Sustained-release Delivery System Research Articles

Encapsulation enhancement and stabilization of insulin in cationic liposomes

The purpose of this study was to enhance encapsulation efficiency and sustained-release delivery for parenteral administration of a protein drug. To reduce the administration frequency of protein drugs, it is necessary to develop sustained delivery systems. In this study, protein drug-loaded cationic liposomes were formulated with dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), dioleoyl-3-trimethylammonium-propane (DOTAP), and cholesterol (CH) at a molar ratio of DOPE/DOTAP/CH of 2/1.5/2. Five mol% of distearoylphosphatidyl ethanolamine polyethylene glycol (DSPE-PEG) was added prior to encapsulation of the drug into liposomes. Insulin was chosen as a model protein drug and encapsulation efficiency was evaluated in various liposomes with and without DSPE-PEG. Scanning electron microscopy was used to examine the insulin-loaded cationic liposomes. Structural analysis was performed using spectropolarimetry. Additionally, the stability and cytotoxicity of insulin-loaded cationic liposomes were evaluated. Liposomes coated with DSPE-PEG showed higher insulin encapsulation efficiency than did those without DSPE-PEG, but not significantly. Moreover, among the liposomes coated with DSPE-PEG, those hydrated with 10% sucrose showed higher encapsulation efficiency than did liposomes hydrated in either phosphate-buffered saline or 5% dextrose. In vitro release of insulin was prolonged by cationic liposomes. Our findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of protein and peptide drugs to prolong efficacy and improve bioavailability.

A study of dimensional, swelling, and gel changes in hydrophilic and hydrophobic polymer mixtures of chitosan and their possible use as carriers for sustained release drug delivery

AbstractThe aim of this investigation was to study and estimate the dimensional changes, gel evolution, swelling, and erosion of chitosan lactate mixture tablets with Polyox or Ethocel, in distilled water and 0.1 N hydrochloric acid (HCI) solution, using an image analysis method. This method permits the accurate measurement and evaluation of dimensional changes, core changes, and gel growth. All tablets displayed greater dimensional expansion in water than in HCI. The fastest and greatest swelling was exhibited in water, whereas, in contrast, the greatest erosion was observed in HCI. Chitosan/Polyox tablets exhibited greater expansion, swelling, and gel growth than the equivalent chitosan/Ethocel tablets. The thickness of the gel layer in chitosan/Polyox tablets, particularly, increased considerably with time up to 8 h, indicating that the development of a thick and durable gel barrier is a characteristic necessity for the preparation of sustained drug release delivery systems. In addition, the differentiation of the above‐mentioned characteristics in relation to changes in pH values also gives useful information about sustained release preparations made from these polymers, since it is well known that the gastrointestinal tract is characterized by a range of pH values. In general, the polymer mixtures studied comprise a useful and promising combination of materials for the development and manufacturing of sustained release devices based on these polymers. © 2011 Wiley Periodicals, Inc. Adv Polym Techn 30: 110–121, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/adv.20208

Polyrotaxanes for applications in life science and biotechnology

Due to their low cytotoxicity, controllable size, and unique architecture, cyclodextrin (CD)-based polyrotaxanes and polypseudorotaxanes have inspired interesting exploitation as novel biomaterials. This review will update the recent progress in the studies on the structures of polyrotaxanes and polypseudorotaxanes based on different CDs and polymers, followed by summarizing their potential applications in life science and biotechnology, such as drug delivery, gene delivery, and tissue engineering. CD-based biodegradable polypseudorotaxane hydrogels could be used as promising injectable drug delivery systems for sustained and controlled drug release. Polyrotaxanes with drug or ligand-conjugated CDs threaded on polymer chain with biodegradable end group could be useful for controlled and multivalent targeting delivery. Cationic polyrotaxanes consisting of multiple oligoethylenimine-grafted CDs threaded on a block copolymer chain were attractive non-viral gene carries due to the strong DNA-binding ability, low cytotoxicity, and high gene transfection efficiency. Cytocleavable end caps were also introduced in the polyrotaxane systems in order to ensure efficient endosomal escape for intracellular trafficking of DNA. Finally, hydrolyzable polyrotaxane hydrogels with cross-linked α-CDs could be a desirable scaffold for cartilage and bone tissue engineering.

