Modeling vancomycin release kinetics from microporous calcium phosphate ceramics comparing static and dynamic immersion conditions

The release kinetics of vancomycin from calcium phosphate dihydrate (brushite) matrices and polymer/brushite composites were compared using different fluid replacement regimes, a regular replacement (static conditions) and a continuous flow technique (dynamic conditions). The use of a constantly refreshed flowing resulted in a faster drug release due to a constantly high diffusion gradient between drug loaded matrix and the eluting medium. Drug release was modeled using the Weibull, Peppas and Higuchi equations. The results showed that drug liberation was diffusion controlled for the ceramics matrices, whereas ceramics/polymer composites led to a mixed diffusion and degradation controlled release mechanism. The continuous flow technique was for these materials responsible for a faster release due to an accelerated polymer degradation rate compared with the regular fluid replacement technique.     

Preparation and characterization of starch-poly-ε-caprolactone microparticles incorporating bioactive agents for drug delivery and tissue engineering applications

One limitation associated with the delivery of bioactive agents concerns the short half-life of these molecules when administered intravenously, which results in their loss from the desired site. Incorporation of bioactive agents into depot vehicles provides a means to increase their persistence at the disease site. Major issues are involved in the development of a proper carrier system able to deliver the correct drug, at the desired dose, place and time. In this work, starch-poly-ε-caprolactone (SPCL) microparticles were developed for use in drug delivery and tissue engineering (TE) applications. SPCL microparticles were prepared by using an emulsion solvent extraction/evaporation technique, which was demonstrated to be a successful procedure to obtain particles with a spherical shape (particle size between 5 and 900 μm) and exhibiting different surface morphologies. Their chemical structure was confirmed by Fourier transform infrared spectroscopy. To evaluate the potential of the developed microparticles as a drug delivery system, dexamethasone (DEX) was used as model drug. DEX, a well-known component of osteogenic differentiation media, was entrapped into SPCL microparticles at different percentages up to 93%. The encapsulation efficiency was found to be dependent on the polymer concentration and drug-to-polymer ratio. The initial DEX release seems to be governed mainly by diffusion, and it is expected that the remaining DEX will be released when the polymeric matrix starts to degrade. In this work it was demonstrated that SPCL microparticles containing DEX can be successfully prepared and that these microparticular systems seem to be quite promising for controlled release applications, namely as carriers of important differentiation agents in TE.     

Hydrolytic degradation and drug release properties of ganciclovir-loaded biodegradable microspheres

The in vitro hydrolytic degradation of ganciclovir (GCV)-loaded biodegradable microspheres of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers were studied. Microspheres of size 120+/-40 microm were prepared using an oil-in-water emulsification/solvent evaporation technique. The effects of polymer molecular weight, lactide (LA) to glycolide (GA) ratio and GCV payload on the degradation and drug release profiles were investigated in vitro in phosphate-buffered solution (pH 7.0) at 37 degrees C. GCV accelerated the hydrolysis process of the low (5-7 wt.%) GCV-loaded microspheres due to a basic catalytic effect, giving a larger degradation rate, k', compared with blank and high (18-20 wt.%) GCV-loaded microspheres. In the high GCV-loaded microspheres, hydrolysis of the polymer backbone occurred with little and/or no autocatalytic effect, resulting in a smaller k' compared with low GCV-loaded microspheres. This was due to pores and microchannels created at the surface following the initial burst release, which increased water uptake and the dissolution and diffusion of GCV and degradation products from the matrix. The rate of hydrolytic degradation was also affected by the LA to GA ratio. For polymers of similar LA to GA ratio, those with a higher degree of blockiness had faster hydrolytic degradation rates irrespective of the initial molecular weight. The release profile had a biphasic pattern, which closely followed the degradation profile of the polymer. The time taken for the complete release of GCV was controlled by the diffusion phase and was dependent on the hydrolytic degradation rate of the polymers.     

