Push Layer Research Articles

Bioavailability Study of Experimental Push–pull Osmotic Pump Tablet of Nifedipine in Dogs

This study aimed to assess the bioavailability of experimental extended-release nifedipine tablets of push-pull osmotic pump type composed of a semipermeable membrane-coated bilayer core tablet containing PEO N10 and PEO 303 in drug layer and push layer, respectively on dogs. A test on dogs was performed using a two-way randomized crossover design with a single oral dose, fasting condition. Plasma samples were obtained at intervals and analyzed for nifedipine by UPLC-MS/MS after liquid-liquid extraction using glibenclamide as the internal standard. The pharmacokinetic parameters were calculated and the bioavailability of nifedipine extended-release tablets was evaluated by comparing the pharmacokinetic parameters between the prepared extended-release tablets of 30 mg NIF and the reference tablets of Adalat LA 30 mg. It was found that the prepared push-pull osmotic pump tablets of 30 mg nifedipine were equivalent in bioavailability to Adalat LA reference tablets of 30 mg nifedipine in experimental dogs according to the regulations of US-FDA and Vietnamese pharmacopeia 5th edition. The main pharmacokinetic parameters of nifedipine test and reference tablets after a single oral administration were as follows: Cmax 26.95 ± 7.82 (ng.mL-1) and 27.20 ± 6.99 (ng.mL-1), Tmax 12.33 ± 3.44 hours and 11.50 ± 3.33 hours, AUC0-96 728.96 ± 328.87 (ng.h.mL-1) and 702.48 ± 404.48 (ng.h.mL-1), AUC0-∞, 741.05 ± 340.39 (ng.h.mL-1) and 710.71 ± 408.76 (ng.h.mL-1), MRT 21.80 ± 5.25 hours and 22.06 ± 5.20 hours, respectively. The 90% confidence intervals for the ratio of Cmax, AUC0-∞, and MRT values for the test and reference products, using logarithmically transformed data were 90.82% - 108.09%, 91.97% - 118.21%, 90.74% -107.62%, respectively. No statistically significant difference was found for the Tmax value.

사포그릴레이트 염산염을 함유하는 신규 OROS 정의 제제 설계 및 용출 거동

Sarpogrelate hydrochloride (SGH) is a drug that improves ischemic symptoms such as ulcers, pain, and feeling of cold caused by chronic arterial occlusion, and has a short half-life of 0.6 to 0.8 hours. Also, reference drug (SarpodipilⓇ SR tablet) is affected by drug release depending on pH. To overcome this, the osmotic controlled release oral delivery system (OROS) utilizes push-pull osmotic pump (PPOP) technology that can achieve zero-order drug release over 24 hours by osmotic pressure. OROS tablet is double-layer tablet consisting of a drug layer (L200-PEO) and a push layer (H5,000- PEO). OROS tablet coated with a semi-permeable film has a orifice of a certain size made by a laser drill, so that the drug is released at a constant rate. The dissolution of the OROS tablet was not affected by the amount of sodium chloride in the drug layer and the number of orifice, but was affected by amount of coating, cellulose acetate (CA) : polyethylene glycol 3350 (PEG 3350) ratio and the size of orifice. Accordingly, as the amount of coating increased and PEG 3350 decreased, the dissolution rate decreased. The developed OROS tablet (formulation C), unlike the reference drug, is not affected by pH, showing high similarity factors of 76.0, 86.1, and 91.2 at pH 1.2, pH 4.0, and pH 6.8 when compared to distilled water. In conclusion, we developed OROS tablet containing SGH, showing zero-order release that continuously releases the drug for 24 hours regardless of pH, and confirmed the factors affecting dissolution.

Fabrication, optimization and characterization of an osmotic push-pull drug delivery system for paliperidone

