Pulsatile Release Profile Research Articles

Development and Evaluation of a Novel Topical Treatment for Acne with Azelaic Acid-Loaded Nanoparticles

Azelaic acid (AzA) is used in the treatment of acne. However, side effects and low compliance have been associated with several topical treatments with AzA. Nanotechnology presents a strategy that can overcome these problems. Polymeric nanoparticles can control drug release and targeting and reduce local drug toxicity. The aim of this study was to produce and evaluate an innovative topical treatment for acne with AzA-loaded poly-DL-lactide/glycolide copolymer nanoparticles. A soft white powder of nanoparticles was prepared. The mean size of loaded nanoparticles was < 400 nm and zeta potential was negative. Spherical nanoparticles were observed by scanning electron microscopy. Encapsulation efficiency was around 80% and a strong interaction between the polymer and the drug was confirmed by differential scanning calorimetric analysis. In vitro drug release studies suggested a controlled and pulsatile release profile. System efficacy tests suggested similar results between the loaded nanoparticles and the nonencapsulated drug against the most common bacteria associated with acne. Cytotoxicity of AzA-loaded nanoparticles was concentration dependent, although not pronounced. The occluded patch test seemed to indicate that the formulation excipients were safe and thus AzA-loaded nanoparticles appear to be an efficient and safe treatment for acne.

An implantable thermoresponsive drug delivery system based on Peltier device

Locally dropping the temperature in vivo is the main obstacle to the clinical use of a thermoresponsive drug delivery system. In this paper, a Peltier electronic element is incorporated with a thermoresponsive thin film based drug delivery system to form a new drug delivery device which can regulate the release of rhodamine B in a water environment at 37 °C. Various current signals are used to control the temperature of the cold side of the Peltier device and the volume of water on top of the Peltier device affects the change in temperature. The pulsatile on-demand release profile of the model drug is obtained by turning the current signal on and off. The work has shown that the 2600 mAh power source is enough to power this device for 1.3 h. Furthermore, the excessive heat will not cause thermal damage in the body as it will be dissipated by the thermoregulation of the human body. Therefore, this simple novel device can be implanted and should work well in vivo.

Design, engineering and structural integrity of electro-responsive carbon nanotube- based hydrogels for pulsatile drug release.

Triggerable drug delivery from polymeric implants offers the possibility to generate remote-controlled drug release profiles that may overcome the deficiencies of conventional administration routes (intravenous injections and oral administration) including the toxicity due to overdose and systemic administration. An electro-responsive delivery system was engineered to deliver drug molecules in a pulsatile manner, controlled by the on/off application of electric voltage. Pristine multi-walled carbon nanotubes (pMWNTs) were incorporated into a polymethacrylic acid (PMAA)-based hydrogel matrix by in situ radical polymerisation. The effect of pMWNTs and cross-linker concentration on the electrical and mechanical properties of the hydrogel hybrids was thoroughly investigated. The incorporation of pMWNTs into the polymeric network improved the electrical properties of the hydrogel hybrids and drug release from the gels was significantly enhanced at high pMWNT concentrations, reaching 70% of the loaded dose after two short electrical stimulations. The presence of pMWNTs within the hydrogel matrix affected however the mechanical properties of the hydrogel by decreasing the pore size and therefore the swelling/de-swelling of the gels. The damage to the hybrid gel surfaces after electrical stimulation and the loss of the pulsatile release profile at high cross-linker concentrations suggested that the mechanism of drug release involved a compressing effect and intensified the stress on the polymeric network as a result of the electrical properties of pMWNTs.

A novel plug-controlled colon-specific pulsatile capsule with tablet of curcumin-loaded SMEDDS

This study developed and evaluated a colon-specific pulsatile capsule with tablet of self-microemulsifying drug delivery system (SMEDDS). This system is based on an impermeable capsule containing a rapid-disintegrating curcumin-loaded SMEDDS tablet inside it, and a highly methoxylated pectin (H-pectin)/lactose tablet plugged in the capsule mouth. The SMEDDS tablet enhanced the solubility of curcumin, a water-insoluble drug. An in vitro release study of the pulsatile capsule showed a typical pulsatile release profile with a specific lag time. The lag time, which determines the efficiency of colon-specific delivery, could be regulated by varying the H-pectin/lactose ratio. Pectinase and rat cecal contents added to the release medium significantly shortened the erosion time, which proved that the H-pectin plug is sensitive to enzyme degradation. These results show that the pulsatile capsule with SMEDDS tablet has potential for the colon-specific delivery of water-insoluble drugs.