Preparation of collagen modified hyaluronan microparticles as antibiotics carrier

Hyaluronan (HA), a natural glycoaminoglycan featuring an extracellular matrix, has been suggested as an effective biocompatible material. In this study, the effectiveness of HA microparticles as a carrier system for antibiotics was evaluated, and their physicochemical characteristics were determined. Microparticles were fabricated by the gelation of sulfadiazine (SD) loaded HA solution with calcium chloride through either a granulation (GR-microparticles) or encapsulation (EN-microparticles) process, and atelocollagen was incorporated into the microparticles as an additive in order to improve their physical properties. The characteristics of the microparticles were examined by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and swelling test. In vitro release experiments were performed for 7 days and the released amount of SD was determined using high-performance liquid chromatography (HPLC). Microscopic observations revealed that the collagen incorporated HA particles had a more compact surface than the HA particles. DSC analysis determined a loss of SD crystallinity in the particles. Calcium chloride retarded the swelling of particles, whereas the loaded drug contents did not affect this property. Both GR-and EN-microparticles sustained SD release with initial bursting effect. SD release from EN-microparticles was faster than from GR-microparticles. In addition, the release rate was dependent on the SD content in the microparticles. These results suggest that collagen modified HA microparticles have a potential as a release rate controlling material for crystalline drugs such as SD.     

药物控释载体材料的研究与应用

背景：作为控制释放体系的药物载体材料大多是高分子材料,但部分纳米无机材料也正逐步应用到药物控释材料体系中并取得了很好的研究成果。因此,药物控释用载体材料的设计与研究应用越来越受到重视。 目的：对国内外药物控释载体材料的应用及最新研究进展作一综述。 方法：应用计算机检索CNKI和Elsevier SD数据库中1999-01/2011-01关于药物控缓释材料的文章,在标题和摘要中以“高分子,介孔材料,无机硅,磷酸盐,控释”或“polymer,mesoporous materials,Inorganic silicon ,calcium phosphate,controlled release”为检索词进行检索。选择文章内容与药物控缓释有关者,同一领域文献则选择近期发表或发表在权威杂志文章。纳入25篇文献进行综述。 结果与结论：药物控缓释载体材料以用药量小、作用时间长、靶向作用好等特点被广泛关注,但是仍存在载药后药物失活,丧失生物活性等缺陷,目前随着复合药物载体材料和经皮给药装置研究的发展,控缓释材料在临床治疗中的应用必将更加广泛。     

Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method

The surface and internal morphology, drug distribution and release kinetics at 22 degrees C of polyesters such as PCL (polycaprolactone) and PLGA (poly(DL-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM (confocal laser scanning microscope) micrographs reveal that the polyvinylalcohol (PVA as an emulsifier) concentration in the external water phase strongly influences drug distribution within microspheres and release profiles. The presence of PVA in the internal water phase enhances the stabilization of inner water droplets against coalescence. This results in a more uniform drug distribution and a slower BSA release. Different oil-phase volumes and polymer concentrations yield different solvent exchange and precipitation mechanisms, which lead to different morphologies. A low oil-phase volume yields microspheres with a porous matrix and defective skin surface, which gives a high initial BSA burst as well as a fast release profile. Microspheres fabricated from a low polymer concentration have less defective skin surface, but with a less tortuous inner matrix which results in a more rapid BSA release. A higher BSA loading yields a larger concentration gradient between the emulsion droplet and the continuous water phase as well as between the microspheres and the in vitro medium. The former results in a lower encapsulation efficiency, whereas the latter yields a faster initial burst and a more rapid release profile. High stirring speed can reduce microsphere size, but decreases the yield of microspheres.     

Molecularly imprinted composite bacterial cellulose nanofibers for antibiotic release

The aim of this work is to develop drug carrier system with high loading capacity and controlled drug release profile for antibiotic release. For this purpose, composite molecularly imprinted nanofibers were prepared via in-situ graft polymerization of methacrylic acid as a monomer, N,N’-methylene bisacrylamide as a crosslinker and gentamicin sulfate as a template molecule onto surface-modified bacterial cellulose nanofibers. Gentamicin imprinted microparticles were fabricated onto bacterial cellulose nanofibers resulting in the formation of composite BC nanofibers. Thus, the composite nanofibers incorporated with gentamicin imprinted microparticles were achieved to fabricated. The in-vitro drug release tests were performed to evaluate the release performance of the resultant composite nanofibers at 37?°C. Also, kinetic models were applied to the drug release data. It was determined that the drug release from the composite molecularly imprinted nanofibers fit well in the Korsmeyer-Peppas model.     

