Evaluation of powder-layering vs. spray-coating techniques in the manufacturing of a swellable/erodible pulsatile delivery system.

A swellable/erodible system for oral time-dependent release, demonstrated to provide consistent pulsatile and colonic delivery performance, has been manufactured through a range of coating techniques to achieve the functional hydroxypropyl methylcellulose (HPMC) layer. Although aqueous spray-coating has long been preferred, the processing times and yields still represent open issues, especially in view of the considerable amount of polymer required to give in vivo lag phases of proper duration. To make manufacturing of the delivery system more cost-efficient, different coating modes were thus evaluated, namely top and tangential spray-coating as well as powder-layering, using a fluid bed equipment. To this aim, disintegrating tablets of 5 mm in diameter, containing a tracer drug, were coated up to 50% weight gain with low-viscosity HPMC, either as a water solution or as a powder formulation. In all cases, process feasibility was assessed following setup of the operating conditions. Irrespective of the technique employed, the resulting dosage forms exhibited uniform coating layers able to defer the onset of release as a function of the amount of polymer applied. The structure and thickness of such layers differed depending on the deposition modes. With respect to top spray-, both tangential spray-coating and powder-layering were shown to remarkably ameliorate the process time, which was reduced to approximately 1/3 and 1/6, and to enhance the yield by almost 20 and 30%, respectively. Clear advantages associated with such techniques were thus highlighted, particularly with respect to powder-layering here newly proposed for application of a swellable hydrophilic cellulose derivative.

Industrial Development of a 3D-Printed Nutraceutical Delivery Platform in the Form of a Multicompartment HPC Capsule.

Following recent advances in nutrigenomics and nutrigenetics, as well as in view of the increasing use of nutraceuticals in combination with drug treatments, considerable attention is being directed to the composition, bioefficacy, and release performance of dietary supplements. Moreover, the interest in the possibility of having such products tailored to meet specific needs is fast growing among costumers. To fulfill these emerging market trends, 3D-printed capsular devices originally intended for conveyance and administration of drugs were proposed for delivery of dietary supplements. Being composed of separate inner compartments, such a device could yield customized combinations of substances, relevant doses, and release kinetics. In particular, the aim of this work was to face early-stage industrial development of the processes involved in fabrication of nutraceutical capsules for oral pulsatile delivery. A pilot plant for extrusion of filaments based on pharmaceutical-grade polymers and intended for 3D printing was set up, and studies aimed at demonstrating feasibility of fused deposition modeling in 3D printing of capsule shells according to Current Good Manufacturing Practices for dietary supplements were undertaken. In this respect, the stability of the starting material after hot processing and of the resulting items was investigated, and compliance of elemental and microbiological contaminants, as well as of by-products, with internal specifications was assessed. Finally, operating charts highlighting critical process variables and parameters that would serve as indices of both intermediate and final product quality were developed.

Investigating effects of hydroxypropyl methylcellulose (HPMC) molecular weight grades on lag time of press-coated ethylcellulose tablets.

The research undertaken exemplifies the effects of hydroxypropyl methylcellulose (HPMC) molecular weight (MW) grades of on lag time of press-coated ethylcellulose (EC) tablets. The formulation comprised an immediate release core (containing prednisone as a model drug) surrounded by compression coating with variegated EC-HPMC blends. Five selected HPMC grades (E5, E15, E50, K100LV and K4M) were explored at three different concentrations (10% w/w, 20% w/w and 30% w/w in outer coat) to understand their effects on lag time and drug release. In vitro drug release testing demonstrated that, with increase in concentration of E5 and E15, up to 30% w/w, the mean lag time decreased progressively; whereas with remaining grades, the mean lag time initially decreased up to 20% w/w level and thereafter increased for 30% w/w level. Importantly, with increase in HPMC concentration in the outer coat, the variability in lag time (%RSD; n = 6) was decreased for each of E5, E15 and E50, whereas increased for K100LV and K4M. In general, the variability in lag time was increased with increase in HPMC MW at studied concentration levels. Markedly, tablets with 30% w/w K4M in outer coat exhibited slight premature release (before the rupture of outer coat) along with high variability in lag time. Overall, the study concluded that low MW HPMCs (E5, E15 and E50) were found rather efficient than higher MW HPMCs for developing robust EC-based press-coated pulsatile release formulations where precise lag time followed by sharp burst release is desired.

Investigating critical effects of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose tablets.

