Pulsatile Drug Release Research Articles

DESIGN AND EVALUATION OF CHRONOTHERAPEUTIC PULSATILE DRUG DELIVERY SYSTEM OF CILNIDIPINE

Objectives: Cilnidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function used for the treatment of hypertension. The aim of present work is formulate and evaluate a press coated pulsatile release tablets of Cilnidipine using an admixture of hydrophilic polymers in order to achieve a predetermined lag time for chronopharmacotherapy of Hypertension. Methods: The pulsatile drug release tablets were prepared by compression coating method. The tablets prepared were evaluated for different properties like bulk density, tapped density, angle of repose and Carr’s index), hardness, thickness, weight variation, friability, drug content uniformity and in vitro drug release study. Results: All formulations have shown good flow properties. The hardness of tablets ranged between 4.93±0.08 to 5.96±0.11 kg/cm2, percentage friability of tablets ranged between 0.68±0.21 to 0.82±0.06. Maximum drug release was found to be 94.39%. Conclusion: Study concludes that the prepared pulsatile drug delivery system can be considered as one of the promising formulation technique for delivery of Cilnidipine. Formulation of batch CPT1was found to be optimum. Peer Review History: Received 15 September 2017; Revised 28 October; Accepted 5 November, Available online 15 November 2017 Academic Editor: Ahmad Najib, Universitas Muslim Indonesia, Indonesia, ahmad.najib@umi.ac.id UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 4.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewer(s) detail: Dr. Viney Chawla, University Institute of Pharmaceutical Sciences, Baba Farid University of Health Sciences, Sadiq Road, Faridkot-Punjab 151203, drvineychawla@gmail.com Dr. Barkat Ali Khan, Kampala International University , Uganda, barki.gold@gmail.com

Nanographene oxide as a switch for CW/pulsed NIR laser triggered drug release from liposomes

The application of pulsed and continuous wave (CW) lasers in nanomedicine has increased significantly over the last decade. Near infrared (NIR) lasers can be used for the precise control of drug release at the target site in a non-invasive manner. In this study, we have prepared nanographene oxide (nGO, size ~40nm) integrated liposomes (size ~900nm). The nGOs were not simply adsorbed onto the liposome surface but was embedded inside the liposomes as characterized by cryo-TEM, selected area electron diffraction (SAED), and fluorescence quenching studies. The embedded nGOs could act as a molecular switch for NIR light controlled drug release from the liposomes. Calcein was encapsulated into the liposome as a model drug to evaluate the efficiency of light controlled release. An on-demand pulsatile drug release was achieved by irradiation of CW/pulsed NIR lasers into the nGO-liposome suspension. Triggering with a pulsed laser resulted in larger release of calcein with a minimal temperature increase (~2°C) of the liposome solution, compared to lower release rate and a significant temperature increase (~8°C) by a CW laser with the same light energy, suggesting two separate mechanisms and different potential applications depending on the laser type.

Polydopamine Nanoparticles Modulating Stimuli-Responsive PNIPAM Hydrogels with Cell/Tissue Adhesiveness.

Stimuli-responsive hydrogels can respond to stimuli by phase transformation or volume change and exhibit specific functions. Near-infrared (NIR)-responsive hydrogel is a type of stimuli-responsive hydrogel, which can be precisely controlled by altering the radiation intensity, exposure time of the light source, and irradiation sites. Here, polydopamine nanoparticles (PDA-NPs) were introduced into a poly(N-isopropylacrylamide) (PNIPAM) network to fabricate a PDA-NPs/PNIPAM hydrogel with NIR responsibility, self-healing ability, and cell/tissue adhesiveness. After incorporation of PDA-NPs into the hydrogel, the PDA-NPs/PNIPAM hydrogel showed phase transitions and volume changes in response to NIR. Thus, the hydrogel can achieve triple response effects, including pulsatile drug release, NIR-driven actuation, and NIR-assisted healing. After coating PDA-NPs onto hydrogel surfaces, the hydrogel showed improved cell affinity, good tissue adhesiveness, and growth factor/protein immobilization ability because of reactive catechol groups on PDA-NPs. The tissue adhesion strength to porcine skin was as high as 90 KPa. In vivo full-skin defect experiments demonstrated that PDA-NPs coating on the hydrogel and an immobilized growth factor had a synergistic effect on accelerating wound healing. In summary, we combined thermosensitive PNIPAM and mussel-inspired PDA-NPs to form a NIR-responsive hydrogel, which may have potential applications for chemical and physical therapies.