Morphological and degradation studies of sirolimus-containing poly(lactide-co-glycolide) discs

The effect of residual solvent and copolymer ratio on the in vitro degradation and drug release behavior of a bioabsorbable polymer/drug system was investigated in an effort to understand and develop the use of these excipients for controlled drug delivery devices. Sirolimus-containing poly(lactide-co-glycolide) (PLGA) discs were fabricated by a solution-casting method using dimethyl sulfoxide (DMSO) as the solvent. The residual DMSO was removed from a set of discs by supercritical carbon dioxide extraction, and reflections of crystalline sirolimus were observed in the wide-angle X-ray scattering profile observed after extraction. A correlation was not observed between the extent of drug crystallization and extraction conditions and copolymer ratio. Mass loss, molecular weight, and sirolimus release were monitored during an in vitro study of the oven-dried neat PLGA, sirolimus-containing PLGA, and extracted sirolimus-containing PLGA discs during 56 days. The sirolimus-containing PLGA discs with residual DMSO exhibited a faster sirolimus release rate compared to the extracted discs. The residual DMSO facilitated release of sirolimus. The discs that contained PLGA with higher glycolide content, particularly 50% glycolide, degraded faster and exhibited faster sirolimus release.     

Biodegradable polyhydroxyalkanoate implants for osteomyelitis therapy: in vitro antibiotic release

Various random copolyesters of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and 3-hydroxybutyrate and 4-hydroxybutyrate P(3HB-4HB) were used in the construction of biodegradable, implantable rods for the local delivery of antibiotics (Sulperazone and Duocid) in chronic osteomyelitis therapy. Drug loading, type of active agent, and additional coating of the implant surface all have significant contributions to the in vitro release profile. The rate and duration of Sulperazone release from P(3HB-4HB) rods were controlled by the polymer/drug ratio (drug loading). The rate of drug dissolution was substantially higher than that of polymer degradation. Therefore, the release phenomenon was more dependent on drug dissolution rather than on polymer degradation or diffusion. Coating rods with the same type of polymer substantially reduced the initial burst effect observed with the uncoated rods, and significantly decreased the release rate so that the release kinetics became almost zero order. Antibiotic release from coated rods was sustained for over a period of 2 weeks at a constant rate, whereas uncoated rods released their contents in less than a week. Impregnation of Duocid into the hydrophobic polymer matrix yielded a rod with a smoother surface topography. The release from these rods was significantly higher than for rods loaded with Sulperazone and a zero order release could not be obtained with these samples.     

Correlation between heparin release and polymerization degree of organically modified silica xerogels from 3-methacryloxypropylpolysilsesquioxane

This work aimed to investigate the use of an organically modified porous silica matrix (poly(methacryloxypropyl)–poly(silsesquioxane); P-MA–PS) as a release system for heparin. The matrices were obtained from methacryloxypropyltrimethoxysilane (MAS) via the sol–gel process under acidic conditions following photochemical polymerization and cross-linking of the organic matrix. Modulation of the polymerization degree of the organic matrix in the range 0–71% allowed adjusting the release kinetics of heparin according to therapeutic needs. It was demonstrated that higher drug loads and a decreasing polymerization degree resulted in a faster release profile of heparin, which followed a square root of time kinetic according to the Higuchi model. The hydrolytic degradation of hybrid xerogel was found to follow a zero-order kinetic whereas the heparin concentration did not show an influence on the degradation rate of the matrix. Since the released heparin retained its biological activity, the P-MA–PS matrices are of clinically interest, e.g. as coating on drug eluting coronary stents.     

