Controlled release of verapamil hydrochloride from waxy microparticles prepared by spray congealing.

In this work, the potential of waxes for preparing with the ultrasonic spray congealing technique microparticles for controlling the in vitro release of verapamil HCl was investigated. The first part of the study encompassed the optimisation of the formulation to achieve an efficient drug incorporation together with a satisfactory in vitro drug release rate. In particular, microcrystalline wax, stearyl alcohol and mixtures of the two were used. Also a surfactant (soya lecithin) was added to the formulations. After the particle size analysis, the characterisation of the microparticles involved the study of the solid state of drug and carriers in the systems (DSC, HSM and XRD) and the morphological and chemical analyses of the microparticle surface (SEM and XPS). Finally, the drug release mechanism from these devices was evaluated using the statistical moment analysis. The results of this study show that by selecting the type and the amount of the carriers, microparticles with a spherical shape and a good encapsulation efficiency were observed. These particles showed a zero-order release for 8 h, without modifying the solid state properties of the drug. Therefore, waxy microparticles prepared by the ultrasonic spray congealing technique are promising solvent-free devices for controlling the release of verapamil HCl.     

Controlled release from fibers of polyelectrolyte complexes.

Controlled release systems for delicate compounds, such as proteins, often suffer the drawbacks of decreased bioactivity and low encapsulation efficiency. This study introduces the concept of producing drug-loaded fibers from interfacial polyelectrolyte complexation. Chitosan-alginate fibers were produced by pulling from the interface between two polyelectrolyte solutions at room temperature. Depending on the component properties, the release time of encapsulated components from these fibers can range from hours to weeks. Dexamethasone was completely released within 2 h, whereas charged compounds such as BSA, PDGF-bb, and avidin showed sustained release for 3 weeks. The fibers were able to release PDGF-bb in a steady fashion for over 3 weeks without an initial burst. Furthermore, the bioactivity of PDGF-bb was retained over this period. Release kinetics could be controlled by the inclusion of heparin, which contains specific binding sites for various growth factors. By varying the alginate/heparin ratios in the anionic polyelectrolyte solution, the release of PDGF-bb could be significantly altered. In this study, interfacial polyelectrolyte complexation has been demonstrated to be a promising technique for producing drug-loaded fibers with high encapsulation efficiency, sustained release kinetics, and capacity to retain the bioactivity of the encapsulants.     

Controlled drug release from hydrogel nanoparticle networks.

Monodisperse nanoparticles of poly-N-isopropylacrylamide-co-allylamine (PNIPAM-co-allylamine) and PNIPAM-co-acrylic acid (PNIPAM-co-AA) were synthesized. The close-packed PNIPAM-co-allylamine and PNIPAM-co-AA nanoparticles were converted to three-dimensional gel networks by covalently crosslinking neighboring particles at room temperature and neutral pH using glutaric dialdehyde and adipic acid dihydrazide, respectively. Controlled release studies were conducted using dextran markers of various molecular weights as model macromolecular drugs. Release was quantified under various physical conditions, including a range of temperatures and dextran molecular weights. Dextran, entrapped in cavities in the nanoparticle network, was released with a rate regulated by their molecular weights and cavity size. No release from a conventional bulk PNIPAM gel, with high crosslinking density, was observed. The rate of release from the PNIPAM-co-allylamine network was temperature-dependent, being much faster at room temperature than that at human body temperature. In contrast, release of low molecular weight dextrans from the PNIPAM-co-AA network showed a temperature-independent release profile. These nanoparticle networks have several advantages over conventional bulk gels for controlling the release of high molecular weight biomolecules.     

Mechanistic aspects of the release of levamisole hydrochloride from biodegradable polymers.

The release of levamisole hydrochloride from poly-DL-lactide-co-glycolide compacts prepared at 5, 10 and 20% drug loading using two different particle size fractions of drug (90-125 and 125-250 microm) was investigated. Release profiles were significantly different from those previously reported for compacts prepared using the base form of the drug. Release was found to occur in a biphasic manner, with an initial fast release phase followed by a slower polymer degradation controlled release phase. The drug release profiles were successfully described by a model combining contributions from a first-order initial release phase and a polymer degradation controlled drug release phase. The fraction of drug released in the initial burst phase (F(B)) was attributed to the dissolution of drug domains situated at the surface of the polymer-drug compact and this fraction tended to increase with increasing drug particle size, as expected from the model. The increase in F(B) with increased loading was attributed to the clumping of dispersed drug particles which effectively increased the proportion of drug linked to the compact surface.     