Triamcinolone and Intraocular Sustained-Release Delivery Systems in Diabetic Retinopathy

Diabetic retinopathy (DR) still represents one of the leading causes of vision loss worldwide. Since this condition affects the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, considering that they seldom reach therapeutic levels in the affected tissues. Systemic medications can be insufficient due to the eye's immunoprivileged condition and existence of both inner and outer blood-retinal barriers, which place limitations on the potential role of this route of administration for retinal diseases. In this setting, intraocular therapies have emerged as novel and vital tools in the ophthalmologist's armamentarium against DR, allowing for maximization of drug efficacy and limited risk of systemic side effects. Intravitreal injections of triamcinolone acetonide have been widely used for treating DR particularly in the 21(st) century. Other agents targeting molecules, such as anti-vascular endothelial growth factor, have also demonstrated a potential therapeutic role for treatment. Recent advances in ocular drug delivery methods have led to the development of intraocular implants, which help to provide prolonged treatment with controlled drug release. Moreover, they may add some potential advantages over traditional intraocular injections by delivering certain rates of drug directly to the site of action, amplifying the drug's half-life, contributing in the minimization of peak plasma levels of the drug, and avoiding the side effects associated with repeated intravitreal injections.

Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes

The purpose of this study is to develop a thermoresponsive sustained release delivery system combining phytantriol cubosomes and poloxamer 407 (P407). P407 undergoes thermoreversible gelation, where it exists as a free-flowing liquid at low temperature and gels upon heating. However, this polymer has the major draw back of fast erosion in aqueous environments which needs to be addressed. Three different concentrations of P407 (12%, 15% and 17% (w/v)) were formulated with various additives (methyl cellulose (MC), dextran, carrageenan and Pluronic-R (25R4)). The rheological characteristics and in vitro stability were investigated. The sol–gel transition temperature of P407 was lowered in the presence of the phytantriol cubosomes. The addition of MC and dextran did not affect the sol–gel transition temperature whereas 25R4 increased the gelation temperature. No transition was observed for the carrageenan formulations. The presence of 25R4 allowed the development of formulations that were free flowing liquid at working temperature (22°C), gelled at body temperature (37°C) and had improved stability in an aqueous environment.Both rheological and in vitro stability studies suggested that cubosome-loaded 17% (w/v) P407 with 25R4 in 1:1 molar ratio may have a potential as sustained release delivery system.

Characterization of Human Erythrocytes as Potential Carrier for Pravastatin: An In Vitro Study

Drug delivery systems including chemical, physical and biological agents that enhance the bioavailability, improve pharmacokinetics and reduce toxicities of the drugs. Carrier erythrocytes are one of the most promising biological drug delivery systems investigated in recent decades. The bioavailability of statin drugs is low due the effects of P-glycoprotein in the gastro-intestinal tract as well as the first-pass metabolism. Therefore in this work we study the effect of time, temperature as well as concentration on the loading of pravastatin in human erythrocytes to be using them as systemic sustained release delivery system for this drug. After the loading process is performed the carriers' erythrocytes were physically and cellulary characterized. Also, the in vitro release of pravastatin from carrier erythrocytes was studied over time interval. Our results revealed that, human erythrocytes have been successfully loaded with pravastatin using endocytosis method either at 25(o)C or at 37(o)C. The loaded amount at 10 mg/ml is 0.32 mg/0.1 ml and 0.69 mg/0.1 ml. Entrapment efficiency is 34% and 94% at 25(o)C and 37(o)C respectively at drug concentration 4 mg/ml. Moreover the percent of cells recovery is 87-93%. Hematological parameters and osmotic fragility behavior of pravastatin loaded erythrocytes were similar that of native erythrocytes. Scanning electron microscopy demonstrated that the pravastatin loaded cells has no change in the morphology. Pravastatin releasing from carrier cell was 83% after 23 hours in phosphate buffer saline and decreased to 72% by treatment of carrier cells with glutaraldehyde. The releasing pattern of the drug from loaded erythrocytes obeyed first order kinetics. It concluded that pravastatin is successfully entrapped into erythrocytes with acceptable loading parameters and moderate morphological changes, this suggesting that erythrocytes can be used as prolonged release for pravastatin.