Electroresponsive Polymer–Carbon Nanotube Hydrogel Hybrids for Pulsatile Drug Delivery In Vivo

Drug release triggered by an external non-invasive stimulus is of great interest for the development of new drug delivery systems. The preparation of an electroresponsive multiwalled carbon nanotube/poly(methylacrylic acid) (MWNT/PMAA)-based hybrid material is reported. The hydrogel hybrids achieve a controlled drug release upon the ON/OFF application of an electric field, giving rise to in vitro and in vivo pulsatile release profiles.

A mathematical model for pulsatile release: Controlled release of rhodamine B from UV-crosslinked thermoresponsive thin films

A controlled drug delivery system fabricated from a thermoresponsive polymer was designed to obtain a pulsatile release profile which was triggered by altering the temperature of the dissolution medium. Two stages of release behaviour were found: fast release for a swollen state and slow (yet significant and non-negligible) release for a collapsed state. Six cycles of pulsatile release between 4°C and 40°C were obtained. The dosage of drug (rhodamine B) released in these cycles could be controlled to deliver approximately equal doses by altering the release time in the swollen state. However, for the first cycle, the swollen release rate was found to be large, and the release time could not be made short enough to prevent a larger dose than desired being delivered. A model was developed based on Fick's law which describes pulsatile release mathematically for the first time, and diffusion coefficients at different temperatures (including temperatures corresponding to both the fully swollen and collapsed states) were estimated by fitting the experimental data with the theoretical release profile given by this model. The effect of temperature on the diffusion coefficient was studied and it was found that in the range of the lower critical solution temperature (LCST), the diffusion coefficient increased with decreasing temperature. The model predicts that the effective lifetime of the system lies in the approximate range of 1–42h (95% of drug released), depending on how long the system was kept at low temperature (below the LCST). Therefore this system can be used to obtain a controllable pulsatile release profile for small molecule drugs thereby enabling optimum therapeutic effects.

Preparation of konjac glucomannan-based pulsatile capsule for colonic drug delivery system and its evaluation in vitro and in vivo.

The current study aims to develop and evaluate a colon-specific, pulsatile drug delivery system based on an impermeable capsule. A pulsatile capsule was prepared by sealing a 5-aminosalicylic acid rapid-disintegrating tablet inside an impermeable capsule body with a konjac glucomannan (KGM)-hydroxypropyl methylcellulose (HPMC)-lactose plug. The drug delivery system showed a typical pulsatile release profile with a lag time followed by a rapid release phase. The lag time was determined by the KGM/HPMC/lactose ratio, the type of HPMC, and the plug weight. The addition of β-glucanase and rat cecal contents into the release medium shortened the lag time significantly, which predicted the probable enzyme sensitivity of the KGM plug. The in vivo studies show that the plasma drug concentration can only be detected 5h after oral administration of the capsule, which indirectly proves the colon-specific characteristics. These results indicate that the pulsatile capsule may have therapeutic potential for colon-specific drug delivery.

Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: Influence of the core composition on release characteristics

The design of a film coating technology which allows a tablet to deliver the drug in the ileocolonic segment would offer new treatment possibilities. The objective is to develop a platform technology that is suitable for a broad range of drug compounds. We developed a coated tablet with a delayed, pulsatile release profile based on a pH-sensitive coating technology (ColoPulse). The production process was validated, and the effect of core composition on the in vitro release and water uptake investigated. The release profile of the standard tablet core composition, based on the use of cellulose as a filler, was independent of the coat thickness in a range of 9.0–13.2 mg/cm2. The release profile of a coated tablet was strongly influenced when cellulose was partly replaced by the model substance glucose (loss of sigmoidal release), citric acid (stabilization), sodium bicarbonate (destabilization) or sodium benzoate (destabilization). The film coating takes up water when below the pH-threshold. However, this did not cause early disintegration of the coating. The ColoPulse technology is successfully applied on tablets. The in vitro release characteristics of the coated tablets are influenced by the composition of the core.

Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings

Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope 13C 6-glucose as the test compound were administered and the occurrence of 13CO 2 in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines.