The research envisaged focuses on vital impacts of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose (EC) tablets using prednisone as a model drug. Several lubricants and glidants such as magnesium stearate, colloidal SiO2, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol (6000) and glyceryl behenate were investigated to understand their effects on lag time by changing their concentrations in outer coat. Further, the effects of hydrophilic additives on lag time were examined for hydroxypropylmethylcellulose (E5), hydroxypropylcellulose (EF and SSL), povidone (K30), copovidone, polyethylene glycol (4000), lactose and mannitol. In vitro drug release testing revealed that each selected lubricant/glidant, if present even at concentration of 0.25% w/w, significantly reduced the lag time of press coated tablets. Specifically, colloidal SiO2 and/or magnesium stearate were detrimental while other lubricants/glidants were relatively less injurious. Among hydrophilic additives, freely water soluble fillers had utmost influence in lag time, whereas, comparatively less impact was observed with polymeric binders. Concisely, glidant and lubricant should be chosen to have minimal impact on lag time and further judicious selection of hydrophilic additives should be exercised for modulating lag time of pulsatile release formulations.

3D printing of multi-unit gastro-retentive tablets for the pulsatile release of artesunate.

Pulsatile drug delivery is hardly achieved by conventional gastro-retentive dosage forms. Artesunate as a typical anti-malaria medicine needs oral pulsatile release. Here, artesunate-loaded pulsatile-release multi-unit gastro-retentive tablets (APGTs) were prepared with a semi-solid extrusion three-dimensional (3D) printing method. An APGT was composed of three units: artesunate-loaded immediate and delayed release units and a block unit. The matrix of the immediate/delayed release units consisted of polyvinylpyrrolidone (PVP) K30 and croscarmellose sodium, which improved the rapid release of artesunate when contacting water. The block unit consisted of octadecanol, hydroxypropyl methyl cellulose K15M, PVP K30, and poloxamer F68. APGTs showed multi-phase release in simulated gastric liquids (SGLs). The first immediate release phase continued for 1 h followed by a long block phase for 7 h. The second rapid release phase was initiated when the eroded holes in the block unit extended to the inner delayed release unit, and this phase continued for about 14 h. Low-density APGTs could ensure their long-term floating in the stomach. Oral APGTs remained in the rabbit stomach for about 20 h. 3D printing provides a new strategy for the preparation of oral pulsatile-release tablets.

The Promoting Effect of a Local Pulsatile Parathyroid Hormone Delivery on Healing of the Mandibular Fracture in Rats.

Parathyroid hormone (PTH) can promote bone formation and mineralization in mandibular fractures, and is systemically administered through daily injections. In this study, the local delivery of PTH using carboxymethyl chitosan/polyvinyl alcohol and alginate was investigated. Bovine serum albumin was used as a drug substitute, and the delivery system was verified to release drugs in a pulsed rhythm. After the delivery system was subcutaneously implanted in Sprague-Dawley (SD) rats, no rejection reaction was detected, indicating that it has good biocompatibility and biodegradability in vivo. Then, an SD rat model of mandibular fracture was established, and 24 rats were randomly divided into two groups. The control group was reduced and fixed with screws and a microplate, and the experimental group received pulsatile PTH release system (14 µg PTH) + screws and microplate fixation. The animals were euthanized on postoperative weeks 1-4. Observation of gross specimens, digital radiography, and hematoxylin and eosin showed that the local PTH pulsatile release system promoted osteogenesis and accelerated fracture healing. In summary, PTH can be loaded by biomaterials to locally target the fracture and stimulate bone formation. Moreover, the pulsatile PTH release system provides a potential therapeutic protocol for mandibular fracture. Impact statement Our study prepares a drug release system that could impulsively release parathyroid hormone. The system could enhance bone regeneration in rats with mandibular fracture. These data provide a foundation for future studies aimed to understand and optimize the use of bioactive molecule pulsatile delivery for bone regeneration and tissue engineering applications.

A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release.