Novel poly-DL-lactide-polycaprolactone copolymer based flexible drug delivery system for sustained release of ciprofloxacin

This research evaluated 7525DLPCL for soft flexible drug delivery systems. The effect of ciprofloxacin hydrochloride (CIP) loading at three levels (10, 20, and 30%), on thermo-mechanical properties was studied. CIP release was monitored for 12 weeks. Addition of CIP to 7525DLPCL caused an increase in compressive modulus of 7525DLPCL. CIP release was found to be sigmoidal with two phenomena (apart from a minor burst) contributing to release–diffusion and later diffusion plus erosion. An increased burst was observed with greater CIP loading and the majority of CIP (> 70%) was released as an effect of diffusion plus erosion. Additional factors, like the effect of CIP particle size, had no significant effect on drug release. Change in the implant shape from a cylinder (5 mm diameter; 3 mm thickness) to disc (6 mm diameter, 0.5 mm thickness) also failed to show a significant impact on drug release. Erosion of 7525DLPCL is a major contributing factor towards this release and other factors like shape of implants and particle size of drug have little effect on CIP release. Such flexible drug delivery systems offer new avenues for long-term skeletal drug delivery of antibiotics for conditions like osteomyelitis or periodontitis.

Intra-articular drug delivery: The challenge to extend drug residence time within the joint

The rationale behind developing sustained release microsphere formulations of non-steroidal anti-inflammatory drugs (NSAIDs) administered via the intra-articular (IA) route is to minimise the systemic bioavailability and attendant side-effects associated with oral drug administration. Overall dose is reduced whilst therapeutic benefit within the joint is maintained. The potential benefits of IA therapy for osteoarthritis (OA) are not achieved using currently available medications and delivery vehicles due to the rapid clearance of therapeutic substances from the synovial space. There is a need for sustained release delivery systems if the potential of IA drug administration is to be realised. Rationally designed microspheres taken up by synovial macrophages offer a strategy to sustain drug delivery within the joint, and to deliver NSAIDs directly to pivotal inflammatory cells. The efficacy of microsphere candidates may be evaluated in large animal models of OA. The principles of IA microsphere drug delivery may also be applicable to other classes of drugs.

Formulation optimization of nifedipine containing microspheres using factorial design.

Nifedipine is a calcium channel blocker which is used in the treatment of hypertension angina pectoris. The aim of this study was to formulate and optimize nifedipine containing microspheres in an attempt to prepare a suitable sustained release delivery system using factorial design. Drug loaded microspheres were prepared using Eudragit RL100, through solvent evaporation technique. In the next step, the effect of different formulation variables, including the amount of polymer (1 - 2 g), stabilizer (0.1 - 0.5 g) and drug/polymer ratio (0.05:1 – 0.1:1) on the appearance, physical properties of particles, and the amount of loaded drug was investigated. Based on the type and the variables studied, 8 formulations were designed using factorial design method, and were then prepared and their drug contents were determined. In order to detect the precise effect of the formulation variables and their interactions, design expert software was used. Data analysis showed that microspheres with optimum drug loading could be prepared using 1 g polyvinylalcohol, 1 – 2 g polymer and 0.07:1 drug/polymer ratio. Among the formulations suggested and based on the predicted responses and their desirability indices, 6 formulations were selected as the optimum formulations. Finally, selected microspheres were evaluated from the view points of morphology and release pattern. Results revealed that microspheres obtained from the formulations S19, S20and S24 could be selected as the best and optimized formulations due to their high drug contents, appropriate invitro drug release after 12 h and desired morphology. Key words: Nifedipine, microsphere, solvent evaporation, eudragit RL100, factorial design.