Drug release behavior of chitosan–montmorillonite nanocomposite hydrogels following electrostimulation

Nanocomposites hydrogel (nanohydrogel) composed of chitosan (CS) and montmorillonite (MMT) were prepared and systematically studied for drug release behavior following electrostimulation. The deterioration of the responsiveness and reversibility of CS upon repeated on–off electrostimulation switching operations are major limitations for clinical applications, as it suffers from too much structural instability for the precise control of the release of drug upon cyclic electrostimulation. To overcome these limitations, an inorganic phase, MMT, was incorporated in the CS matrix to enhance the anti-fatigue property and corresponding long-term stable release kinetics. X-ray diffraction analysis and time-dependent optical absorbance showed that the MMT incorporated into the nanohydrogel exhibited an exfoliated nanostructure. The exfoliated silica nanosheets are able to act as cross-linkers to form a network structure between the CS and MMT, and this difference in the cross-linking density strongly affects the release of vitamin B 12 under electrostimulation. With a lower MMT concentration (1 wt.%), the release kinetics of vitamin B 12 from the nanohydrogel shows a pseudo-zero-order release, and the release mechanism was changed from a diffusion-controlled mode to a swelling-controlled mode under electrostimulation. Further increasing the MMT content reduced both the diffusion exponent n and the responsiveness of the nanohydrogel to electrostimulation. In addition, a consecutively repeated “on” and “off” operation shows that the electroresponsiveness of the nanohydrogel with higher MMT concentrations was reduced, but its anti-fatigue behavior was considerably improved. In this work, the nanohydrogel with 2 wt.% MMT achieved a mechanically reliable and practically desirable pulsatile release profile and excellent anti-fatigue behavior, compared with that of the pure CS.

Bioerodible devices for intermittent release of simvastatin acid

The association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used to create intermittent release devices for mimicking the daily injection of simvastatin that has been reported to stimulate bone formation. To enhance solubility in water, prodrug simvastatin was modified by lactone ring opening, which converts the molecule to its hydroxyacid form. CAP/PF-127 microspheres incorporating simvastatin acid were prepared by a water–acetone–oil–water (W/A/O/W) triple emulsion process. Devices were then fabricated by pressure-sintering UV-treated blank and drug-loaded microspheres. Using a multilayered fabrication approach, pulsatile release profiles were obtained. Delivery was varied by changing loading, number of layers, blend ratio, and incubation conditions. To determine the cellular effects of intermittent exposure to simvastatin acid, MC3T3-E1 cells were cultured with either alternating or sustained concentrations of simvastatin acid in the medium, and DNA content, alkaline phosphatase activity, and osteocalcin secretion were measured. For all three cell responses, cultures exposed to simvastatin acid showed higher activity than did control cultures. Furthermore, cell activity was greater for cells cultured with intermittent concentrations of simvastatin acid compared to cells that were constantly treated. These results imply that devices intermittently releasing simvastatin acid warrant further study for locally promoting osteogenesis.

Design and Gamma-Scintigraphic Evaluation of a Floating and Pulsatile Drug Delivery System Based on an Impermeable Cylinder

A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. The objective of this study was to develop and evaluate a floating and pulsatile drug delivery system based on an impermeable cylinder. Pulsatile capsule was prepared by sealing the drug tablet and the buoyant material filler inside the impermeable capsule body with erodible plug. The drug delivery system showed typical floating and pulsatile release profile with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of plugs and the composition of the plug could be controlled by the weight of the plug. The buoyancy of the whole system depended on the bulk density of the dosage form. Gamma-scintigraphic evaluation in humans was used to establish methodology capable of showing the subsequent in vivo performance of the floating and pulsatile release capsule. Developed formulations showed instantaneous floating with no drug release during the lag time followed by a pulse drug release. From the gamma-scintigraphic results, the pulsatile release capsule we prepared could achieve a rapid release after lag time in vivo, which was longer than that in vitro. The scintigraphic evaluation could confirm qualitatively that the system with in vitro lag time of 4.0 h provided, with relatively high reproducibility, a pulsatile release occurred around 5.0 h after administration.

Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles

The objective of this study was to develop and evaluate a rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule itself was insufficient to rupture the external polymer coating, an additional swelling layer was applied between the capsule and the polymer coating. Croscarmellose sodium (Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and therefore more complete drug release than the flexible polymer coating, Eudragit RS. The lag time of the release system increased with higher polymer coating levels and decreased with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing amount of the intermediate swelling layer. The water uptake of the capsules was linear until rupture and was higher with CAPr than with EC. Soft gelatin capsule-based systems showed shorter lag times compared to hard gelatin capsules because of the higher hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore more directed to the external polymer coating with the soft gelatin capsules. Typical pulsatile drug release profiles were obtained at lower polymer coating levels, while the release was slower and incomplete at the higher coating levels. CAPr-coated capsules resulted in a more complete release than EC-coated capsules.

