Basic drug--enterosoluble polymer coevaporates: development of oral controlled release systems

Precipitation of basic drugs within oral prolonged release systems, at the higher pH values of the intestine, would affect drug release. Coevaporates of a model basic drug verapamil HCl, in single or mixed polymer systems, containing Eudragit L100 (L100) and ethyl cellulose or Eudragit RS100, were prepared from ethanolic solution. XRD and DSC indicated loss of crystallinity of the drug in the coevaporates. The presence of the enterosoluble polymer in the system was found to aid in faster dissolution of the drug at higher pH values. This was affected by the presence and type of retarding polymer present in the system. Compression of the coevaporates resulted in either very slow release of the drug or undesirable changes in the release profile. Pelletization of a coevaporate containing drug and L100 yielded systems, which released the drug uniformly when studied by the buffer change method in simulated gastric (SGF) and intestinal (SIF) fluids. The presence of L100 in intimate contact with the drug was found to be essential for the desirable drug release properties of the system. The drug release occurred predominantly by diffusion in SGF and by a combination of diffusion and polymer dissolution/erosion in SIF. Appropriate choice of release modifiers and formulation variables and development of suitable formulations can yield systems which compensate for the reduced solubility of the drug in the higher pH environments of the intestine.     

Study of mesoporous silica/magnetite systems in drug controlled release

Ordered mesoporous materials like SBA-15 have a network of channels and pores with well-defined size in the nanoscale range. This particular silica matrix pore architecture makes them suitable for hosting a broad variety of compounds in very promising materials in a range of applications, including drug release magnetic carriers. In this work, magnetic nanoparticles embedded into mesoporous silica were prepared in two steps: first, magnetite was synthesized by oxidation-precipitation method, and next, the magnetic nanoparticles were coated with mesoporous silica by using nonionic block copolymer surfactants as structure-directing agents. The materials were characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), N(2) adsorption, and scanning electron microscopy (SEM). The influence of magnetic nanoparticles on drug release kinetics was studied with cisplatin, carboplatin, and atenolol under in vitro conditions in the absence and in the presence of an external magnetic field (0.25 T) by using NdFeB permanent magnet. The constant external magnetic field did not affect drug release significantly. The low-frequency alternating magnetic field had a large influence on the cisplatin release profile.     

Spray-drying as a method for microparticulate controlled release systems preparation: advantages and limits. I. Water-soluble drugs

Spray-drying was used for the preparation of paracetamol/eudragit RS or RL or ethylcellulose microspheres to verify the possibility of their use in controlled-release solid-dosage forms formulation and try to determine advantages and limits of the technique of such use. Microspheres were first characterized by scanning electron microscopy, differential scanning calorimetry, x-ray diffractometry, and in vitro dissolution studies and then used for the preparation of tablets. During this step, the compressibility of the spray-dried powders was also evaluated. In vitro dissolution studies were performed also on the tablets and their release control was accessed. Although powders were unable to slow down drug release, tablets obtained from microsphere compression showed a good capability of controlling paracetamol release when eudragit RS or ethylcellulose was used, even at low polymer amounts.     

Biopharmaceutical evaluation of diclofenac sodium controlled release tablets prepared from gum karaya--chitosan polyelectrolyte complexes

The phenomena of polymer interactions and formation of polyelectrolyte complexes (PECs) of oppositely charged polymers have been the focus of interest in fundamental and applied research. Such PECs may possess unique properties that are different from those of individual polymers. In the present study, attempts were made to prepare PECs of negative colloid gum karaya (GK) and positively charged polysaccharide chitosan (CH). The association and factors affecting the interactions between GK and CH were studied by pH and conductivity studies. The dried complexes were characterized by X-ray diffraction, Fourier transformed Infrared (FTIR) Spectroscopy, Scanning Electron Microscopy. The PECs were utilized for encapsulation of diclofenac sodium. Selected polyelectrolyte microparticles were compressed into tablets and were compared with commercial sustained release product Voveran SR?. Positive results of the study indicated the applicability of PECs in the design of oral controlled release drug delivery systems.     