ObjectivesPaliperidone is a BCS class II drug with low solubility and high permeability. It has 28% absolute oral bioavailability and an elimination half-life of 23 h. An osmotic push–pull trilayer tablet currently available on the market has achieved controlled release of a low dose over an extended time period, while avoiding the need for a loading dose. However, this trilayer tablet has several disadvantages, such as complicated processing, high production costs and difficulty in achieving uniformity of the contents. Thus, the objective of this study was to overcome the above difficulties associated with paliperidone and to formulate a bilayer tablet with a similar drug profile to that of the reference listed drug Invega®. MethodsThe bilayer tablets were prepared by optimization of the core and semi-permeable membrane. Effects of the curing time, and the size and number of orifices on the prepared tablets’ dissolution profile were analyzed. Two different grades of polyethylene oxide were used in the core and push layer as pore formers. ResultsThe weight variation, friability and hardness values of the prepared tablets were well within compendium limits. The optimized bilayer parameters for the prepared tablets were curing time, 5 h; seal coat, 7% w/w; ER coat, 13% w/w; orifice size, 0.6 mm; and orifice number, 2. Further tablet formulation resulted in an F2 value of 75.67, indicating a dissolution profile similar to that of Invega®. ConclusionBi-layer tablets of paliperidone overcoming the drawbacks of the marketed formulation were successfully prepared, and offer advantages such as a simpler preparation process, cost effectiveness and faster preparation of the tablet core.

ROLE OF QUALITY BY DESIGN FOR THE OPTIMIZATION OF PUSH PULL OSMOTIC PUMP OF S-METOPROLOL SUCCINATE

The present research was focus on the preparation and evaluation of push pull osmotic pump of S-metoprolol succinate based on Quality by Design (QbD) approaches. For preparation of push pull osmotic pump, pull layer of S-metoprolol succinate was prepared using low molecular weight Polyox by wet granulation. Push layer containing higher molecular weight polyox and sodium chloride as osmotic agents were prepared by wet granulation. Both layers were compressed to get bilayer tablets and these bilayer tablets were coated with cellulose acetate, which act as a semipermeable membrane, and polyethylene glycol, which act as pore former. Extended release coated tablets were laser drilled on drug layer side to allow delivery of drug. The formulation was optimized using a center composite design (CCD). The effect of different drilled diameter on drug release was also evaluated. Extended release coating (%), concentration of sodium chloride (%w/w) and cellulose acetate : PEG 3350 ratio impact on drug release was optimized using center composite design (CCD). 20% Extended release coating. 20% w/w concentration of sodium chloride, and 90:10 cellulose acetate : PEG 3350 ratio gave zero order release (R2 value greater than 0.9) up to 20 h. Push pull osmotic pump of S-metoprolol succinate was successfully developed using low molecular weight polyox in pull layer and higher molecular weight of polyox in push layer.

Redefinition to bilayer osmotic pump tablets as subterranean river system within mini-earth via three-dimensional structure mechanism

Defining and visualizing the three-dimensional (3D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography (SR-μCT). In situ formed 3D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral “roadways”. Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed 3D microstructures, a “subterranean river model” for the drug release mechanism has been defined to explain the drug release mechanism.

Development, optimization and pharmacokinetic evaluation of biphasic extended-release osmotic drug delivery system of trospium chloride for promising application in treatment of overactive bladder

BackgroundThe research was aimed with an approach to formulate biphasic extended-release system of trospium chloride resulting in controlled release of drug up to 24 h with prospects of better control on urinary frequency, efficacy, tolerability, and improved patient compliance. The push–pull osmotic pump (PPOP) bi-layered tablet of trospium chloride (60 mg) was developed with the use of immediate-release polymers in the pull layer (30 mg drug) and polyethylene oxide in the push layer (remaining 30 mg drug). The tablet was formulated by compression after non-aqueous granulation, seal coating, and semipermeable coating. The tablet prepared was laser drilled to create an orifice for drug release.ResultsComparative in vitro dissolution and in vivo pharmacokinetic analysis of available marketed formulations demonstrated the complete drug release within 16–18 h; hence the developed biphasic extended-release system has its great importance as it provides zero-order release up to 24 h.ConclusionsThe developed biphasic extended-release drug delivery system of trospium chloride provides the drug release for 24 h with effective plasma concentration in comparison with the available marketed formulation. Extended release of drug from the developed formulation provides scope for its promising application in the treatment of overactive bladder (OAB).