Pulsatile Drug-Delivery Systems

Delivery systems with a pulsatile-release pattern are receiving increasing interest for the development of drugs for which conventional controlled drug-release systems with a continuous release are not ideal. These drugs often have a high first-pass effect or special chronopharmacological needs. A pulsatile-release profile is characterized by a time period of no release (lag time) followed by a rapid and complete drug release. Pulsatile drug-delivery systems can be classified into site-specific systems in which the drug is released at the desired site within the intestinal tract (e.g., the colon), or time-controlled devices in which the drug is released after a well-defined time period. Site-controlled release is usually controlled by environmental factors, like the pH or enzymes present in the intestinal tract, whereas the drug release from time-controlled systems is controlled primarily by the delivery system and, ideally, not by the environment. This review covers various single- and multiple-unit oral pulsatile drug-delivery systems with an emphasis on time-controlled drug-release systems.

Pulsatile release from subcutaneous implants

Pulsatile delivery of antigens and hormones from subcutaneous implants could have uses in the animal production and veterinary medicine. Development of single-shot vaccines which release both initial and booster antigen from a single administration and hormonal preparations that release in a similar manner to the natural secretion patterns are two areas with potential. Formulation approaches employed to produce subcutaneous implants with pulsatile release profiles are reviewed.

Pulsatile drug release from an insoluble capsule body controlled by an erodible plug.

The objective of this study was to develop and evaluate a pulsatile drug delivery system based on an impermeable capsule body filled with drug and an erodible plug placed in the opening of the capsule body. The erodible plugs were either prepared by direct compression followed by placing the tablets in the capsule opening or by congealing a meltable plug material directly within the capsule opening. The disintegration/erosion properties of these plugs were determined and optimized for the final delivery system. In order to assure rapid drug release of the capsule content after erosion of the plug, various excipients (fillers, effervescent agents) and drugs with different solubilities were evaluated. The lag time prior to drug release and the subsequent drug release were investigated as function of capsule content, plug composition, plug preparation technique, plug hardness, weight, and thickness. The erosion time of the compressed plugs increased with increasing molecular weight of the hydrophilic polymer (e.g. hydroxypropyl methylcellulose, polyethylene oxide), decreasing filler (lactose) content and decreased with congealable lipidic plugs with increasing HLB-value and inclusion on surfactants. For complete and rapid release of the drug from the capsule body, effervescent agents had to be included in the capsule content. The drug delivery system showed typical pulsatile release profiles with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of the plugs and, besides the composition of the plug, could be controlled by the thickness (weight) of the plug. A single-unit, capsular-shaped pulsatile drug delivery system was developed wherein the pulsatile release was controlled by the erosion properties of a compressed or congealed plug placed within the opening of the capsule opening.

Photoperiodic modulation of luteinizing hormone secretion in orchidectomized Syrian hamsters and the influence of excitatory amino acids.

The effect of N-methyl-D,L-aspartate (NMA) on LH secretion was investigated in Syrian hamsters of the LSH/Ss Lak strain, maintained under either long days (14 h of light, 10 h of darkness) or short days (6 h of light, 18 h of darkness). After 6 weeks of photoperiodic treatment, the animals were orchidectomized. Ten days later, 10-min blood samples were remotely collected from each animal, using surgically implanted intraatrial catheters, and individual pulsatile LH release profiles were subsequently determined by RIA. At the end of the 4-h sampling period, NMA was administered iv (30 mg/kg BW), and the LH response was determined in the next three plasma samples. Hamsters maintained under long days had very high mean plasma LH levels (453 +/- 46 ng/ml) and displayed episodic release patterns characterized by high amplitude pulses. In marked contrast, hamsters that were maintained under short days had significantly (P less than 0.001) lower mean plasma LH levels (90 +/- 12 ng/ml) and showed a significantly (P less than 0.001) lower mean pulse amplitude. The interpulse interval was similar in both of the groups, with LH peaks occurring, on the average, once every 65 min. When challenged with NMA, the long-day hamsters showed only a 37% increase in mean plasma LH levels, which was not statistically significant. In contrast, the short-day hamsters showed a highly significant (P less than 0.01) increase of 294%. Interestingly, the mean plasma LH levels after NMA administration were the same in the two photoperiodic groups despite a marked difference in the plasma levels that preceded the administration. These findings demonstrate that short days can inhibit the neuroendocrine activity of the hamster's reproductive axis independently of gonadal influences. They also suggest that the LHRH neurons have an intrinsic capacity to secrete very high levels of the neuropeptide, regardless of the photoperiod. Taken together, the results support the hypothesis that the breeding season in the hamster is regulated by a gonad-independent mechanism involving a photoperiodic modulation of neuroexcitatory inputs to the LHRH neurons.