Polymeric nanoparticles as drug controlled release systems: a new formulation strategy for drugs with small or large molecular weight

We report a study evaluating the encapsulation and release modalities from poly(D,L lactic acid) (PLA) or poly(D,L-lactide-co-glicolide) (PLGA) micro- and nano-particles of the antiischemic drug N6-cyclopentyladenosine (CPA) and bovine serum albumin (BSA), chosen as protein model. The results obtained by classical preparation methods (nanoprecipitation, single or double emulsion/solvent evaporation) of the particles were compared with those obtained by their formulation with a novel method, employing a thermosensible gel of Pluronic F-127, whose aqueous solutions can be liquid when refrigerated, but gel upon warming. Our results indicate that CPA-loaded nanoparticles, obtained by classical methods, drastically reduce their drug content showing, moreover, any control of the drug release with respect to CPA-loaded microparticles. The novel preparation method allowed us to obtain, instead, CPA encapsulation values in nanoparticles similar to those obtained for microparticles, achieving also a weak control of the drug release. Any drastic reduction of BSA particle content was obtained by decreasing their size from micro- to nano-scales, independently on the employment of classical or novel preparation methods. Moreover, the size reduction induced only a weak increase of the BSA release rate. The patterns of protein released from micro- and nano-particles obtained by the same formulation method were similar. In particular, the micro- and nano-spheres prepared by double emulsion technique showed an incomplete BSA release, characterized by an elevated burst effect followed by a very slow phase. On the other hand, the release from micro- and nano-particles obtained by the novel method was complete and quite regular, being characterized by a little burst release followed by a fast phase. These results have been related to the strong BSA distribution (observed by confocal laser scanning microscope) in the surface or in the core of microparticles obtained by the classical or novel methods, respectively.     

Poly (lactic-co-glycolic acid) as a controlled release delivery device

Poly (lactic-co-glycolic acid) (PLGA) is a biodegradable polymer used to make resorbable sutures, and is also used in other applications in tissue engineering. Being an artificial polymer, its degradation rate can be tailored to suit its application. It can be easily moulded into structures with suitable mechanical strength and degrades into relatively harmless products in the body. Its adjustable degradation rate also makes it a potentially excellent controlled release delivery device. However, the functionalization of PLGA with bioactive molecules usually requires extensive chemical modification. Chemical modification may compromise the mechanical strength of PLGA and inactivate the bioactive molecules. In this paper, a study is done to investigate the coating of an angiogenic factor on unmodified PLGA suture substrates for the differentiation of human mesenchymal stem cells (hMSC) into endothelial cells (EC). The results show that the method used to anchor vascular endothelial growth factor (VEGF) onto the PLGA surface can enable the gradual release of VEGF from the substrate into solution to induce the differentiation of hMSCs into ECs. Thus, this method can potentially be used to coat PLGA materials like sutures, meshes and scaffolds, rendering them functional as effective controlled release delivery devices for a wide range of bioactive molecules.     

Dithiocarbamate chitosan as a potential polymeric matrix for controlled drug release

Objective: To develop a polymer matrix for controlled release of drugs, chitosan, a linear aminopolysaccharide, was chemically modified to dithiocarbamate chitosan (DTCC) to afford a matrix where metal–drug complexes could be attached and released in a controlled manner depending on the binding nature between the drugs and the metals.

Materials and methods: DTCC was treated with metal-tetracycline (Tc) complexes to prepare DTCC–Ca(II)–Tc, DTCC–Mg(II)–Tc, DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc.

Results: The binding amount of Tc was in the order of DTCC–Zn(II)–Tc?≈?DTCC–Mg(II)–Tc?≈ DTCC–Ca(II)–Tc?>?DTCC–Cu(II)–Tc. The biphasic binding profiles, where Tc binding increased initially and then decreased, were shown for DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc. In a flow method, Tc was released slowly from DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc compared with Tc release from DTCC–Tc. In parallel with the results of the release experiment, DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc presented a prolonged antibacterial activity in an antibacterial test. The antibacterial activity of DTCC–Ca(II)–, –Mg(II)– and –Zn(II)–Tc complexes lasted for 28–44 days, while free Tc and DTCC–Tc lasted for 7–12 days.