Insulin micropiles comprising biodegradable polymers for production of a long-term hypoglycemic effect

As a percutaneous sustained-release preparation, insulin micropiles (MPs) were prepared with biodegradable polymers poly(lactic acid) (PLA), poly(ϵ-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA) as the base. The obtained PLA, PCL, and PLGA MPs of which the insulin:polymer ratio was 1:2 were administered to rat skin at 40 IU/kg and hypoglycemic effects measured for 6 days. The order of the hypoglycemic effect was PLA>PCL>PLGA. PLA MP showed the strongest hypoglycemic effect (2 days). The hypoglycemic effect of insulin PLA MP was dependent on the formulation; the order was insulin:PLA (2:1)>insulin:PLA (1:1)>insulin:PLA (1:2). As the ratio of insulin to the polymer base increased, the hypoglycemic effect increased. The area above the plasma glucose levels vs. time curves for 6 days from insulin:PLA (2:1) MPs, 10, 20, 30, and 40 IU/ kg, were 249 ± 108, 2003 ± 379, 3960 ± 794, and 6311 ± 726%·h. A dose-dependent hypoglycemic effect was obtained at 10–40 IU/kg and pharmacological availabilities were 11.1%, 44.5%, 58.6%, and 70%, respectively. Insulin:PLA (2:1) MP showed high plasma insulin level, 86.9–134.7 IU/mL, for 3 days. There was no damage to rat skin. These results suggest the usefulness of insulin:PLA (2:1) MP as a sustained-release percutaneous delivery system for insulin.

Sustained release of hydroxycamptothecin after subcutaneous administration using a novel phospholipid complex—DepoFoam™ technology

Objective: In order to prolong the duration of drug in the circulation, multivesicular liposome (MVL, namely DepoFoam™) was utilized as a sustained-release delivery system for hydroxycamptothecin (HCPT). Methods: HCPT is insoluble in both water and physiological acceptable organic solvents; therefore, HCPT–phospholipid complex (HCPT–PCC) was prepared by solvent evaporation method to improve its liposolubility. In this study, preparation, characterization, in vitro release, and in vivo pharmacokinetics of HCPT–phospholipid complex-loaded MVLs (HCPT-MVLs) were investigated. Results: The results showed that the average particle size of HCPT-MVL was 9 μm and the encapsulation efficiency was 90%. In addition, HCPT-MVLs could improve both in vitro release and in vivo pharmacokinetic behaviors of the original drug, with a sustained release of drugs over 5–6 days. Conclusion: These data suggested that by combined use of DepoFoam™ and phospholipid complex formation technique HCPT could be successfully entrapped into the MVLs, which might provide a paradigm for sustained release of insoluble drugs.

An injectable oxidized carboxymethylcellulose/N-succinyl-chitosan hydrogel system for protein delivery

This work is focused on the development of a new injectable drug delivery system for proteins sustained release. A series of in situ forming hydrogels derived from oxidized carboxymethylcellulose (OCMC) and N-succinyl-chitosan (NSC) were prepared by Schiff base reaction. OCMC was prepared by cleaving the vicinal glycols in carboxymethylcellulose with sodium periodate and NSC was obtained by introduction of succinyl groups into chitosan N-terminal of the glucosamine units, respectively. The gelation readily took place at physiological pH and temperature. Several parameters, such as matrix gelation time, equilibrium swelling ratio, matrix degradation rate and drug release profile, were investigated. The in vitro cytotoxicity studies showed that the OCMC/NSC hydrogels were non-cytotoxic and preserved the viability of the entrapped cells. The release profile of BSA was divided into four stages, indicating that the release of BSA was controlled by both diffusion and degradation. Importantly, activity of released BSA was retained regardless of the oxidation degree. This newly described OCMC/NSC hydrogels demonstrated attractive properties and would be a suitable injectable and biodegradable system for the delivery of protein drugs.