Controlled release of fragrances from polymers I. Thermodynamic analysis

The feasibility of preparation of novel controlled release systems for the delivery of fragrances was investigated. The thermodynamic interactions of model substances which are typical constituents of fragrances with various copolymers were analyzed in the presence of a surrounding fluid. Conditions of favorable release were established by estimating the fragrance partition coefficient. Infinite dilution Flory interaction parameters of various fragrances in contact with a polymer or a surrounding fluid were determined. Generalized expressions were derived for the liquid lattice site sizes of various fragrance compounds.     

Controlled release of anti-inflammatory agent alpha-MSH from neural implants.

Si-multi-electrode arrays implanted into brain tissue for long-term recording lose electrical connectivity due to the post-implantation inflammatory reaction. This inflammatory reaction creates a physical and electrical gap between the electrode and the surrounding neurons. In this study, novel nitrocellulose-based coatings were developed for the sustained delivery of the anti-inflammatory neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH). alpha-MSH was incorporated in micron-scale nitrocellulose coatings and slow, sustained release over 21 days was attained in vitro. The alpha-MSH released on day 21 was still bioactive, and successfully inhibited nitric oxide (NO) production by LPS-stimulated microglia. The amount of initial drug loading directly affected the release rate, with higher initial loading increasing the mass released but not the percent of drug released. The surface morphology and thickness of the coatings were examined by scanning electron microscopy (SEM) and profilometry. In addition, impedance measurement showed that the alpha-MSH loaded nitrocellulose coatings reduced the magnitude of electrode impedance at the biologically relevant frequency of 1 kHz. In conclusion, nitrocellulose-based, bioactive coatings that release anti-inflammatory agents without increasing the impedence of the electrode were successfully fabricated. These coatings have the potential to reduce inflammation at the electrode-brain interface in vivo, and facilitate long-term recordings from Si-multi-electrode arrays.     

Controlled release of hyaluronan oligomers from biodegradable polymeric microparticle carriers.

In the present study, biodegradable microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) were explored as a potential carrier for the controlled release of polysaccharide oligomers. To this end, hyaluronan (HY) oligomers of varying molecular weights were incorporated into PLGA/PEG microparticles. Using a two-level fractional factorial experimental design, four microparticle formulation parameters, the amount of PEG included in the microparticles, the initial HY loading of the microparticles, the molecular weight of HY, and the molecular weight of PLGA, were studied for their influence on the incorporation and in vitro release of HY over the period of 28 days. The entrapment efficiencies were found to range between 10+/-1% and 24+/-2% depending on the initial loading and the molecular weight of the HY oligomer used in the fabrication of the microparticles. The HY was released in a multiphasic fashion including an initial burst release, followed by two separate periods of linear release. The normalized cumulative mass released during the burst release ranged from 25.1+/-9.2% to 93.0+/-0.7% and was found to be significantly influenced by the initial HY loading, the HY molecular weight, and the PLGA molecular weight. The initial period of linear release lasted from day 1 to day 14 and displayed normalized cumulative rates of release from 0.1+/-0.0%/day to 1.4+/-0.2%/day. During this period, PEG content of the microparticles and HY molecular weight exerted the greatest influence on the rate of release. Finally, the second period of linear release lasted through the final time-point at day 28. Here, the normalized cumulative rate of release values ranged from 0.2+/-0.1%/day to 3.6+/-0.7%/day and were dependent on all formulation parameters studied. These results demonstrate the potential of PLGA/PEG blend microparticles for the controlled release of HY oligomers.     

Controlled release of the fibronectin central cell binding domain from polymeric microspheres.

Non-ionic surfactants have been employed as alternatives to PVA for the emulsification-encapsulation of a conformationally labile protein (FIII9'-10) into PLGA microspheres. FIII9'-10 was encapsulated using a w/o/w double emulsification-evaporation technique and the microspheres fabricated were characterized by SEM and CLSM. The peptide backbone integrity of FIII9'-10 was assayed by SDS-PAGE and the degree of unfolding of FIII9'-10 following emulsification-encapsulation was assessed using a fibroblast cell-attachment assay. The encapsulation efficiency for FIII9'-10 was 25% when using PVA, compared to 50-60% when using Igepal CA-630 or Triton-X100, with values below for the other surfactants. FIII9'-10 released from microspheres promoted cell attachment in a concentration-dependent manner, only Igepal CA-630 and Triton X-100 maintaining near-maximal cell attachment, indicating that the conformation of the relatively unstable FIII9' domain was preserved. All non-ionic surfactants reduced microsphere surface porosity, compared to PVA, and an increasing surface rugosity (leading to minor 'ridges') could be correlated with decreasing surfactant HLB. Low surface porosities did not effect the diffusion of FIII9'-10 from the microspheres' internal pores in a 'burst release', as may have been imagined. In summary, non-ionic surfactants should be considered over PVA for the maintenance of biological activity of conformationally labile proteins during encapsulation.     