Discussion and conclusion: Taken together, our data suggest that DTCC could be used for a polymeric matrix for controlled release of drugs such as Tc, which possess functional groups for ionic and/or coordinate bond with metals.     

pH响应性可控释放材料

智能可控释放材料由于具有多种潜在的用途而引起广泛关注.其中,具有pH响应性的可控释放材料被认为是较易获得并对外界环境刺激响应较敏感的一类智能响应性材料.本文综述了具有不同结构的pH响应性可控释放材料的研究进展,包括pH响应性微胶囊、pH响应性聚合物微球、pH响应性水凝胶、pH响应性介孔材料的制备、可控释放作用及其应用.     

Multi-unit controlled release systems of nifedipine and nifedipine:pluronic F-68 solid dispersions: characterization of release mechanisms

Nifedipine (N) and nifedipine:Pluronic® F-68 solid dispersion (SD) pellets were developed and characterized for drug release mechanisms from a multi-unit erosion matrix system for controlled release. Nifedipine was micronized using a jet mill. Solid dispersion with Pluronic F-68 was prepared by the fusion method. Nifedipine and SD were characterized by particle size analysis, solubility, differential scanning calorimetry (DSC), and x-ray diffraction (XRD) studies. Samples were subsequently processed into matrix pellets by extrusion/spheronization using Eudragit® L 100-55 and Eudragit® S 100 as release rate-controlling polymers. Drug release mechanisms from pellets were characterized by microscopy and mercury intrusion porosimetry; DSC and XRD studies indicated no polymorphic changes in N after micronization and also confirmed the formation of SD of N with Pluronic F-68. Pellets of N showed a 24-hr drug release profile following zero-order kinetics. Pellets of SD showed a 12-hr release profile following first-order kinetics. Aqueous solubility of N after SD formation was found to be increased 10-fold. Due to increased solubility of N in SD, the drug release mechanism from the multi-unit erosion matrix changed from pure surface erosion to an erosion/diffusion mechanism, thereby altering the release rate and kinetics.     

Acrylic-phosphate glasses composites as self-curing controlled delivery systems of antibiotics

New antibiotic delivery systems based on self-hardening methyl methacrylate (MMA)/polymethyl methacrylate (PMMA) systems and phosphate glasses (PG) in the system P₂O₅–CaO–Na₂O have been developed. Self-curing formulations were prepared by mixing the solid component containing PMMA beads, different proportions of PG (30–70 wt %) and vancomycin (5 wt %) as antibiotic, with the liquid component made of MMA monomer. Dough and setting times increased with the content of PG but peak temperature decreased to values well below to guarantee the chemical stability of the antibiotic drug, gentamicin or vancomycin. Mechanical properties of the PMMA/PG composites were evaluated in compression test giving rise to values of compressive strength in the range of 100 MPa. The release of vancomycin was analyzed in vitro by immersion of samples in phosphate buffer of pH=7.4. Release profiles were influenced by the content of PG present in the cement. An initial burst of drug release was observed in all cases. The composites with 70 wt % PG released nearly the total amount of drug loaded in a period of 45 days, and those containing 60 wt % PG released the 70% of the vancomycin in the same period of time. However, either the control of the composite with 30 wt % PG released only the 30% of the drug in 10–15 days. The surface of the drug-loaded composites before and after release experiments was analyzed by ESEM. The deposition of some aggregates at certain points of the surface was detected for the specimens immersed in buffer phosphate after 45 days. This material was characterized by FTIR and Raman spectroscopy as an amorphous phosphate formed by calcium ortho and pyrophosphates, and indicates an interaction between the hydrated layer at the place of the glass and the surrounding medium.     