Electroconductive nanocomposite hydrogel for pulsatile drug release

Polyacrylamide (PAAm) hydrogel containing nanofibers of polyaniline (PANI) has been prepared in order to evaluate it as electric stimuli-responsive material. Amoxicillin was loaded onto chemically synthesized PANI nanofibers of large-aspect-ratio. Composite hydrogel was obtained by the in situ incorporation of amoxicillin-loaded PANI during polymerization and reticulation of acrylamide. TEM images of cross sections of PAAm/amoxicillin-loaded PANI composite revealed a continuous 3D nanofiber network of PANI supported by the hydrogel matrix. The antibiotic molecules were accurately released (or sustained) from composite hydrogel in response to application (or removal) of cathodic electrical stimulation. In vitro cytotoxicity evaluation of composite hydrogel extract on mouse subcutaneous connective tissue has shown cell viability higher than 80%. The tuning release profile and minimal toxicity of the material evidenced its potential for electrically controlled drug delivery applications such as implantable devices and transdermal drug delivery systems.

Microstructured poly(N-isopropylacrylamide) hydrogels with fast temperature response for pulsatile drug delivery

Microstructured, temperature-sensitive poly(N-isopropylacrylamide) hydrogels were prepared with different proportions of poly(N-isopropylacrylamide) microparticles. The materials presented fast shrinkage at a temperature above their transition temperature (LCST = 32 °C), with highly reproducible swelling/shrinking cycles when temperature oscillates between below and above the LCST. They showed positive solute release control as a function of the temperature when small amount of microparticles were included in the hydrogels, making these hydrogels suitable for temperature controlled pulsatile drug release. The degree of crosslinking had a smaller impact than the percentage of microparticles in swelling and drug release in response to temperature. The inclusion of a small proportion of microparticles improved the mechanical propertied of the hydrogels. In addition, the polymerization steps are carried on in aqueous media, being a facile, scalable, and environmentally friendly technology.

Design of experiment approach for formulating multi-unit colon-targeted drug delivery system: in vitro and in vivo studies

Objective: The objective of the present investigation was to develop systematically optimized multiunit formulation for colon targeted delivery of metronidazole (MTZ) by employing design of experiment (DoE) and evaluate it for in vitro as well as in vivo drug release study.Methods: Core of mini-tablets of MTZ was prepared using drug along with suitable swelling agents to provide pH sensitive pulsatile drug delivery. Eudragit® S 100 (ES) and ethyl cellulose (EC) were used as coating polymers to prevent initial drug release in gastric region. The coating composition was systematically optimized using 32-full factorial design and optimized formulation was evaluated in vitro and then in vivo, to confirm colon targeting ability of the developed system. Stability study of optimized formulation was performed for 6 months as per ICH guidelines.Results: The optimized coating composition was selected from the results of design batches. The optimized formulation showed 6.99 ± 1.5% drug release up to 5 h and 100% drug release within 7.2 ± 0.2 h indicating pH sensitive pulsatile behavior of formulation. Similar drug release profile was observed while performing in vivo study in rabbits with a lag time of 4 h and Cmax of 190 ± 4.9 ng/ml being achieved after 7 h. Stability study indicated insignificant difference in properties of tablets and their drug release patterns.Conclusion: Optimization of coating composition (EC and ES) and thickness could offer pH sensitive pulsatile release of drugs at colon. Furthermore, in vivo results confirmed the successful development of colon targeted formulation of MTZ.

Magnetically-controlled, pulsatile drug release from poly(ε-caprolactone) (PCL) particles with hollow interiors

This paper describes a new system for magnetically-controlled release of drugs. The system consists of a poly(ε-caprolactone) (PCL) particle with a hollow interior, accompanied by a shell containing magnetic nanoparticles. When exposed to an external AC magnetic field, the interior void will be shrunk to pump out the pre-loaded drug molecules. The amount of molecules released at each pumping event can be adjusted by the strength of applied field. This magnetic response leads to the efficient intranuclear release of Doxorubicin (DOX) from the hollow particles, achieving the significant enhancement of anticancer activity in combination with the hyperthermia effect given by the magnetic nanoparticles.