Delivery of celecoxib for treating diseases of the eye: influence of pigment and diabetes

Importance of the field: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two major causes of blindness. In these disorders, growth factors such as vascular endothelial growth factor (VEGF) are upregulated, leading to either enhanced vascular permeability or proliferation of endothelium. While corticosteroid therapies available at present suffer from side effects including cataracts and elevated intraocular pressure, anti-VEGF antibody therapies require frequent intravitreal injections, a procedure that can potentially lead to retinal detachment or endophthalmitis. Thus, there is a need to develop safe, sustained release therapeutic approaches for treating AMD and DR.Areas covered in this review: This review discusses the pharmacological basis for using celecoxib, an anti-inflammatory drug capable of selectively inhibiting cycloxygenase 2, in treating AMD and DR. In addition, this article discusses the safety, delivery advantage and efficacy of celecoxib by transscleral retinal delivery, a periocular delivery approach that is less invasive to the globe compared with intravitreal injections.What the reader will gain: The reader will gain insights into the development of a pharmacological agent and a sustained release delivery system for treating DR and AMD. Further, the reader will gain insights into the influence of eye physiology including pigmentation and disease states such as DR on retinal drug delivery.Take home message: Transscleral sustained delivery of anti-inflammatory agents is a viable option for treating retinal disorders.

Two- and three-layer tablet drug delivery systems for oral sustained release of soluble and poorly soluble drugs

Background: Multilayer tablets are gaining importance in oral sustained drug delivery. They consist of an active matrix core and one or more layers applied during tableting which may act as barriers and regulate drug release. Objective: To examine the release performance of two model drugs, diclofenac sodium and furosemide, from two- and three-layer drug delivery systems using as carriers hydrophilic swellable polymers, namely, Metolose, Polyox, Xantham gum, and an erodible material Gantrez. Results and discussion: All prepared formulations demonstrated sustained release profiles. They also indicated that the carrier characteristics (particularly swelling-expansion, erosion-dissolution) and drug solubility in combination with tablet structure considerably influenced the performance of examined formulations as well as their mode and mechanisms of release. In general our findings show that the differences in drug release between the two- and three-layer tablets are small as it appears that two-layer tablets exhibit a slightly higher release. Because of its greater erosion Gantrez formulations displayed faster release relative to Xantham gum, as did Metolose formulations compared to Polyox formulations. A faster release rate was also noted with diclofenac formulations compared to those of furosemide because of diclofenac's higher solubility mainly seen at early time period. Conclusions: All three-layer Gantrez tablets containing either diclofenac or furosemide and the two-layer furosemide formulation demonstrated a biphasic release. The above indicate that both structures may be used successfully for sustained release drug delivery. In addition the use of multilayer tablets, consisting of materials with suitable properties, may result in modulation of drug release.

Comparison of gastroretentive microspheres and sustained-release preparations using theophylline pharmacokinetics