Biopharmaceutic and pharmacokinetic aspects in the design of controlled release peroral drug delivery systems

Abstract

Present peroral controlled release drug delivery systems (CRDDS) are for a maximum of 24 hours clinical effectiveness. Such systems are primarily for drugs of short elimination half-life. However, also drugs of long half-life qualify if a reduction in steady state fluctuation is desired. The biopharmaceutic evaluation of a drug for potential use in CRDDS requires knowledge on the absorption mechanism of the drug from the G. I. tract, the general absorbability, the drug's molecular weight, pKa, solubility at different pH and apparent partition coefficient. The pharmacokinetic evaluation requires knowledge on a drug's elimination half-life, total clearance, absolute bioavailability, possible first-pass effect, and the desired steady concentrations for peak and trough. Even if a drug's disposition after I. V and peroral fast release administration is best described by a two-or higher-compartment model, one can collapse these for all practical purposes to a one-compartment model for the design of a CRDDS if the release rate is much smaller than the intrinsic absorption rate and the distribution rates, and is the actual rate-limiting process. Two simple approaches for the pharmacokinetic design of required release characteristics and required maintenance dose to achieve desired steady state maximum and minimum concentrations are discussed, one for zero-order and one for first-order release.     

Biopharmaceutic and pharmacokinetic aspects in the design of controlled release peroral drug delivery systems

Present peroral controlled release drug delivery systems (CRDDS) are for a maximum of 24 hours clinical effectiveness. Such systems are primarily for drugs of short elimination half-life. However, also drugs of long half-life qualify if a reduction in steady state fluctuation is desired. The biopharmaceutic evaluation of a drug for potential use in CRDDS requires knowledge on the absorption mechanism of the drug from the G. I. tract, the general absorbability, the drug's molecular weight, pKa, solubility at different pH and apparent partition coefficient. The pharmacokinetic evaluation requires knowledge on a drug's elimination half-life, total clearance, absolute bioavailability, possible first-pass effect, and the desired steady concentrations for peak and trough. Even if a drug's disposition after I. V and peroral fast release administration is best described by a two-or higher-compartment model, one can collapse these for all practical purposes to a one-compartment model for the design of a CRDDS if the release rate is much smaller than the intrinsic absorption rate and the distribution rates, and is the actual rate-limiting process. Two simple approaches for the pharmacokinetic design of required release characteristics and required maintenance dose to achieve desired steady state maximum and minimum concentrations are discussed, one for zero-order and one for first-order release.     

Haemocompatiblity of controlled release glass

There are many medical applications which benefit from the use of soluble biomaterials, including the sustained release of drugs over a precise period of time, or temporary conduits for controlling nerve regrowth. We have manufactured a series of phosphate-based controlled release glasses (CRGs) in which the solubility could be controlled by varying the concentration of CaO and Na2O. Fibres of the CRG containing iron and cerium were placed into direct contact with human neutrophils and macrophages in tissue culture for 2.5 and 24 h respectively and the responses analysed by scanning electron microscopy (SEM) and confocal microscopy. The supernatants were analysed for the cytokine IL-1 by enzyme-linked immunosorbent assay (ELISA). Disks of CRG of various compositions were placed in contact with whole blood for 30 min and platelet adhesion assessed by SEM. Activation of platelets, granulocytes and complement were quantified by ELISA for -thromboglobulin, elastase and iC3b. Intrinsic coagulation activation was measured by timing the clotting of recalcified plasma. Only the cerium fibre inhibited IL-1 release from macrophages. No platelet adhesion was observed to any disk composition. Three compositions containing MgO inhibited plasma clotting and showed an insignificant level of complement activation. This study has demonstrated the development of a number of compositions of CRG, which have great potential in a wide variety of biomedical applications.     

Applications of poly(ethylene oxide) in controlled release tablet systems: a review

To improve therapeutic effects and compatibility of patients, controlled release tablet systems based on polymers are of great interest for pharmaceutical technologies. Poly(ethylene oxide) (PEO) is a non-ionic linear hydrophilic and uncrosslinked polymer available in a number of molecular weights. It is synthesized by ethylene oxide and has many desirable properties for drug delivery applications. This review article aims to summary the recent developments on physicochemical properties of PEO and focus on the recent efforts and developments on PEO as oral controlled release matrix tablets, bioadhesive hydrophilic matrices and osmotic pump tablets. Commercial products employed PEO were also discussed.     