3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs

The aim of the present work was to explore the feasibility of fused deposition modeling (FDM) 3D printing in the manufacturing of capsular devices for oral pulsatile release based on a swellable/erodible polymer (hydroxypropyl cellulose, HPC). This involved an experimental evaluation of the possibility of fabricating hollow structures via FDM and the production of HPC filaments by hot melt extrusion (HME), which are not commercially available. Moreover, the set-up of appropriate computer aided design files had to be faced. A twin-screw extruder equipped with a rod-shaped die and a purposely designed pulling/calibrating device as well as a MakerBot Replicator 2 3D printer were employed for HME and FDM processing, respectively. Bodies and caps with satisfactory physico-technological properties were obtained. The release test of assembled capsular devices pointed out a lag phase before rapid and quantitative liberation of the drug. The morphological changes undergone by the device when in contact with water and their release performance turned out comparable with those of analogous systems fabricated by injection molding. The possibility of manufacturing capsular devices for oral pulsatile release by FDM 3D printing starting from HPC filaments purposely prepared was thus demonstrated, and the real-time prototyping potential of FDM was assessed.

Pharmacokinetic Study of a Capsule-based Chronomodulated Drug Delivery System of Salbutamol Sulphate in Rabbits

Purpose: To develop and determine the in vivo performance of a capsule-based pulsatile drug delivery system containing salbutamol sulphate Methods: A controlled pulsatile release of drug after a programmed 4 h lag period was achieved from cross-linked gelatin capsule shells containing salbutamol pellets, and sealed with a suitable mixture of sodium alginate and ethyl cellulose as plug. In order to confirm the utility of developed system for the management of nocturnal asthma, a crossover study was conducted. six male rabbits were fasted overnight and divided into two groups comprised of 3 rabbits each. The individual rabbits were administered the developed pulsatile capsule and immediate release salbutamol capsule as reference, separately. Blood samples were collected from the ear vein of the animals into heparinized tubes and used to determine pharmacokinetic parameters, namely, maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration - time curve (AUC0-∞) using a validated HPLC method. Results: It was observed that drug release from the optimized time-controlled capsule stopped for a period of approximately 4.25 h with an average Cmax and Tmax of 271.54 ± 58.95 ng/ml and 6.00 ± 0.25 h. The AUC0-∞ of salbutamol after administration of the time-controlled pulsatile system was 2494.73 ± 525.95 ng h/ml while that of the immediate-release formulation was 2352.77 ± 432.51 ng h/ml. Using ANOVA at a significant difference of p < 0.05 (CI 95%), there was no significant difference for the AUC0∞ between immediate release and the pulsatile capsule developed. Conclusion: The developed system is capable of releasing salbutamol after a 4 h lag period and can be considered as promising delivery system for time-controlled (pulsatile) delivery of the medication for the management of nocturnal asthma.

Pharmacokinetic Study of a Capsule-based Chronomodulated Drug Delivery System of Salbutamol Sulphate in Rabbits

Purpose: To develop and determine the in vivo performance of a capsule-based pulsatile drug delivery system containing salbutamol sulphate Methods: A controlled pulsatile release of drug after a programmed 4 h lag period was achieved from cross-linked gelatin capsule shells containing salbutamol pellets, and sealed with a suitable mixture of sodium alginate and ethyl cellulose as plug. In order to confirm the utility of developed system for the management of nocturnal asthma, a crossover study was conducted. six male rabbits were fasted overnight and divided into two groups comprised of 3 rabbits each. The individual rabbits were administered the developed pulsatile capsule and immediate release salbutamol capsule as reference,seeparately. Blood samples were collected from the ear vein of the animals into heparinized tubes and used to determine pharmacokinetic parameters, namely, maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), and area under the plasma concentration - time curve (AUC0-‡) using a validated HPLC method.Results: It was observed that drug release from the optimized time-controlled capsule stopped for a period of approximately 4.25 h with an average Cmax and Tmax of 271.54 } 58.95 ng/ml and 6.00 } 0.25h. The AUC0-‡ of salbutamol after administration of the time-controlled pulsatile system was 2494.73 } 525.95 ng h/ml while that of the immediate-release formulation was 2352.77 } 432.51 ng h/ml. UsingANOVA at a significant difference of p &lt; 0.05 (CI 95%), there was no significant difference for the AUC0-‡ between immediate release and the pulsatile capsule developed.Conclusion: The developed system is capable of releasing salbutamol after a 4 h lag period and can be considered as promising delivery system for time-controlled (pulsatile) delivery of the medication for the management of nocturnal asthma.Keywords: pH-controlled release, Lag time, Pulsatile release, Hydrocolloid plug, Nocturnal asthma.

