides showed a similarly slow clearance of the antigen with a T 1/2 of approximately 24 to 48 hours. These data suggest that adequately treated cases of cryptococcosis may have a predictable rate of antigen clearance from the serum during convalescence.     

Comparison of therapeutic and immunosuppressive effects of azathioprine,prednisolone and combined therapy in nzp/nzw mice

Since NZB/NZW mice develop an immune nephritis similar to that of systemic lupus erythematosus in man, a study was designed in these mice to compare the clinical and immunologic effects of three immunosuppressive drug regimens. For 72 weeks, groups of 20 mice received daily oral therapy with a) no drugs, b) azathioprine, c) prednisolone or d) combined azathioprine-prednisolone. The combined regimen was superior to either drug used alone in preventing deaths from renal disease. Prednisolone alone also prolonged life significantly, but not as effectively as combination therapy. Azathioprine alone was not effective. All drugs suppressed the antibody response to an exogenous antigen (Vi polysaccharide) equally well. None of the drug regimens prevented the appearance of proteinuria, antinuclear antibodies, Coombs' antibody, or γ-globulin deposits in glomeruli. However, the ability of a therapeutic regimen to suppress antibodies to native DNA correlated well with its ability to suppress renal disease. No malignancies were found among 73 animals autopsied, but significant hepatic damage occurred in the groups receiving prednisolone. Thus, combined therapy was superior to either drug used alone, and the immunosuppressive effect of greatest clinical importance seemed to be the ability to prevent formation of anti-DNA antibodies.     

Simultaneously Embedding Indomethacin and Electrodeposition of Polypyrrole on Various CoCr Alloys from Ionic Liquids

The aim of the present investigation is the electrochemical deposition of polypyrrole films from choline chloride-based ionic liquids at various potential, period times and simultaneously an indomethacin embedding and release. The electrodeposition films were performed on CoCr commercial type Wirobond C (WBC) and, Heraenium CE (Hera) using as electroprocedures for deposition cyclic voltammetry and chronoamperometry. The morphology of obtained films was investigated using scanning electron microscopy (SEM). An FT-IR investigation of CoCr alloys before and after electrodeposition was able to identify the presence of polymer and drug. The research included an evaluation of the hydrophilic character of all studied samples and their electrochemical characterization in Tanni Zuchi artificial saliva. In the electrochemical study, the following methods have been used: open circuit potential, electrochemical impedance spectroscopy and potentiodynamic polarization. Indomethacin release from the polymeric film was determined using UV-VIS spectra. Based on Fick’s law of diffusion and indomethacin release profile, a kinetic law for release was established and discussed.     

Bio-based Films from Linter Cellulose and Its Acetates: Formation and Properties

This paper describes the results obtained on the preparation of films composed of linter cellulose and the corresponding acetates. The acetylation was carried out in the LiCl/DMAc solvent system. Films were prepared from a LiCl/DMAc solution of cellulose acetates (degree of substitution, DS 0.8–2.9) mixed with linter cellulose (5, 10 and 15 wt %). Detailed characterization of the films revealed the following: (i) they exhibited fibrous structures on their surfaces. The strong tendency of the linter cellulose chains to aggregate in LiCl/DMAc suggests that these fibrous elements consist of cellulose chains, as can be deduced from SEM images of the film of cellulose proper; (ii) the cellulose acetate films obtained from samples with DS 2.1 and 2.9 exhibited microspheres on the surface, whose formation seems to be favored for acetates with higher DS; (iii) AFM analysis showed that, in general, the presence of cellulose increased both the asperity thickness and the surface roughness of the analyzed films, indicating that cellulose chains are at least partially organized in domains and not molecularly dispersed between acetate chains; and (iv) the films prepared from cellulose and acetates exhibited lower hygroscopicity than the acetate films, also suggesting that the cellulose chains are organized into domains, probably due to strong intermolecular interactions. The linter and sisal acetates (the latter from a prior study), and their respective films, were prepared using the same processes; however, the two sets of films presented more differences (as in humidity absorption, optical, and tensile properties) than similarities (as in some morphological aspects), most likely due to the different properties of the starting materials. Potential applications of the films prepared in tissue engineering scaffold coatings and/or drug delivery are mentioned.     