Pulsatile drug delivery systems have the potential to improve patient adherence and therapeutic efficacy by providing a sequence of doses in a single injection. Herein, a novel platform, termed Particles Uniformly Liquified and Sealed to Encapsulate Drugs (PULSED) is developed, which enables the high-throughput fabrication of microparticles exhibiting pulsatile release. In PULSED, biodegradable polymeric microstructures with an open cavity are formed using high-resolution 3D printing and soft lithography, filled with drug, and sealed using a contactless heating step in which the polymer flows over the orifice to form a complete shell around a drug-loaded core. Poly(lactic-co-glycolic acid) particles with this structure can rapidly release encapsulated material after delays of 10 ± 1, 15 ± 1, 17 ± 2, or 36 ± 1 days in vivo, depending on polymer molecular weight and end group. The system is even compatible with biologics, releasing over 90% of bevacizumab in its bioactive form after a two-week delay in vitro. The PULSED system is highly versatile, offering compatibility with crystalline and amorphous polymers, easily injectable particle sizes, and compatibility with several newly developed drug loading methods. Together, these results suggest that PULSED is a promising platform for creating long-acting drug formulations that improve patient outcomes due to its simplicity, low cost, and scalability.

Single-injection COVID-19 subunit vaccine elicits potent immune responses.

Current vaccination schedules, including COVID-19 vaccines, require multiple doses to be administered. Single injection vaccines eliciting equivalent immune response are highly desirable. Unfortunately because unconventional release kinetics are difficult to achieve it still remains a huge challenge. Herein a single-injection COVID-19 vaccine was designed using a highly programmable release system based on dynamic layer-by-layer (LBL) films. The antigen, S1 subunit of SARS-CoV-2 spike protein, was loaded in CaCO3 microspheres, which were further coated with tannic acid (TA)/polyethylene glycol (PEG) LBL films. The single-injection vaccine was obtained by mixing the microspheres coated with different thickness of TA/PEG films. Because of the unique constant-rate erosion behavior of the TA/PEG coatings, this system allows for distinct multiple pulsatile release of antigen, closely mimicking the release profile of antigen in conventional multiple dose vaccines. Immunization with the single injection vaccine induces potent and persistent S1-specific humoral and cellular immune responses in mice. The sera from the vaccinated animal exhibit robust in vitro viral neutralization ability. More importantly, the immune response and viral inhibition induced by the single injection vaccine are as strong as that induced by the corresponding multiple dose vaccine, because they share the same antigen release profile. STATEMENT OF SIGNIFICANCE: Vaccines are the most powerful and cost-effective weapons against infectious diseases such as COVID-19. However, current vaccination schedules, including the COVID-19 vaccines, require multiple doses to be administered. Herein a single-injection COVID-19 vaccine is designed using a highly programmable release system. This vaccine releases antigens in a pulsatile manner, closely mimicking the release pattern of antigens in conventional multiple dose vaccines. As a result, one single injection of the new vaccine induces an immune response and viral inhibition similar to that induced by the corresponding multiple-dose vaccine approach.

Trimetazidine Dihydrochloride Pulsatile-Release Tablets for the Treatment of Morning Anginal Symptoms: Dual Optimization, Characterization and Pharmacokinetic Evaluation.

OBJECTIVE: This research work aimed to target the early morning peak symptoms of chronic stable angina through formulating antianginal drug, Trimetazidine (TMZ) in a pulsatile-release tablet. METHODS: The core formulae were optimized using 22 .31 factorial design to minimize disintegration time (DT) and maximize drug release after 5 minutes (Q5min). Different ratios of Eudragit S100 and Eudragit L100 were used as a coating mixture for the selected core with or without a second coating layer of hydroxypropyl methylcellulose (HPMC E50). The different formulation variables were statistically optimized for their effect on lag time and drug release after 7 hours (Q7h) using BoxBehnken design. The optimized formula (PO) was subjected to stability study and pharmacokinetic assessment on New Zealand rabbits. RESULTS: The optimal core (F8) was found to have 1.76 min disintegration time and 61.45% Q5min PO showed a lag time of 6.17 h with 94.80% Q7h and retained good stability over three months. The pharmacokinetics study confirmed the pulsatile-release pattern with Cmax of 206.19 ng/ml at 5.33 h (Tmax) and 95.85% relative bioavailability compared to TMZ solution. CONCLUSION: Overall pulsatile-release tablets of TMZ successfully released the drug after a desirable lag time, providing a promising approach for early morning anginal symptoms relief.

Erodible coatings based on HPMC and cellulase for oral time-controlled release of drugs.