The objective of this study was to use the pharmacokinetics of theophylline to compare various gastroretentive microspheres. Three types of theophylline microspheres prepared from a hydrophobic dextran derivative were characterized in terms of drug release in-vitro and floating and mucoadhesive properties. Theophylline pharmacokinetic studies were conducted in Beagle dogs, comparing bulk powder, commercial sustained-release granules (Theodur), sustained-release microspheres, floatable microspheres and mucoadhesive microspheres. Theodur and sustained-release microspheres resulted in a lower maximum concentration (Cmax) (P < 0.01) and larger values for mean residence time (MRT) (P < 0.05) than bulk powder, whereas area under the concentraion-time curve (AUC) were lower. The floatable microspheres showed a larger value for MRT than bulk powder (P < 0.01), and a larger AUC than Theodur (P < 0.05). The pharmacokinetic parameters of the mucoadhesive microspheres indicated an increase in AUC without decreasing the rate of bioavailability. Overall, the gastroretentive microspheres improved the extent of bioavailability of theophylline, which is absorbable from the entire gastrointestinal tract. The mucoadhesive microsphere showed a prolonged serum drug level, indicating a superior sustained-release delivery system for theophylline.

Synthesis of nicotinamide-based molecularly imprinted microspheres and in vitro controlled release studies

Nicotinamide (NAM), which is one of the two principal forms, together with nicotinic acid, of vitamin B3, is both a food nutrient and a drug. Controlled NAM release systems are useful to extend the duration of the drug’s pharmacological activity and to minimize administration frequency. In this paper, molecularly imprinted polymers (MIPs) have been used as unconventional synthetic polymeric carriers, to prepare drug delivery systems for sustained release of NAM molecules. In the present study, various MIPs micro-spheres have been synthesized by using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker. Different stoichiometric ratios of the reagents have been used, in order to evaluate their influence on NAM recognition and release properties. Non-imprinted systems have been also been prepared as controls. MIPs binding capacity has been evaluated; NAM loading and in vitro release studies, in buffer solution (pH 7.2), that mimics blood plasma conditions, have been performed. Polymer P4 has given the best results since it enables it to rebind selectively and to prolong the release of NAM with higher performance than the non-imprinted one.

Chlorhexidine varnishes effectively inhibit Porphyromonas gingivalis and Streptococcus mutans - An in vivo study

Background:Chlorhexidine varnish (Cervitec- Ivoclar Vivadent- Liechtenstein) is a sustained-release delivery system that can provide protection against white spots and gingivitis, which are common iatrogenic side effects of orthodontic treatment. Chlorhexidine in varnish form does not depend on patient compliance, does not stain teeth or alter taste sensation like the mouth rinse.Materials and Methods:A split-mouth technique was followed in the treatment of 30 patients selected by stringent selection criteria, evaluating a single application of the test varnish on two randomly allotted quadrants along with a placebo on the other two quadrants. Streptococcus mutans counts responsible for white spots and P. gingivalis count [using PCR test] responsible for gingivitis were done at the start of the study, and then 1 and 3 months later.Results:The chlorhexidine varnish reduced the Streptococci mutans count at the end of 1 month, and this reduction was statistically significant. At the end of 3 months, there was no difference in the S. mutans counts between the two groups. There was a statistically significant reduction in the P. gingivalis count at the end of both 1 and 3 months in comparison to the placebo group.Conclusion:Chlorhexidine varnishes are capable of reducing S. mutans and P. gingivalis and gingivitis, thus improving the overall oral health of the patient. The side effects of chlorhexidine mouth rinses are not seen with this varnish. An application schedule of at least once a month is recommended as the effectiveness is reduced comparatively at the end of 3 months.

Preparation, Characterization, and Pharmacodynamics of Exenatide-Loaded Poly(DL-lactic-co-glycolic acid) Microspheres