Use of Amphoteric Copolymer Films as Sacrificial Layers for Constructing Free-Standing Layer-by-Layer Films

The present paper reports the use of an amphoteric copolymer, poly(diallylamine-co-maleic acid) (PDAMA), as a component of precursor layers (or sacrificial layers) for constructing free-standing layer-by-layer (LbL) films. A PDAMA-poly(styrenesulfonate) (PSS) film or PDAMA-poly(dimethyldiallylammonium chloride) (PDDA) film was coated on the surface of a quartz slide at pH 4.0 or 8.0, respectively, as a sacrificial layer that can be removed by changing the pH. The surface of the sacrificial layer was further covered with LbL films composed of poly(allylamine hydrochloride) (PAH) and PSS. The PAH-PSS films were released from the substrate upon immersing the film-coated quartz slide in acidic or neutral/basic solution, respectively, as a result of the pH-induced dissolution of the PDAMA-PDDA or PDAMA-PSS sacrificial layer. Thus, PDAMA-based sacrificial layers have been demonstrated to dissolve in both acidic and neutral solutions, depending on the type of counter polymer. The thicknesses of the sacrificial layers and released LbL films are crucial factors for constructing free-standing LbL films. The releasing kinetics also depended on the thickness of the crucial layers. The free-standing PAH-PSS films obtained were stable in water or in air in the dry state. PDAMA-based sacrificial layers may be useful in constructing free-standing LbL films containing biomolecules with limited pH stability.     

An Overview on Thermosensitive Oral Gel Based on Poloxamer 407

In this review, we describe the application of thermosensitive hydrogels composed of poloxamer in medicine, especially for oral cavities. Thermosensitive hydrogels remain fluid at room temperature; at body temperature, they become more viscous gels. In this manner, the gelling system can remain localized for considerable durations and control and prolong drug release. The chemical structure of the poloxamer triblock copolymer leads to an amphiphilic aqueous solution and an active surface. Moreover, the poloxamer can gel by forming micelles in an aqueous solution, depending on its critical micelle concentration and critical micelle temperature. Owing to its controlled-release effect, a thermosensitive gel based on poloxamer 407 (P407) is used to deliver drugs with different characteristics. As demonstrated in studies on poloxamer formulations, an increase in gelling viscosity decreases the drug release rate and gel dissolution time to the extent that it prolongs the drug’s duration of action in disease treatment. This property is used for drug delivery and different therapeutic applications. Its unique route of administration, for many oral diseases, is advantageous over traditional routes of administration, such as direct application and systemic treatment. In conclusion, thermosensitive gels based on poloxamers are suitable and have great potential for oral disease treatment.     

Micro-emulsion based emulgel: a novel topical drug delivery system

Topical delivery systems for drugs make localized administration of the drug anywhere in the body through ophthalmic, vaginal, skin and rectal routes. Topical formulations encompass a wide variety of formulations intended for cosmetic or dermatological application, to healthy as well as diseased skin. Drugs may be administered for localized or systemic effect. Topical preparations can be formulated with varying physico-chemical properties, as solid, semisolid or liquid. Micro-emulsion of drug is prepared and incorporated into emulgel, having novel topical drug delivery system as dual release control system. Micro-emulsions are micronized; thermodynamically stable systems having low interfacial tension prepared by adding co-surfactant have several features like enhanced permeability, good thermodynemic stability and prolong release. Emulgel prolongs the drug release, increases patient compliance and stability of emulsion. The prepared emulgel is evaluated for various parameteres like pH, viscosity, globule size; spreadability etc. whereas micro-emulsion is evaluated for various parameters like viscosity, pH, zeta-potential etc.     

Characterization and Stability of Tanshinone IIA Solid Dispersions with Hydroxyapatite

Solid dispersions of tanshinone IIA (TanIIA) using hydroxyapatite (HAp) as the dispersing carrier (TanIIA-HAp SDs) were prepared by the solvent evaporation method. The formed solid dispersions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry analysis (DSC), X-ray powder diffraction (XRPD) and Fourier transforms infrared (FTIR) spectroscopy. The in vitro dissolution rate and the stability of TanIIA-HAp SDs were also evaluated. DSC and XRPD showed that TanIIA was changed from a crystalline to an amorphous form. FTIR suggested the presence of interactions between TanIIA and HAp in solid dispersions. The result of an in vitro dissolution study showed that the dissolution rate of TanIIA-HAp SDs was nearly 7.11-folds faster than free TanIIA. Data from stability studies for over one year of TanIIA-HAp SDs performed under room temperature revealed no significant differences in drug content and dissolution behavior. All these results indicated that HAp may be a promising carrier for improving the oral absorption of TanIIA.     