Oral drug delivery systems for time-controlled release, intended for chronotherapy or colon targeting, are often in the form of coated dosage forms provided with swellable/soluble hydrophilic polymer coatings. These are responsible for programmable lag phases prior to release, due to their progressive hydration in the biological fluids. When based on high-viscosity polymers and/or manufactured by press-coating, the performance of functional hydroxypropyl methylcellulose (HPMC) layers was not fully satisfactory. Particularly, it encompassed an initial phase of slow release because of outward diffusion of the drug through a persistent gel barrier surrounding the core. To promote erosion of such a barrier, the use of a cellulolytic product (Sternzym® C13030) was here explored. For this purpose, the mass loss behavior of tableted matrices based on various HPMC grades, containing increasing percentages of Sternzym® C13030, was preliminarily studied, highlighting a clear and concentration-dependent effect of the enzyme especially with high-viscosity polymers. Subsequently, Sternzym® C13030-containing systems, wherein the cellulolytic product was either incorporated into a high-viscosity HPMC coating or formed a separate underlying layer, were manufactured. Evaluated for release, such systems gave rise to more reproducible profiles, with shortened lag phases and reduced diffusional release, as compared to the reference formulation devoid of enzyme.

Surfactant-assisted-water-exposed versus surfactant-aqueous-solution-exposed electrospinning of novel super hydrophilic polycaprolactone based fibers: Analysis of drug release behavior.

Surface hydrophilicity and scaffold integrity determine the drug release behavior of drug loaded electrospun fibrous mats. When mixture miscibility is acceptable, blend electrospinning of hydrophobic with hydrophilic polymers can improve scaffold hydrophilicity while the hydrophobic polymer maintains the mechanical strength of scaffold. Polycaprolactone (PCL) and Pluronic P123 (P123) blend electrospinning has been investigated. In routine blend electrospinning, surface enrichment of Pluronic sets a limit for P123 weight ratio in which exceeding from that limit causes the excess P123 to be accumulated within the electrospun fiber core. To overcome this setback, a method named surfactant assisted water exposed (SAWE) electrospinning was introduced which was proven to be effective for increasing the surface enrichment of Pluronic. In order to test the validity of this method, the electrospinning of solution containing PCL which is exposed to aqueous solution of P123 was investigated. This new method was named surfactant aqueous solution exposed (SASE) electrospinning. Myelin formation at the contact interface of aqueous solution and chloroform solution was studied and it was found that this layer can effectively barricade the migration of Pluronic chains between immiscible phases. For SASE, fiber surface coverage by P123 was uneven and loose. Electrospun scaffolds from SAWE and SASE were loaded with drug to investigate the effect of the exposure time during electrospinning on in vitro drug release. By increasing the exposure time, the abnormal two-stage phased release profile of SAWE became normal with moderate initial burst. Longer exposure time increased the initial burst of the drug loaded SASE fibers. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 597-609, 2019.

Colon-specific pulsatile drug release provided by electrospun shellac nanocoating on hydrophilic amorphous composites.

BACKGROUND: Colon-specific pulsatile drug release, as a combined drug controlled-release model, is a useful drug delivery manner for a series of diseases. New nanomedicines and related preparation methods are highly desired. METHODS: With diclofenac sodium (DS) as a model drug, a new type of structural nanocomposite (SC), in which composite polyvinylpyrrolidone (PVP)-DS core was coated by shellac, was fabricated via modified coaxial electrospinning. For comparison, traditional PVP-DS monolithic hydrophilic nanocomposites (HCs) were generated using a traditional blending process. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), water contact angle (WCA), and in vitro dissolution and ex vivo permeation tests were conducted to characterize the composites. RESULTS: SEM images demonstrated that both composites were linear nanofibers with smooth surface morphology and cross sections. TEM disclosed that the SCs had a thin shellac sheath layer of approximately 12 nm. XRD and ATR-FTIR results demonstrated that the crystalline DS was converted into amorphous composites with PVP because of favorable secondary interactions. WCA and in vitro dissolution tests demonstrated that the sheath shellac layers in SC could resist acid conditions and provide typical colon-specific pulsatile release, rather than a pulsatile release of HC under acid conditions. Ex vivo permeation results demonstrated that the SCs were able to furnish a tenfold drug permeation rate than the DS particles on the colon membrane. CONCLUSION: A new SC with a shellac coating on hydrophilic amorphous nanocomposites could furnish a colon-specific pulsatile drug release profile. The modified coaxial process can be exploited as a useful tool to create nanocoatings.

The mechanism behind the biphasic pulsatile drug release from physically mixed poly(dl-lactic(-co-glycolic) acid)-based compacts.