A new perspective in understanding the dissolution behavior of nifedipine controlled release tablets by NIR spectroscopy with aquaphotomics

The in vitro dissolution profile is a key parameter which reflects the quality of sustained-release tablets. Most studies were used to determine the dissolution of tablets utilizing dissolution curves. This study aimed to investigate the role of water during nifedipine controlled release tablets dissolution process in order to provide a new way to understand the dissolution behavior. Dissolution liquid was added to the drug-containing layer slowly, and near infrared spectra were acquired according to the set time. NIR spectroscopy with aquaphotomics were introduced to determine different water patterns. The results showed that, the structural change of water was consistent with the dissolution process. During hydration stage, it was mainly Sr combined with the semi-permeable membrane to form a channel. Then S0, S1, S2 and S3 combined with the drug layer and the push layer. Finally, it was relied on the swelling of the push layer to push the drug layer out at the release process. This study not only deepens the understanding of the dissolution process, but also opens a new perspective in molecular interaction analysis in aqueous system by understanding the roles of water.

Preparation of Nifedipine Push-Pull Osmotic Pump Tablets

This study aims to investigate the influence of the formulation factors on the drug release kinetics, thereby selecting the compositions of extended-release nifedipine tablet based on the similarity coefficient f2 obtained when compared with Adalat LA tablet. The formulation factors such as: molecular weight of the polyethylene oxide (PEO) and osmotic agent amount in drug layer and push layer, semi permeable membrane thickness (estimated by coating weight gain), orifice size, type of plasticizers and ratios of coating polymer to plasticizer in semipermeable membrane were evaluated. It was found that developed tablets were able to deliver nifedipine in an approximate zero-order manner up to 20 hours and drug release profile of developed tablets was similar to that from Adalat LA tablets. The developed tablet contained: PEO N10, PEO 303 in drug layer and push layer, respectively; percentages of osmotic agent in drug layer and push layer were 10% and 30%, respectively; weight gain of semipermeable coating was 12%; and orifice size was 0.8 mm.
 Keywords
 Nifedipine, GPKD, push-pull osmotic pump, PEO, Tlag.
 References
 [1] Vietnamese National Drug Formulary Council, Nifedipine, Vietnamese National Drug Formulary, 2nd edition, Medical Publising House, Hanoi, 2018, pp. 1056-1058 (in Vietnamese).[2] A. Nokhodchi, M.N. Momin, J. Shokri, et al., Factors affecting the release of nifedipine from a swellable elementary osmotic pump, Drug Delivery, 15 (1) (2008) 43-48. https://doi.org/10.1080/10717540701829028[3] R.K. Verma, D.M. Krishna, S. Garg, Formulation aspects in the development of osmotically controlled oral drug delivery systems, Journal of controlled release 79 (1-3) (2002) 7-27. https://doi.org/10.1016/s0168-3659(01)00550-8.[4] The United States Pharmacopeial Convention, Nifedipine Extended-Release Tablets, The United States Pharmacopeia, 41st edition, United Book Press, Baltimore, 2018, pp. 2938 - 2944.[5] V. Malaterre, J. Ogorka, N. Loggia, et al., Approach to design push–pull osmotic pumps, International Journal of Pharmaceutics 376 (1–2) (2009) 56-62. http://dx.doi.org/10.1016/j.ijpharm.2009.04.015.[6] S. Missaghi, P. Patel P, Farrell T. P., et al., Investigation of critical core formulation and process parameters for osmotic pump oral drug delivery, AAPS PharmSciTech 15 (1) (2014) 149-160. http://doi.org/10.1208/s12249-013-0040-4.[7] V. Malaterre, H. Metz, J. Ogorka , et al., Benchtop-magnetic resonance imaging (BT-MRI) characterization of push-pull osmotic controlled release systems, J Control Release 133 (1) (2009) 31-36. http://doi.org/10.1016/j.jconrel.2008.09.007.[8] Z. Zhang, W. Li, S. Nie, et al., Overcome side identification in PPOP by making orifices on both layers, International journal of pharmaceutics 371 (1-2) (2009) 1-7. http://dx.doi.org/10.1016/j.ijpharm.2008.12.006[9] C. Wu, Z. Zhao, Y. Zhao, et al., Preparation of a push–pull osmotic pump of felodipine solubilized by mesoporous silica nanoparticles with a core–shell structure, International Journal of Pharmaceutics,475 (1-2) (2014) 298 - 305 . http://dx.doi.org/10.1016/j.ijpharm.2014.08.033.[10] V. Patel, A. Chudasama, M. Nivsarkar, et al., Push-pull osmotic pump for zero order delivery of lithium carbonate: Development and in vitro characterization, Pharmaceutical development and technology, 17 (3) (2012) 375-382. http://doi.org/10.3109/10837450.2010.542577.[11] C.N. Patra, S. Swain, J. Sruti, et al., Osmotic drug delivery systems: Basics and design approaches, Recent Patents on Drug Delivery & Formulation 7(2) (2013) 1 - 12. http://doi.org/10.2174/1872211311307020007.
 