Time-and pH-dependent colon-specific drug delivery for orally administered diclofenac sodium and 5-aminosalicylic acid

AIM: To investigate Time- and pH-dependent colon-specific drug delivery systems (CDDS) for orally administered diclofenac sodium (DS) and 5-aminosalicylic acid (5-ASA), respectively.METHODS: DS tablets and 5-ASA pellets were coated by ethylcellulose (EC) and methacrylic acid copolymers (Eudragit[] L100 and S100), respectively. The in vitro release behavior of the DS coated tablets and 5-ASA coated pellets were examined, and then in vivo absorption kinetics of DS coated tablets in dogs were further studied.RESULTS: Release profile of time-dependent DS coated tablets was not influenced by pH of the dissolution medium,but the lag time of DS release was primarily controlled by the thickness of the coating layer. The thicker the coating layer, the longer the lag time of DS release is. On the contrary, in view of the pH-dependent 5-ASA coated pellets,5-ASA release was significantly governed by pH. Moreover,the 5-ASA release features from the coated pellets depended upon both the combination ratio of the Eudragit[] L100 and S100 pH-sensitive copolymers in the coating formulation and the thickness of the coating layer. The absorption kinetic studies of the DS coated tablets in dogs demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release.CONCLUSION: Two types of CDDS, prepared herein by means of the regular coating technique, are able to achieve site-specific drug delivery targeting at colon following oral administration, and provide a promising strategy to control drug release targeting the desired lower gastrointestinal region.     

MMX mesalamine

Most current drug delivery systems in the treatment of ulcerative colitis and Crohn's disease release the active drug at the least effective location for treatment. The pharmaceutical industry has been developing different delivery systems for Multi-Matrix System (MMX) mesalamine for the treatment of Crohn's disease and ulcerative colitis. The new oral mesalamine formulation is a once-daily MMX tablet that delivers the mesalamine to the colon, making it most useful in the treatment of ulcerative colitis. The MMX coating matrix and coating system begin dissolution in the final portion of the ileum. This type of oral formulation may make MMX a preferred agent over other oral mesalamine and mesalamine-prodrug formulations that release the drug proximally in the gastrointestinal tract. Unlike previous formulations, it can be administered once daily for the treatment of ulcerative colitis.     

Gallstone dissolution therapy with ursodiol

Ursodeoxycholic acid (ursodiol) has been shown to be an effective oral agent for dissolution of gallstones that also has a favorable safety profile. In the selection of patients as candidates for this treatment, stone characteristics and the functional status of the gallbladder are the two most important criteria. Small, primarily cholesterol stones (radiolucent on plain film) are the most suitable for oral dissolution therapy. In addition, a functioning gallbladder (as evidenced by visualization on oral cholecystogram) is required to concentrate the ursodiol-enriched bile and effect stone dissolution. Ursodiol should not be used during pregnancy, in women likely to become pregnant, or in severe acute or chronic intrahepatic cholestasis. Acute cholestasis and common bile duct obstruction also preclude this treatment. Screening tests include basic laboratory tests of liver function, sonographic evaluation of the gallbladder and biliary tree, plain film of the abdomen, and oral cholecystogram. Since few patients meet all the selection criteria ideally, the decision to undertake treatment with ursodiol must be based on the entire clinical profile and on the patient's willingness to accept the predicted likelihood of success.     

Dissolution of pancreatic stones by oral trimethadione in a dog experimental model

Experiments were conducted to develop a dissolution therapy for human pancreatic calculi in a dog experimental model of pancreatic calculi surgically prepared. On plain x-ray films of the abdomen, pancreatic calculi appeared in 19 of 39 dogs within 12 mo after operation. The antiepileptic agent trimethadione was given orally to 13 dogs at a dose of 1.0-1.5 g daily. Pancreatic calculi disappeared in 13 of 15 observations. The scanning electron microscopy, the elemental analysis, and the powder x-ray diffractometry of pancreatic calculi in this model revealed that the calculi closely resembled human pancreatic calculi, consisting mainly of a calcite of calcium carbonate. There was no histologic finding suggesting drug toxicity in the liver, the kidney, and the blood. Pancreatic calculi in 6 control dogs without the treatment neither disappeared nor diminished spontaneously. The oral treatment with trimethadione may have potential for dissolving human pancreatic calculi.