Controlled release of the herbicide simazine from computationally designed molecularly imprinted polymers.

The present study describes the development of materials suitable for environmental control of algae. Molecularly imprinted polymers (MIPs) were used as simazine carriers able to provide the controlled release of simazine into water. Three polymers were designed using computational modelling. The selection of methacrylic acid (MA) and hydroxyethyl methacrylate (HEM) as functional monomers was based on results obtained using the Leapfrog algorithm. A cross-linked polymer made without functional monomers was also prepared and tested as a control. The release of simazine from all three polymers was studied. It was shown that the presence of functional monomers is important for polymer affinity and for controlled release of herbicide. The speed of release of herbicide correlated with the calculated binding characteristics. The high-affinity MA-based polymer released approximately 2% and the low-affinity HEM-based polymer released approximately 27% of the template over 25 days. The kinetics of simazine release from HEM-based polymer show that total saturation of an aqueous environment could be achieved over a period of 3 weeks and this corresponds to the maximal simazine solubility in water. The possible use of these types of polymers in the field of controlled release is discussed.     

Motoneuron excitability modulation after desensitization of the skin by iontophoresis of lidocaine hydrochloride.

Soleus motoneuron excitability was monitored after skin desensitization by iontophoresis of lidocaine hydrochloride in able-bodied subjects. Motoneuron excitability was measured by plotting H-reflex recovery curves before and after the application of lidocaine hydrochloride or a placebo. Significant H-reflex augmentation between 50 and 1,000 msec resulted after both iontophoretic application of the drug and the placebo (p less than .05). In addition, H-reflex initial recovery decreased by 20 to 30 msec in 75% of the subjects tested (p less than .05). H-reflex recovery curve facilitation lasted 30 minutes and returned to control values 45 minutes post-iontophoresis. H-reflex facilitation was not significantly different between the drug and the placebo treatments. It was concluded from these results that low-voltage, galvanic electric stimulation associated with iontophoresis predominantly caused the increase in motoneuron excitability, although other peripheral facilitatory factors may have been involved. Furthermore, cutaneous desensitization appeared not to have an effect on motoneuron excitability. This conclusion was based on the observation that similar H-reflex amplitude augmentation resulted after administration of a placebo as well as an active drug.     

盐酸利多卡因注射液在上消化道内镜下注射止血中的价值

目的研究盐酸利多卡因注射液在上消化道内镜下注射止血中的价值。方法选择该院2003年10月～2010年10月共158例非静脉曲张性上消化道出血需行急诊内镜下注射止血的患者,其中,男93例,女65例;年龄25～88岁,平均(54.2±11.3)岁。随机分为两组,Ⅰ组73例为单纯注射高渗钠-肾上腺素溶液(HSE),Ⅱ组85例添加盐酸利多卡因注射液,比较两组的急诊止血率、不良反应率、疼痛感知率。结果两组患者一般资料差异无显著性(P>0.05)。Ⅰ组急诊止血率达90.41%,不良反应率5.47%,疼痛感知率84.93%;Ⅱ组急诊止血率达98.82%,不良反应率为2.35%,疼痛感知率为38.82%;两组急性出血止血率及并发症发生率差异无显著性(P>0.05)。两组的疼痛感知率差异有显著性(P<0.05)。结论在非静脉性上消化道出血急诊内镜下注射止血中添加盐酸利多卡因能减轻患者痛苦,是安全、有效的。     

Controlled release of oxytetracycline in sheep.