Visualized analysis and evaluation of simultaneous controlled release of metformin hydrochloride and gliclazide from sandwiched osmotic pump capsule

The aim of this study was to develop the Metformin Hydrochloride and Gliclazide (MH-GZ) sandwiched osmotic pump capsule which could overcome the problems associated with short half-life and burst release. The system could deliver drugs with different solubility simultaneously at zero-order rate, in which MH-GZ were filled in both sides of the push layer respectively. The single factor and orthogonal test were employed to obtain the optimized formulation with the evaluation index of similarity factor (ƒ2). R language was used to visualized analyze the main influence factors of drug release and their correlations. Pharmacokinetic study was performed in beagle dogs compared to the marketed conventional product, which showed decreased Cmax, prolonged Tmax, and improved bioavailability, independent of pH and agitational speed but related to osmotic pressure differences across the semi permeable membrane. The designed sandwiched osmotic pump capsule proposed a promising substitute for the marketed product for the treatment of type 2 diabetes.

Evaluation of the Effect of Dissolution Conditions on the Release Profiles of Felodipine from the Extended Release Push-Pull Osmotic Tablets

The bilayered push–pull osmotic tablets of 5 mg felodipine were prepared by the double compression method, then the core tablets were coated with cellulose acetate as a semipermeable membrane. One releasing orifice was drilled by laser on the drug side of tablets. The osmotic tablets of felodipine containing low molecular weight PEO (200.000) as the primary component in the drug layer, high molecular weight PEO (5.000.000) as a swelling agent in the push layer and natri chloride as osmotic agent in both drug and push layers which were semi-permeable membrane coated with a weight gain of 8.5 % and the drilled release orifice of 0.8 mm. The influence of dissolution conditions on the release profiles of felodipine from the extended release push-pull osmotic tablets was studied. Dissolution studies of the osmotic tablets of felodipine were carried out in dissolution media with different media pH, stirring speeds or osmotic pressures. The results of the study showed that the drug release profile was similar in dissolution media containing surfactant mimics the in vivo state with varying pH and stirring speeds. However, felodipine released from the osmotic tablets was inversely proportional to the osmotic pressure of the dissolution medium. Therefore, the drug release rate from the osmotic tablets was independent of media pH and stirring speeds, but dependent on the osmotic pressure of the dissolution medium.
 Keywords
 Felodipine, push - pull osmotic pump, pH, stirring speeds, osmotic pressure.
 References
 

Sustained release formulation of Ondansetron HCl using osmotic drug delivery approach

Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70–75% of the drug in plasma is protein-bound and terminal elimination half-life is about 3 h after oral administration. The study was aimed to develop Push–pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6 mm), and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in vitro drug release. The analytical methods were developed and validated to estimate in vitro drug potency, drug release, and in vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of in vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 h.

Double-layered osmotic pump controlled release tablets of actarit: In vitro and in vivo evaluation

The aim of the study was to develop actarit double-layered osmotic pump tablets to overcome the weak points of actarit common tablets, such as short half-life and large plasma concentration fluctuations. Single factor experiment and orthogonal test were applied to optimize the formulation; the pharmacokinetic study was performed in beagle dogs adopting actarit common tablets as reference tablets. The optimal formulation was as follows: drug layer: 150 mg actarit, 240 mg PEO-N80, 50 mg NaCl; push layer: 140 mg PEO-WSR303, 20 mg NaCl; coating solution: 30 g cellulose acetate and 6 g PEG 4000 in 1000 ml 94% acetone solution, 60 mg coating weight gain. The pharmacokinetic study showed that Tmax was prolonged by the contrast of commercial common tablets with constant drug release rate, but the bioavailability was equivalent. And a good in vivo–in vitro correlation of the actarit osmotic pump tablets was also established. The designed actarit osmotic pump tablets can be applied for rheumatoid arthritis, proposing a promising replacement for the marked common products.