Successful immunization often requires a primer, and after a certain lag time, a booster administration of the antigen. To improve the vaccinees' comfort and compliance, a single-injection vaccine formulation with a biphasic pulsatile release would be preferable. Previous work has shown that such a release profile can be obtained with compacts prepared from physical mixtures of various poly(dl-lactic(-co-glycolic) acid) types (Murakami et al., 2000). However, the mechanism behind this release profile is not fully understood. In the present study, the mechanism that leads to this biphasic pulsatile release was investigated by studying the effect of the glass transition temperature (Tg) of the polymer, the temperature of compaction, the compression force, the temperature of the release medium, and the molecular weight of the incorporated drug on the release behavior. Compaction resulted in a porous compact. Once immersed into release medium with a temperature above the Tg of the polymer, the drug was released by diffusion through the pores. Simultaneously, the polymer underwent a transition from the glassy state into the rubbery state. The pores were gradually closed by viscous flow of the polymer and further release was inhibited. After a certain period of time, the polymer matrix ruptured, possibly due to a build-up in osmotic pressure, resulting in a pulsatile release of the remaining amount of drug. The compression force and the molecular weight of the incorporated drug did not influence the release profile. Understanding this mechanism could contribute to further develop single-injection vaccines.

Influence of temperature and relative humidity conditions on the pan coating of hydroxypropyl cellulose molded capsules.

In a previous study, hydroxypropyl cellulose (HPC)-based capsular shells prepared by injection molding and intended for pulsatile release were successfully coated with 10mg/cm(2) Eudragit® L film. The suitability of HPC capsules for the development of a colon delivery platform based on a time dependent approach was demonstrated. In the present work, data logging devices (PyroButton®) were used to monitor the microenvironmental conditions, i.e. temperature (T) and relative humidity (RH), during coating processes performed under different spray rates (1.2, 2.5 and 5.5g/min). As HPC-based capsules present special features, a preliminary study was conducted on commercially available gelatin capsules for comparison purposes. By means of PyroButton data-loggers it was possible to acquire information about the impact of the effective T and RH conditions experienced by HPC substrates during the process on the technological properties and release performance of the coated systems. The use of increasing spray rates seemed to promote a tendency of the HPC shells to slightly swell at the beginning of the spraying process; moreover, capsules coated under spray rates of 1.2 and 2.5g/min showed the desired release performance, i.e. ability to withstand the acidic media followed by the pulsatile release expected for uncoated capsules. Preliminary stability studies seemed to show that coating conditions might also influence the release performance of the system upon storage.

Formulation and process optimization of multiparticulate pulsatile system delivered by osmotic pressure-activated rupturable membrane.

In this study, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane (Eudragit(®) RS) via osmotic pressure (with NaCl as the osmogent) was developed and characterized for omeprazole, omeprazole sodium, and propranolol HCl which have different water solubilities. Multiparticulates in pellet form for incorporation with or without the osmogent were manufactured by three methods and then used to coat a polymeric membrane. Results demonstrated that drug/osmogent-containing pellets manufactured by the extrusion/spheronization method with incorporation of the osmogent were optimal. The lag time (tL) to initiate pulsatile release is regulated by tL=l(2)/(6×D), which is dependent on the coating levels (l(2)) and plasticizer content (D). The pulsatile release pattern was found to be dependent on the osmotic pressure (osmogent), drug solubility, and mechanical properties of the polymeric membrane (elasticity and toughness). Omeprazole with lower water solubility could not generate sufficient osmotic pressure to create a crack in the membrane to activate pulsatile release, whereas the two other model drugs with higher solubilities could. But adsorption of omeprazole sodium on Eudragit(®) RS via charge-charge interactions led the its incomplete release. Finally, with 4% osmogent of NaCl added, a lag time in a range from 0 to 12h proportionally regulated by varying both the membrane thickness and plasticizer level initiated the complete pulsatile release of propranolol HCl. In conclusion, a multiparticulate pulsatile drug delivery system activated by a rupturable controlled-release membrane via osmotic pressure was successfully developed, and clinical applications of chronotherapy with drugs like propranolol HCl are expected.

Enteric-coating of pulsatile-release HPC capsules prepared by injection molding.