盐酸阿霉素在纳米载体氧化石墨烯上的可控负载与释放

采用改性Hummers法制备了氧化石墨烯,并探索了其在生物医学方面作为纳米药物载体的应用。通过超声、振荡等方法制备了氧化石墨烯-盐酸阿霉素(GO-DXR),采用高分辨透射电镜(HRTEM)、傅里叶变换红外光谱(FT-IR)、紫外-可见分光光谱(UV-Vis)等测试方法对GO负载DXR前后的形貌和结构进行了研究。DXR在GO上的负载量高达4.6mg/mg,DXR的释放量可通过pH值控制,说明GO与DXR之间依靠氢键作用结合。     

Tripartite siRNA micelles as controlled delivery systems for primary dendritic cells

Dendritic cells (DCs) are key cells in immunology that are able to stimulate or inhibit the immune response. RNA interference has appeared of great interest to modulate the expression of immunogenic or tolerogenic molecules. In our study, pH-sensitive polyion complex micelles based on a double-hydrophilic block copolymer and poly-l-lysine were formulated to entrap a small interfering RNA (siRNA). We show that siRNA-loaded micelles were cytotolerant and efficiently endocytosed by DCs. siRNA targeting eGFP, used as model siRNA, was released into the cytosol following endocytosis of the micelles and the silencing of eGFP expression was observed in DC isolated from transgenic mice.

Our results underscore the potential of pH-sensitive polyion complex micelles to formulate therapeutic siRNA for DC engineering in order to maintain the homeostasis of the immune response.     

Atomically controlled electrochemical nucleation at superionic solid electrolyte surfaces

Electrochemical equilibrium and the transfer of mass and charge through interfaces at the atomic scale are of fundamental importance for the microscopic understanding of elementary physicochemical processes. Approaching atomic dimensions, phase instabilities and instrumentation limits restrict the resolution. Here we show an ultimate lateral, mass and charge resolution during electrochemical Ag phase formation at the surface of RbAg(4)I(5) superionic conductor thin films. We found that a small amount of electron donors in the solid electrolyte enables scanning tunnelling microscope measurements and atomically resolved imaging. We demonstrate that Ag critical nucleus formation is rate limiting. The Gibbs energy of this process takes discrete values and the number of atoms of the critical nucleus remains constant over a large range of applied potentials. Our approach is crucial to elucidate the mechanism of atomic switches and highlights the possibility of extending this method to a variety of other electrochemical systems.     

Evaluation of starch based cryogels as potential biomaterials for controlled release of antibiotic drugs

In the present study starch has been blended with poly(vinyl alcohol) to design macroporous architectures following a repeated freeze-thaw method. These macroporous cryogels were loaded with an antibiotic drug, ciprofloxacin hydrochloride (Cfx), and evaluated for its in vitro delivery in a completely controlled manner thus exploring possibilities to use it as a biomaterial in burn or wound healing applications. The key advantage of the present system is that cryogels formed do not contain any chemical crosslinking agent which is often harmful to organic compounds. These Cfx loaded cryogels were characterized by infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) techniques. The controlled release of Cfx drug from cryogels was investigated under varying experimental conditions such as percent loading of the antibiotic drug, chemical architecture of the cryogels and pH, temperature, and nature of the release media. The prepared cryogels show promise to provide a possible pathway for controlling delivery of antibiotic drug thus minimizing the known side effects and improving efficacy also.     

水滑石作为药物载体--萘普生的插层和缓释

水滑石(LDHs)是由带正电荷类水镁石层和层间的可交换阴离子组成的阴离子型粘土化合物,由于它的生物适应性,能够以它为主体,以药物为客体,插层组装成超分子结构复合物.抗炎药萘普生采用共沉淀法一步插层进入LDHs,用X射线衍射、红外光谱及热分析方法表征了超分子结构,表明层间距离扩大了,即萘普生已经插层组装成功,并且以单层、垂直作用在层间.萘普生柱撑水滑石的药物释放度在模拟肠液(pH7.4的缓冲液)条件下测定,结果表明萘普生柱撑水滑石释放速度降低,具有缓释作用,说明药物--无机混合物材料能够用作有效的药物传输系统.