A novel pulsatile drug delivery system based on the physiochemical reaction between acrylic copolymer and organic acid: In vitro and in vivo evaluation

Multilayer-coating technology is the traditional method to achieve pulsatile drug release with the drawbacks of time consuming, more materials demanding and lack of efficiency. The purpose of this study was to design a novel pulsatile drug delivery system based on the physiochemical interaction between acrylic copolymer and organic acid with relatively simpler formulation and manufacturing process. The Enalapril Maleate (EM) pulsatile release pellets were prepared using extruding granulation, spheronization and fluid-bed coating technology. The ion-exchange experiment, hydration study and determination of glass transition temperature were conducted to explore the related drug release mechanism. Bioavailability experiment was carried out by administering the pulsatile release pellets to rats compared with marketed rapid release tablets Yisu. An obvious 4h lag time period and rapid drug release was observed from in vitro dissolution profiles. The release mechanism was a combination of both disassociated and undisassociated forms of succinic acid physiochemically interacting with Eudragit RS. The AUC0-τ of the EM pulsatile pellets and the market tablets was 702.384 ± 96.89 1 hn g/mL and 810.817 ± 67.712 h ng/mL, while the relative bioavailability was 86.62%. These studies demonstrate this novel pulsatile release concept may be a promising strategy for oral pulsatile delivery system.

Binary Blend of Glyceryl Monooleate and Glyceryl Monostearate for Magnetically Induced Thermo-Responsive Local Drug Delivery System

To develop a novel monoglycerides-based thermal-sensitive drug delivery system, specifically for local intracavitary chemotherapy. Lipid matrices containing mixtures of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were evaluated for their potential application as magnetically induced thermo-responsive local drug delivery systems using a poorly water-soluble model drug, nifedipine (NF). Oleic acid-modified iron oxide (OA-Fe3O4) nanoparticles were embedded into the GMO-GMS matrix for remote activation of the drug release using an alternating magnetic field (AMF). The crystallization behavior of binary blends of GMO and GMS as characterized by DSC did show temperature dependent phase transition. GMO-GMS (75:25wt%) blend showed a melting (T m ) and crystallization (T c ) points at 42°C and 37°C, respectively indicating the potential of the matrix to act as an 'on-demand' drug release. The matrix released only 35% of the loaded drug slowly in 10days at 37°C whereas 96% release was obtained at 42°C. A concentration of 0.5% OA-Fe3O4 heated the matrix to 42.3 and 45.5°C within 5min and 10min of AMF exposure, respectively. The in vitro NF release profiles form the monoglycerides matrix containing 0.5% OA-Fe3O4 nanoparticles after AMF activation confirmed the thermo-responsive nature of the matrix that could provide pulsatile drug release 'on-demand'.

Osmotic Drug Delivery Systems: Basics and Design Approaches

Osmotic drug delivery system utilizes the principles of osmotic pressure for the controlled delivery of active pharmaceutical ingredient at a predetermined zero order rate. An appropriately designed osmotic drug delivery is not influenced by different physiologic factors but affected by pharmaceutical factors, which play a pivotal role in modulating the release of drug. The present review critically discussed about the factors affecting drug release from the delivery system such as solubility, osmotic pressure, size of delivery orifice and membrane characteristics. The major arena of this review is to highlight about the different types of osmotic drug delivery systems such as implantable, single chamber, multi chamber osmotic pumps and several specialized type of osmotic pumps. Apart from that this system is a versatile technology useful for delivery of drugs with varying solubility. The additional properties of this delivery system can also exhibit pulsatile release, burst release and colon targeting of drug. Because of its versatility, this above system seems to have promising approach which can result in improved safety profile, stable drug concentrations, uniform drug effects and dosing frequency. Current review also briefly discussed about the patents related to delivery of drugs by the principle osmotic pressure.

Evaluation of floating press-coated pulsatile release of Aceclofenac tablets. A solution for Rheumatoid athrites

The objective of this study was to develop and evaluate of a floating presscoated pulsatile drug delivery system intended for treatment of early morning stiffness and symptomatic relief from pain in patients with rheumatoid arthritis with a distinct predetermined lag time of 8 h. Cores containing Aceclofenac as model drug were prepared by direct compression of different Sodium starch glycolate level CT-1 to CT-4) 8 %, 4%, 2% & without disinegrant and Aceclofenac as a model drug by using various proportion of polymers such Hydroxypropyl methylcellulose and Sodium bicarbonate floating layer is prepared. Fifteen formulations were prepared and formulation F15, F18, F22possessed good lag time 8 hr and showed pulsatile drug delivery pattern the tablets In- vitro evaluation tests. Results of this study indicated that by using floating-pulsatile release formulations are suitable to optimize pulsatile drug release formulation of Aceclofenac.