Capsular devices based on hydroxypropyl cellulose (Klucel® LF) intended for pulsatile release were prepared by injection molding (IM). In the present work, the possibility of exploiting such capsules for the development of colonic delivery systems based on a time-dependent approach was evaluated. For this purpose, it was necessary to demonstrate the ability of molded cores to undergo a coating process and that coated systems yield the desired performance (gastric resistance). Although no information was available on the coating of IM substrates, some issues relevant to that of commercially-available capsules are known. Thus, preliminary studies were conducted on molded disks for screening purposes prior to the spray-coating of HPC capsular cores with Eudragit® L 30 D 55. The ability of the polymeric suspension to wet the substrate, spread, start penetrating and initiate hydration/swelling, as well as to provide a gastroresistant barrier was demonstrated. The coating of prototype HPC capsules was carried out successfully, leading to coated systems with good technological properties and able to withstand the acidic medium with no need for sealing at the cap/body joint. Such systems maintained the original pulsatile release performance after dissolution of the enteric film in pH 6.8 fluid. Therefore, they appeared potentially suitable for the development of a colon delivery platform based on a time-dependent approach.

Experimental and theoretical investigations of Lantana camara oil diffusion from polyacrylonitrile membrane for pulsatile drug delivery system.

Porous composite membrane of polyacrylonitrile (PAN) and Lantana camara essential oil was synthesized by solvent casting method. Stability of oil in PAN solution was measured by XiGo nano tool indicating constant relaxation time of 1487 time/s. Pore size of few microns confirmed by electron microscopy was supported by atomic force microscopy indicating roughness factor of 0.9 nm. Contact angle of 2° inveterates superhydrophilicity of the composite membrane. Membrane showed excellent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli with a 7-10mm zone of inhibition. In vitro release of Lantana oil from the composite membrane was carried out in isotonic phosphate buffer solution (pH=7.4). Lantana oil was released for 9h, lag time of 3h with constant 33% release confirmed PAN membranes as potential system for pulsatile drug delivery applications. Diffusion of E-caryophyllene (antibacterial component of oil) which was studied through molecular simulation using Material Studio software ensued diffusion coefficient value of 1.11∗10(-9) m(2)/s. Biocompatibility of the composite membrane was assessed by mouse embryonic fibroblast cell line (NIH 3T3) through MTT assay indicating more than 91% viable cell even at 200 µg/mL concentration. Such membranes can be efficiently used in biomedical applications as antibacterial and antifungal agent.

Chronotherapeutic delivery of hydroxypropylmethylcellulose based mini-tablets: an in vitro-in vivo correlation.

The purpose of the study was to develop and internally validate a nonlinear in vitro-in vivo correlation model for a chronotherapeutically programmed HPMC based propranolol HCl (PHCl) mini-tablet. A simple and sensitive HPLC method was developed for the determination of PHCl content in rabbit plasma. The influence of tri-sodium citrate (TSC) on release behaviour was investigated through in vitro dissolution and in vivo absorption. Linear and nonlinear (quadratic, cubic, sigmoid functions) deconvolution based in vitro-in vivo correlation (IVIVC) models were developed using in vitro dissolution data and bioavailability profile. Prediction errors were investigated for Cmax and AUC in the light of US FDA guidelines for average percent prediction error. Release rate indicated that TSC was directly proportional to its concentration in the formulation. In vitro optimized formulation showed nearly 4.5h lag time and 5.24 ± 1.74% drug releases in initial 4.5h following rapid release 97.11 ± 1.87% in 6h. The deconvolution based IVIVC model appeared to be curvilinear for all three pulsatile formulations. Among various functions investigated the model using cubic function showed a better correlation (r>0.99) and satisfies the US FDA guidelines for average percent prediction error of less than 10%.

Film coatings for oral pulsatile release.

Pulsatile delivery is generally intended as a release of the active ingredient that is delayed for a programmable period of time to meet particular chronotherapeutic needs and, in the case of oral administration, also target distal intestinal regions, such as the colon. Most oral pulsatile delivery platforms consist in coated formulations wherein the applied polymer serves as the release-controlling agent. When exposed to aqueous media, the coating initially performs as a protective barrier and, subsequently, undergoes a timely failure based on diverse mechanisms depending on its physico-chemical and formulation characteristics. Indeed, it may be ruptured because of the gradual expansion of the core, swell and/or erode due to the glassy-rubbery polymer transition or become permeable thus allowing the drug molecules to diffuse outwards. Otherwise, when the coating is a semipermeable membrane provided with one or more orifices, the drug is released through the latter as a result of an osmotic water influx. The vast majority of pulsatile delivery systems described so far have been prepared by spray-coating, which offers important versatility and feasibility advantages over other techniques such as press- and dip-coating. In the present article, the design, manufacturing and performance of spray-coated pulsatile delivery platforms is thus reviewed.