A novel biodegradable injectable formulation of oxytetracycline (OTC) was administered subcutaneously to sheep at a dose of 40 mg/kg. Blood samples were collected from the jugular vein at predetermined time intervals. The concentration of OTC in plasma was analyzed by an HPLC method. The concentrations of OTC in plasma were maintained at or above 0.5 microg/ml (minimum inhibitory concentration) for approximately 6 days. The pharmacokinetic parameters of OTC in sheep were also determined by monitoring the plasma concentration of OTC after a single intravenous injection of a commercially available OTC formulation at 10 mg/kg body weight. The in vivo release profiles of OTC from the biodegradable injectable formulations in sheep were determined from the plasma concentration time profiles by the deconvolution method using PCDCON software. The in vitro release of OTC from the biodegradable injectable formulation was tested in phosphate buffer (pH 7.4), containing 0.686% w/v of sodium sulfite as antioxidant. The correlation between the in vitro and in vivo release of OTC from the injectable formulation was also evaluated. The results of the in vivo evaluation of the formulation in sheep indicated that a controlled release biodegradable injectable dosage form of OTC for food animals is feasible.     

盐酸利多卡因凝胶在清洁灌肠中的应用

[目的]探讨盐酸利多卡因凝胶在清洁灌肠中的应用。[方法]将206例清洁灌肠病人随机分为对照组101例和观察组105例,对照组以凡士林润滑肛门及乳胶肛管,观察组盐酸利多卡因凝胶润滑肛门。比较两组病人清洁灌肠时间、灌肠次数、灌注液用量、灌肠过程中的疼痛评分、灌肠后里急后重的程度。疼痛评分采用Wong-Baker面部表情量表法（WBFPS）和数字分级法（NRS）。[结果]观察组病人清洁灌肠时间短于对照组,灌肠次数、灌注液用量少于对照组,WBFPS和NRS疼痛评分低于对照组,灌肠后里急后重程度低于对照组（P均〈0.05）。[结论]在清洁灌肠前应用盐酸利多卡因凝胶润滑肛门及乳胶肛管,效果优于常规应用凡士林润滑肛门及乳胶肛管。     

Controlled release of biomolecules from temperature-sensitive hydrogels prepared by radiation polymerization.

Poly(acryloyl-L-proline methyl ester)-based hydrogels containing 1 and 5% of a crosslinking agent were studied as drug delivery systems. The drug loading properties were investigated by matrix incubation into solutions containing biomolecules with molecular weight ranging between 300 and 65,000 Da. The loading yield was found to depend on both the crosslinking degree and the molecular weight of the drug. In vitro release studies were carried out with both swollen and dry matrices loaded with gentamicin, isoniazid and insulin. Gentamicin and isoniazid were released by a bimodal Fickian diffusion with a remarkable burst that was found to depend on both matrix crosslinking degree and physical state. In vivo, the subcutaneous implantation into mice of the isoniazid loaded matrices allowed for an efficient drug release for 800 h. In vitro insulin was released from the swollen matrices for 1500 h by diffusional Fickian mechanism while the dry ones displayed a lag time followed by Fickian diffusion release. The subcutaneous implantation of the insulin-loaded matrices into diabetic mice induced a remarkable decrease in the glucose concentrations in blood. In particular, the dry 1% matrices were found to maintain a low glucose level for 700 h.     

Controlled release of a model protein from enzymatically degrading dextran microspheres.

Protein-loaded dextran microspheres were prepared by a water-in-water emulsion technique. With this technique, an aqueous solution of methacrylated dextran (dex-MA) is emulsified in an aqueous solution of poly(ethylene glycol) (PEG). Subsequently, the dispersed dex-MA phase is crosslinked by radical polymerization of the dextran-bound methacryloyl groups. This method renders microspheres with a hydrogel character of which the crosslink density can be controlled by the water content and the degree of substitution of the dex-MA (DS, the number of methacrylates per 100 glucopyranose residues). If an IgG solution was added to the dex-MA/PEG aqueous system prior to the polymerization reaction, the protein could be encapsulated in the dextran microspheres with a high yield (88-98%). The release of IgG was studied as a function of the water content, the DS and the degradation rate of the microspheres. The microspheres were rendered degradable by co-encapsulation of an endo-dextranase. Non-degrading microspheres mainly showed a burst release, which decreased with increasing crosslink density. By either a low water content (50%, w/w, or lower) or a high DS (DS 13), it was possible to reduce the burst release to about 10%, meaning that almost complete entrapment of the protein could be achieved. The release of IgG from degrading microspheres was predominantly dependent on the DS and the amount of encapsulated dextranase. No differences in release of IgG from microspheres with and without dextranase were observed at high DS (DS 13). This was ascribed to the inability of the enzyme to degrade these microspheres. On the other hand, the entrapped protein was completely released from enzymatically degrading microspheres with a DS 4. Moreover, the release rate of IgG was proportional to the degradation rate of these microspheres (depending on the amount of co-encapsulated dextranase). Interestingly, an almost zero-order release was observed from these microspheres for periods up to 30 days.     