Exenatide (synthetic exendin-4), a 39-amino acid peptide, was encapsulated in poly(DL-lactic-co-glycolic acid) (PLGA) microspheres as a sustained release delivery system for the therapy of type 2 diabetes mellitus. The microspheres were prepared by a double-emulsion solvent evaporation method and the particle size, surface morphology, drug encapsulation efficiency, in vitro release profiles and in vivo hypoglycemic activity were evaluated. The results indicated that the morphology of the exenatide PLGA microspheres presented as a spherical shape with smooth surface, and the particle sizes distributed from 5.8 to 13.6 µm. The drug encapsulation efficiency tested by micro-bicinchoninic acid (BCA) assay was influenced by certain parameters such as inner and outer aqueous phase volume, PLGA concentration in oil phase, polyvinyl alcohol (PVA) concentrations in outer aqueous phase. Moreover, in vitro release behaviors were also affected by some parameters such as polymer type, PLGA molecular, internal aqueous phase volume, PLGA concentration. The pharmacodynamics in streptozotocin (STZ)-induced diabetic mice suggested that, exenatide microspheres have a significant hypoglycemic activity within one month, and its controlling of plasma glucose was similar to that of exenatide solution injected twice daily with identical exenatide amount. In conclusion, this microsphere could be a well sustained delivery system for exenatide to treat type 2 diabetes mellitus.

Design and in vitro evaluation of novel sustained-release matrix tablets for lornoxicam based on the combination of hydrophilic matrix formers and basic pH-modifiers

The short half-life of lornoxicam, a potent non-steroidal anti-inflammatory drug, makes the development of sustained-release (SR) forms extremely advantageous. However, due to its weak acidic nature, its release from SR delivery systems is limited to the lower gastrointestinal tract which consequently leads to a delayed onset of its analgesic action. Accordingly, the aim of this study was to develop lornoxicam SR matrix tablets that provide complete drug release that starts in the stomach to rapidly alleviate the painful symptoms and continues in the intestine to maintain protracted analgesic effect as well as meets the reported SR specifications. The proposed strategy was based on preparing directly compressed hydroxypropylmethylcellulose matrix tablets to sustain lornoxicam release. Basic pH-modifiers, either sodium bicarbonate or magnesium oxide, were incorporated into these matrix tablets to create basic micro-environmental pH inside the tablets favorable to drug release in acidic conditions. All the prepared matrix tablets containing basic pH-modifiers showed acceptable physical properties before and after storage. Release studies, performed in simulated gastric and intestinal fluids used in sequence to mimic the GI transit, demonstrate the possibility of sustaining lornoxicam release by combining hydrophilic matrix formers and basic pH-Modifiers to prepare tablets that meet the reported sustained-release specifications.

Spawning performance and plasma levels of GnRHa and sex steroids in cultured female Senegalese sole ( Solea senegalensis) treated with different GnRHa-delivery systems

The aquaculture of Senegalese sole ( Solea senegalensis) is limited by the poor spawning performance of the F1 generation cultured broodstock. The present study compared the efficiency of two sustained-release delivery systems loaded with gonadotropin-releasing hormone agonist (GnRHa) and a single GnRHa injection on the stimulation of oocyte maturation (OM), sex steroid hormone secretion and spawning. Analysis with an ELISA showed that the administered GnRHa was no longer detectable in the plasma 3, 7 and 14 d after administration via a single injection, microspheres and an implant, respectively. All GnRHa treatments induced a transient elevation of testosterone (T) and 17β estradiol (E 2) plasma levels after 1–3 d. Only three spawns were obtained from controls on days 35, 41 and 42 of the study and ovarian biopsies showed abundant fully vitellogenic oocytes, but little OM. Fish given a GnRHa injection spawned sporadically with the first spawn at 20 days post-treatment (dpt). In contrast, GnRHa implants and microspheres stimulated OM and daily spawning starting at 4 and 5 dpt, respectively, and lasting for a period of 28 d. Total fecundity in the broodstock treated with GnRHa-delivery systems was 15–22 times greater than controls and 3–5 times greater than GnRHa-injected fish. Although egg quality appeared to be high, no fertilization was obtained. The results suggest that GnRHa-delivery systems are highly efficient on stimulating OM and spawning in Senegalese sole, presumably through the long-term elevation of pituitary luteinizing hormone release, which in turn stimulated the appropriate changes in ovarian steroidogenesis. However, the effectiveness of the treatment was negated by possible dysfunctions of the male breeders or of the reproductive behavior of the broodstock.