Improved small molecule drug release from in situ forming poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) and hydroxyapatite microparticles

In situ forming implants are an attractive choice for controlled drug release into a fixed location. Currently, rapidly solidifying solvent exchange systems suffer from a high initial burst, and sustained release behavior is tied to polymer precipitation and degradation rate. The present studies investigated addition of hydroxyapatite (HA) and drug-loaded poly(β-amino ester) (PBAE) microparticles to in situ forming poly(lactic-co-glycolic acid) (PLGA)-based systems to prolong release and reduce burst. PBAEs were synthesized, imbibed with simvastatin (osteogenic) or clodronate (anti-resorptive), and then ground into microparticles. Microparticles were mixed with or without HA into a PLGA solution, and the mixture was injected into buffer, leading to precipitation and creating solid scaffolds with embedded HA and PBAE microparticles. Simvastatin release was prolonged through 30?days, and burst release was reduced from 81 to 39% when loaded into PBAE microparticles. Clodronate burst was reduced from 49 to 32% after addition of HA filler, but release kinetics were unaffected after loading into PBAE microparticles. Scaffold dry mass remained unchanged through day 15, with a pronounced increase in degradation rate after day 30, while wet scaffolds experienced a mass increase through day 25 due to swelling. Porosity and pore size changed throughout degradation, likely due to a combination of swelling and degradation. The system offers improved release kinetics, multiple release profiles, and rapid solidification compared to traditional in situ forming implants.     

Semi-interpenetrating network of poly(ethylene glycol) and poly(D,L-lactide) for the controlled delivery of protein drugs

We have prepared a semi-interpenetrating network (IPN) of poly(ethylene glycol) dimethacrylate (PEGDMA) with entrapped poly(D,L-lactide) (PLA) using photochemical techniques. These IPNs were developed for the controlled delivery of protein drugs such as growth factors. The PEG component draws water into the network, forming a hydrogel within the PLA matrix, controlling and facilitating release of the protein drug, while the PLA component both strengthens the PEG hydrogel and enhances the degradation and elimination of the network after the protein drug is released. The rate and extent of swelling and the resultant protein release kinetics could be controlled by varying the PEG/PLA ratio and total PLA content. These IPNs were prepared using a biocompatible benzyl benzoate/benzyl alcohol solvent system that yields a uniform, fine dispersion of the protein throughout the PEG/PLA IPN matrix. IPNs composed of high molecular mass PLA and lower PEG/PLA ratios exhibited lower equilibrium swelling ratios. The release of bovine serum albumin (BSA), a model protein, from these IPNs was characterized by a large initial burst, regardless of the PEG/PLA ratio, due to the entrapment of residual solvent within the network. Microparticles of the PEG/PLA IPNs were also prepared using a modified Prolease strategy. Residual solvent removal was significantly enhanced using this process. The microparticles also exhibited a significant reduction in the initial burst release of protein. Mixtures of different compositions of PEG/PLA microparticles should be useful for the delivery of a variety of protein drugs with different release kinetics from any tissue-engineering matrix.     

Polymers for the controlled release of macromolecules: effect of molecular weight of ethylene-vinyl acetate copolymer

Matrices composed of ethylene-vinyl acetate copolymer (EVAc) have been used for controlled delivery of macromolecular bioactive agents. Three EVAc samples of different molecular weight (MW) were selected from solution fractionated samples. The polymer MW is a sensitive factor in affecting the release rate of bovine serum albumin (BSA); the higher the MW of EVAc, the slower the release rate. Depending on the degree of hydrophilicity of the device, the relatively hydrophilic drug particles would cause various degrees of swelling pressure upon water uptake. The relatively hydrophobic EVAc carrier would impose different degrees of restrictive force as determined by polymer MW. The interaction between the restrictive force of the carrier and the swelling pressure of the drug particles is a key factor in affecting the drug release kinetics. As a result, the selection of the polymer carrier can be used to affect the kinetics of a controlled release device.     

Controlled degradation of multilayered poly(lactide-co-glycolide) films using electron beam irradiation

The ability to undergo predictable and controlled degradation allows biopolymers to release prescribed dosages of drugs locally over a sustained period. However, the bulk or homogeneous degradation of some of these polymers like poly(L-lactide) (PLLA) and poly(lactide-co-glycolide) (PLGA) work against a better controlled release of the drugs. Inducing the polymers to undergo surface erosion or layer-by-layer degradation could provide a better process of controlled drug release from the polymers. This study has demonstrated that surface erosion degradation of PLGA is possible with the use of a multilayer film system, with PPdlLGA [plasticized poly(D,L-lactide-co-glycolide) (PdlLGA)] as the surface layers and poly(L-lactide-co-glycolide) as the center layer. The use of the more hydrophilic PPdlLGA as the surface layer resulted in a faster degradation of the surface layers compared to the center layer, thus giving a surface erosion degradation effect. The rate of surface degradation could also be controlled with electron beam (e-beam) radiation, where e-beam irradiation was shown to alter the degradation time and onset of polymer mass loss. It was also shown that the more highly irradiated PPdlLGA surface layers had an earlier onset of mass loss, which resulted in a faster reduction in overall film thickness. The ability to control the rate of film thickness reduction with different radiation dose promises a better controlled release of drugs from this multilayer PLGA film system.     