Development of pulsatile release of Aceclofenac tablets with swelling and rupturable layers of ethyl cellulose

The objective of this study was to develop and evaluate of Aceclofenac tablets with swelling and rupturable layers of ethyl cellulose. A tablet system consisting Intended for treatment of early morning stiffness and symptomatic relief from pain in patients with rheumatoid arthritis with a distinct predetermined lag time of 6 h. Cores containing Aceclofenac as model drug were prepared by direct compression of different Sodium starch glycolate level CT-1 to CT-4) 8 %, 4%, 2% & without disinegrant and were then coated sequentially with an inner swelling layer containing a superdisintegrant (croscarmellose sodium) and an outer rupturable layer of ethylcellulose. Seven formulations were prepared and formulation F2 possessed good lag time 6 hr and showed pulsatile drug delivery pattern the tablets In- vitro evaluation tests. Results of this study indicated that by using ethyl cellulose are suitable to optimize pulsatile drug release formulation of Aceclofenac.

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.

PULSATILE DRUG DELIVERY AS MODIFIED RELEASE DOSAGE FORM : A REVIEW

Pulsatile drug delivery is a advanced drug delivery system in pharmaceutical field . Pulsatile system is one of the modified release dosage form system and gaining a lot of interest as it is increasing patient compliance by means of providing time- and site-specific drug delivery system. Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period. In various diseases in which we can recomend the pulsatile drug delivery system such as duodenal ulcer, cardiovascular diseases, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension and hypercholesterolemia. This article summarize the various methodologies, evaluation parameters and compile the recent literatures with special focus on the different types and approaches involved in the development of the formulation

Pulsatile Drug Release from PLGA Hollow Microspheres by Controlling the Permeability of Their Walls with a Magnetic Field

Pulsatile release: When a high-frequency magnetic field is applied, heat will be generated by coupling to the iron oxide nanoparticles encapsulated in the shells of PLGA hollow microspheres. As the temperature approaches the T(g) of PLGA, the polymer chains become more mobile, subsequently increasing the free volume of PLGA matrix and significantly enhancing the diffusion of drug molecules.

Polymeric tube-shaped devices with controlled geometry for programmed drug delivery

We developed a modular tube-shaped device as a proof of principle to enable the programmed release of encapsulated molecules for controlled drug delivery. Each drug-delivery tube module was prepared by assembling two separate silicone tubes in a series, one filled with a model compound (sodium fluorescein) and the other with a diffusional barrier material (polyethylene oxide, PEO). We varied the length of the PEO-filled tubes to control the release from the drug-delivery tube devices. The onset times and periods of drug release increased with the length of the PEO tube. To program the drug release, therefore, we prepared devices with combinations of drug-delivery tube modules with different lengths of PEO-filled tubes. Using PEO-filled tubes with very different lengths achieved a pulsatile drug release while a continuous drug release was realized by using PEO-filled tubes with small differences in length. We concluded that the modular combination of drug-delivery tubes, each composed of a diffusionbarrier tube of different length, demonstrates good potential for applications in programmed drug delivery. Open image in new window

Nanoporous Polymeric Nanofibers Based on Selectively Etched PS-b-PDMS Block Copolymers

One-dimensional nanoporous polymeric nanofibers have been fabricated within an anodic aluminum oxide (AAO) membrane by a facile approach based on selective etching of poly(dimethylsiloxane) (PDMS) domains in polystyrene-block-poly(dimethylsiloxane) (PS-b-PDMS) block copolymers that had been formed within the AAO template. It was observed that prior to etching, the well-ordered PS-b-PDMS nanofibers are solid and do not have any porosity. The postetched PS nanofibers, on the other hand, had a highly porous structure having about 20-50 nm pore size. The nanoporous polymeric fibers were also employed as a drug carrier for the native, continuous, and pulsatile drug release using Rhodamine B (RB) as a model drug. These studies showed that enhanced drug release and tunable drug dosage can be achieved by using ultrasound irradiation.