Photoperiodic modulation of luteinizing hormone secretion in orchidectomized Syrian hamsters and the influence of excitatory amino acids

The effect of N-methyl-D,L-aspartate (NMA) on LH secretion was investigated in Syrian hamsters of the LSH/Ss Lak strain, maintained under either long days (14 h of light, 10 h of darkness) or short days (6 h of light, 18 h of darkness). After 6 weeks of photoperiodic treatment, the animals were orchidectomized. Ten days later, 10-min blood samples were remotely collected from each animal, using surgically implanted intraatrial catheters, and individual pulsatile LH release profiles were subsequently determined by RIA. At the end of the 4-h sampling period, NMA was administered iv (30 mg/kg BW), and the LH response was determined in the next three plasma samples. Hamsters maintained under long days had very high mean plasma LH levels (453 +/- 46 ng/ml) and displayed episodic release patterns characterized by high amplitude pulses. In marked contrast, hamsters that were maintained under short days had significantly (P less than 0.001) lower mean plasma LH levels (90 +/- 12 ng/ml) and showed a significantly (P less than 0.001) lower mean pulse amplitude. The interpulse interval was similar in both of the groups, with LH peaks occurring, on the average, once every 65 min. When challenged with NMA, the long-day hamsters showed only a 37% increase in mean plasma LH levels, which was not statistically significant. In contrast, the short-day hamsters showed a highly significant (P less than 0.01) increase of 294%. Interestingly, the mean plasma LH levels after NMA administration were the same in the two photoperiodic groups despite a marked difference in the plasma levels that preceded the administration. These findings demonstrate that short days can inhibit the neuroendocrine activity of the hamster's reproductive axis independently of gonadal influences. They also suggest that the LHRH neurons have an intrinsic capacity to secrete very high levels of the neuropeptide, regardless of the photoperiod. Taken together, the results support the hypothesis that the breeding season in the hamster is regulated by a gonad-independent mechanism involving a photoperiodic modulation of neuroexcitatory inputs to the LHRH neurons.

Nature of Alpha Subunit Secretion in Men: Circadian Rhythms, Pulsatile Release and Secretory Profiles

Alpha subunit complements LH as a marker of the activity of the hypothalamic GnRH pulse generator. To characterize episodes of alpha subunit release and to determine if a circadian pattern of alpha subunit secretion is present in man, spontaneous alpha subunit pulsatility was analyzed in six healthy young men by blood sampling every 5 min for 24 h. The resulting alpha subunit concentration time series were analyzed by two statistically based independent peak detection methods, and subjected to Fourier transformation to assess underlying circadian rhythms. Cross-correlation analyses and multiple parameter deconvolution were used to estimate the concordance of spontaneous and exogenous GnRH-stimulated LH and alpha subunit secretion. These analyses revealed that two independent discrete peak detection algorithms yielded similar estimates of spontaneous alpha subunit pulse frequency, namely, 21 +/- 1.1 (Cluster) and 21 +/- 1.5 (Detect) alpha subunit peaks/24 h. Sampling intensity markedly influenced the estimate of endogenous alpha subunit pulse frequency, inasmuch as estimates from 5-min sampling were significantly greater than those of 10-min or 20-min sampling. Fourier transformation unmasked a significant circadian alpha subunit rhythm in all six men, with maximal concentrations at 0836 h and an average amplitude of 28% of the 24-hr mean hormone concentration. Cross-correlation analysis of spontaneous glycoprotein release revealed that serum LH and alpha subunit concentrations were highly cross-correlated when considered simultaneously, but not at various lags. Finally, deconvolution analysis of exogenous GnRH-stimulated glycoprotein release disclosed distinct half-times of alpha subunit and LH clearance with virtually simultaneous underlying secretory bursts. These data indicate that human alpha subunit is secreted in both a circadian and a discrete pulsatile fashion at a pulse frequency that is significantly underestimated at conventional sampling rates. The approximately hourly alpha subunit interpulse interval (68 +/- 4.6 min) is similar to that reported earlier for LH in peripheral blood and for testosterone in gonadal vein blood in healthy men. Moreover, cross-correlation analysis of endogenous GnRH-driven alpha subunit and deconvolution analysis of exogenous GnRH-stimulated alpha subunit and LH secretion suggest that these glycoproteins are secreted virtually simultaneously, but have significantly different endogenous clearance properties. The remarkably similar in vivo pulse frequencies for alpha subunit, LH, and testosterone in man suggest that the release of these three hormones is coordinately regulated.