Porous silicon-poly(ε-caprolactone) film composites: evaluation of drug release and degradation behavior

This work focuses on an evaluation of novel composites of porous silicon (pSi) with the biocompatible polymer ε-polycaprolactone (PCL) for drug delivery and tissue engineering applications. The degradation behavior of the composites in terms of their morphology along with the effect of pSi on polymer degradation was monitored. PSi particles loaded with the drug camptothecin (CPT) were physically embedded into PCL films formed from electrospun PCL fiber sheets. PSi/PCL composites revealed a release profile of CPT (monitored via fluorescence spectroscopy) in accordance with the Higuchi release model, with significantly lower burst release percentage compared to pSi microparticles alone. Degradation studies of the composites, using gravimetric analysis, differential scanning calorimetry (DSC), and field emission scanning electron microscopy (FESEM), carried out in phosphate-buffered saline (PBS) under simulated physiological conditions, indicated a modest mass loss (15%) over 5 weeks due to pSi dissolution and minor polymer hydrolysis. DSC results showed that, relative to PCL-only controls, pSi suppressed crystallization of the polymer film during PBS exposure. This suppression affects the evolution of surface morphology during this exposure that, in turn, influences the degradation behavior of the polymer. The implications of the above properties of these composites as a possible therapeutic device are discussed.     

Influence of particle size and dissolution conditions on the degradation properties of polylactide-co-glycolide particles

Polymer degradation usually plays a crucial role in drug release from sustained release polyester systems, therefore in order to elucidate the mechanism governing release, it appears essential to analyse the in vitro degradation behaviour of these devices. In this study the influence of processing conditions, particle characteristics and release media temperature on the degradation of PLGA spherical particles were examined. It was found that a linear relationship between the degradation rate and particle size existed, with the larger particles degrading fastest. In smaller particles degradation products formed within the particle can diffuse easily to the surface while in larger particles degradation products have a longer path to the surface of the particle during which autocatalytic degradation of the remaining polymer material can occur. The influence of release media temperature on the degradation of PLGA particles was also examined. At lower incubation temperatures PLGA microparticles showed an induction period after which polymer degradation proceeded. The rate of polymer degradation was found to increase with increasing incubation temperature. The polymer erosion profile was fitted to the Prout-Tompkins equation and the rate constants were used to determine the activation energy of PLGA hydrolysis.     

Effect of synthesis parameters of the sol-gel-processed spray-dried silica gel microparticles on the release rate of dexmedetomidine

The objective of this study was to evaluate the possibilities to control the release rate of dexmedetomidine (DMED) from different spray-dried silica gel microparticle formulations. Microparticles were prepared by spray drying a silica sol polymer solution containing the drug. Drug release was investigated both in vitro and in vivo. The influence of sol-gel synthesis parameters, like pH and the water/alkoxide ratio (r) of the sol, on the release behaviour of the drug was studied. Silica gel microparticles had a smooth surface. Microparticles prepared from diluted sol, however, were more aggregated and clustered. The drug release conformed to zero order release from microparticles prepared near the isoelectric point of silica (pH 2.3 and pH 3) and to the square root of time kinetics from microparticles prepared at pH 1 and pH 5. The release also showed a dual-phasic profile with an initial burst and after that a slower release period. The dexmedetomidine release conformed to zero order kinetics from microparticles prepared at water/ alkoxide ratios between r = 6 and r = 35 (at pH 2.3). The release rate was the slowest from microparticles prepared with water/ alkoxide ratio 35. The bioavailability of dexmedetomidine in dogs showed that the release was sustained from silica gel microparticles as compared with a subcutaneously administered reference dose of 0.1 mg.     