Controlled release of an osteogenic peptide from injectable biodegradable polymeric composites.

Poly(D,L-lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) blend microparticles loaded with the osteogenic peptide TP508 were added to a mixture of poly(propylene fumarate) (PPF), poly(propylene fumarate)-diacrylate (PPF-DA), and sodium chloride (NaCl) for the fabrication of PPF composite scaffolds that could allow for tissue ingrowth as well as for the controlled release of TP508 when implanted in an orthopedic defect site. In this study, PPF composites were fabricated and the in vitro release kinetics of TP508 were determined. TP508 loading within the PLGA/PEG microparticles, PEG content within the PLGA/PEG microparticles, the microparticle content of the PPF composite polymer component, and the leachable porogen initial mass percent of the PPF composites were varied according to a fractional factorial design and the effect of each variable on the release kinetics was determined for up to 28 days. Each composite formulation released TP508 with a unique release profile. The initial release (release through day 1) of the PLGA/PEG microparticles was reduced upon inclusion in the PPF composite formulations. Day 1 normalized cumulative mass release from PPF composites ranged from 0.14+/-0.01 to 0.41+/-0.01, whereas the release from PLGA/PEG microparticles ranged from 0.31+/-0.02 to 0.58+/-0.01. After 28 days, PPF composites released 53+/-4% to 86+/-2% of the entrapped peptide resulting in cumulative mass releases ranging from 0.14+/-0.01 microg TP508/mm(3) scaffold to 2.46+/-0.05 microg TP508/mm(3) scaffold. The results presented here demonstrate that PPF composites can be used for the controlled release of TP508 and that alterations in the composite's composition can lead to modulation of the TP508 release kinetics. These composites can be used to explore the effects varied release kinetics and dosages on the formation of bone in vivo.     

Controlled release of beta-estradiol from PLAGA microparticles: the effect of organic phase solvent on encapsulation and release.

To determine the effect of the organic solvent used during microparticle preparation on the in vitro release of beta-estradiol, a number of formulations were evaluated in terms of size, shape and drug delivery performance. Biodegradable microparticles of poly(lactide-co-glycolide) were prepared containing beta-estradiol that utilized dichloromethane, ethyl acetate or a mixture of dichloromethane and methanol as the organic phase solvent during the particle preparation. The drug delivery behavior from the microparticles was studied and comparisons were made of their physical properties for different formulations. The varying solubilities of beta-estradiol and poly(lactide-co-glycolide) in the solvents studied resulted in biodegradable microparticles with very different physical characteristics. Microparticles prepared from solid suspensions of beta-estradiol using dichloromethane as the organic phase solvent were similar in appearance to microparticles prepared without drug. Microparticles prepared from dichloromethane/methanol solutions appeared transparent to translucent depending on the initial amount of drug used in the formulation. Microparticles prepared using ethyl acetate appeared to have the most homogeneous encapsulation of beta-estradiol, appearing as solid white spheres regardless of initial drug content. Studies showed that microparticles prepared from either ethyl acetate or a mixture of dichloromethane and methanol gave a more constant release profile of beta-estradiol than particles prepared using dichloromethane alone. For all formulations, an initial burst of release increased with increasing drug loading, regardless of the organic solvent used.     

Controlled release systems for DNA delivery.

Adapting controlled release technologies to the delivery of DNA has the potential to overcome extracellular barriers that limit gene therapy. Controlled release systems can enhance gene delivery and increase the extent and duration of transgene expression relative to more traditional delivery methods (e.g., injection). These systems typically deliver vectors locally, which can avoid distribution to distant tissues, decrease toxicity to nontarget cells, and reduce the immune response to the vector. Delivery vehicles for controlled release are fabricated from natural and synthetic polymers, which function either by releasing the vector into the local tissue environment or by maintaining the vector at the polymer surface. Vector release or binding is regulated by the effective affinity of the vector for the polymer, which depends upon the strength of molecular interactions. These interactions occur through nonspecific binding based on vector and polymer composition or through the incorporation of complementary binding sites (e.g., biotin-avidin). This review examines the delivery of nonviral and viral vectors from natural and synthetic polymers and presents opportunities for continuing developments to increase their applicability.