A study on partially biodegradable microparticles as carriers of active glycolipids

This paper describes a study on the preparation and characterisation of partially biodegradable microparticles of poly(ε-caprolactone)/poly(ethyl methacrylate) (PCL/PEMA) as carriers of synthetic glycolipids with antimitotic activity against brain tumour cells. Microparticles prepared by suspension polymerisation of methacrylate in the presence of already polymerised PCL showed a predominantly spherical but complex morphology, with segregation of PCL micro/nano-domains towards the surface. Small diameter discs were prepared by compression moulding of blends of microparticles and the active principle under mild conditions. The in vitro behaviour of the discs and release of the glycolipid were studied in different simulated fluid models. Ingress of fluids increased with increasing hydrophobicity of the medium. Release of the glycolipid was sustained in all fluids, the most prolonged profile being in human synovial fluid and phosphate-buffered saline modified with 20 vol.% dioxane. Slow disintegration of the discs and partial degradation of the microparticles was evident in accelerated studies. The antimitotic activity of glycolipid released from the discs was proved against a human glioblastoma line. This activity, along with selectivity against human fibroblasts, could be controlled by the amount of drug charged in the disc.     

Controlled release properties and final macroporosity of a pectin microspheres–calcium phosphate composite bone cement

The use of calcium phosphate cements (CPC) is restricted by their lack of macroporosity and poor drug release properties. To overcome these two limitations, incorporating degradable polymer microparticles into CPC is an attractive option, as polymer microparticles could help to control drug release and induce macroporosity after degradation. Although few authors have yet tested synthetic polymers, the potentiality of polysaccharides’ assuming this role has never been explored. Low-methoxy amidated pectins (LMAP) constitute valuable candidates because of their biocompatibility and ionic and pH sensitivity. In this study, the potentiality of a LMAP with a degree of esterification (DE) of 30 and a degree of amidation (DA) of 19 was explored. The aim of this study was to explore the influence of LMAP microspheres within the composite on the cement properties, drug release ability and final macroporosity after microspheres degradation. Three LMAP incorporation ratios, 2%, 4% and 6% w/w were tested, and ibuprofen was chosen as the model drug. In comparison with the CPC reference, the resulting composites presented reduced setting times and lowered the mechanical properties, which remained acceptable for an implantation in moderate-stress-bearing locations. Sustained release of ibuprofen was obtained on at least 45 days, and release rates were found to be controlled by the LMAP ratio, which modulated drug diffusion. After 4 months of degradation study, the resulting CPC appeared macroporous, with a maximum macroporosity of nearly 30% for the highest LMAP incorporation ratio, and interconnectivity between pores could be observed. In conclusion, LMAP appear as interesting candidates to generate macroporous bone cements with tailored release properties and macroporosity by adjusting the pectin content within the composites.     

Biodegradable polyhydroxyalkanoate implants for osteomyelitis therapy: in vitro antibiotic release

Various random copolyesters of 3-hydroxybutyrate and 3-hydroxyvalerate (PHBV) and 3-hydroxybutyrate and 4-hydroxybutyrate P(3HB-4HB) were used in the construction of biodegradable, implantable rods for the local delivery of antibiotics (Sulperazone^® and Duocid^®) in chronic osteomyelitis therapy. Drug loading, type of active agent, and additional coating of the implant surface all have significant contributions to the in vitro release profile. The rate and duration of Sulperazone^® release from P(3HB-4HB) rods were controlled by the polymer/drug ratio (drug loading). The rate of drug dissolution was substantially higher than that of polymer degradation. Therefore, the release phenomenon was more dependent on drug dissolution rather than on polymer degradation or diffusion. Coating rods with the same type of polymer substantially reduced the initial burst effect observed with the uncoated rods, and significantly decreased the release rate so that the release kinetics became almost zero order. Antibiotic release from coated rods was sustained for over a period of 2 weeks at a constant rate, whereas uncoated rods released their contents in less than a week. Impregnation of Duocid^® into the hydrophobic polymer matrix yielded a rod with a smoother surface topography. The release from these rods was significantly higher than for rods loaded with Sulperazone^® and a zero order release could not be obtained with these samples.