Push-Pull Controlled Drug Release Systems: Effect of Molecular Weight of Polyethylene Oxide on Drug Release

First, an elementary osmotic pump (EOP) with a simple structure was prepared using polyethylene oxide (PEO) and NaCl as an excipient, and the influence of the molecular weight (Mw) of PEO on drug release was investigated. In the dissolution test of EOP, it was observed that the gelated core tablet was pushed out through the orifice. The dissolution profile of EOP was sigmoidal, and despite the short time, a zero-order release region was observed. The gel swelling rate in the zero-order region was independent of the Mw of PEO. It was also found that higher the Mw of PEO, the larger the saturated swelling amount. Next, a push-pull pump (PPP) with almost identical formulation to that of EOP was prepared, and its drug release characteristics were investigated. PPPs were prepared by varying the combination of Mws of PEO in both layers, and their dissolution profiles were compared. It was found that PPP using a low-Mw PEO for the drug layer and PEO with a high-Mw in the push layer showed the longest dissolution profile of the linear region. The obtained findings suggested that the properties of PEO and its hydrogel play a crucial role in the drug release of PPP.

СУЧАСНИЙ СТАН СТВОРЕННЯ, ВИРОБНИЦТВА ТА ДОСЛІДЖЕННЯ ТАБЛЕТОВАНИХ ЛІКАРСЬКИХ ПРЕПАРАТІВ Повідомлення 25. Осмотичні системи вивільнення та доставки лікарських речовин: характеристика імплантаційних мініосмотичних, оральних та спеціальних типів осмотичних систем, їх застосування

Проведено огляд літературних джерел щодо характеристик та можливостей застосування імплантаційних мініосмотичних, оральних та спеціальних типів осмотичних систем вивільнення та доставки лікарських речовин, наведено приклади осмотичних систем, які зареєстровані на світовому ринку.

Controlled release of metformin hydrochloride and repaglinide from sandwiched osmotic pump tablet

The marketed compound tablet of metformin hydrochloride (MH) and repaglinide (RG) exhibits perfect multidrug therapeutic effect of type 2 diabetes. However, due to the short half life of the drugs, the tablet has to be administered 2 to 3 times a day, causing inconvenience to patient and fluctuations of plasma concentration. Here, a sandwiched osmotic pump tablet was developed to deliver the two drugs simultaneously at zero-order rate, in which MH and RG were loaded in different layers separated by a push layer. The osmotic pump tablet was prepared by a combination of three tableting procedure and film coating method. The factors including type and amount of propellant, osmotic active agents, amount of porogenic agent, coating weight, orifice diameter were optimized. The pharmacokinetic study was performed in beagle dogs, and the drug concentration in plasma samples was assayed by HPLC-MS/MS method. Simultaneous, controlled release of MH and RG in the first 12 and 8h was achieved from the optimized formulation. A significantly decreased Cmax, prolonged Tmax and satisfactory bioavailability of the osmotic pump tablet were obtained, and a good in vivo-in vitro correlation of the two drugs was also established. In summary, the sandwiched osmotic pump tablet released the MH and RG simultaneously at zero-order rate, and exhibited significant sustained release effect in vivo and good in vivo-in vitro correlation. The designed controlled release system for MH and RG proposed a promising replacement for the marked compound product in the therapy of type 2 diabetes.

Nondestructive Analysis of Structure and Components of Tablet Coated with Film by the Usage of Terahertz Time-Domain Reflection Spectroscopy

Nondestructive analysis of tablet is of great importance from the aspect of productivity and safety. In terahertz (THz) region, however, the analysis of core of coated tablet has not been progressed. In this study, we have measured a flat-surface push–pull osmotic pump tablet, having no orifice, having bilayer core and a coating film layer. The bilayer core was made from the drug layer and the push layer, and acetaminophen was contained in the drug layer as a model drug. To study its structure and components, we have obtained reflection spectra from the drug layer side and the push layer side measurements using THz time-domain reflection spectroscopy (THz-TDRS). From these results, detection of the peak of acetaminophen in the spectrum from the drug layer side measurements was confirmed. We have made ridges approximated toward the peak using a general method of linear regression analysis in both spectra. Two-sample t-test was applied to their gradients, and significant difference between the drug layer and the push layer was shown. These results suggested that THz-TDRS is applicable to the analysis of structure and component of a coated tablet.

A novel bi-layer ascending release osmotic pump tablet: In vitro investigation and in vivo investigation in pharmacokinetic study and IVIVC evaluation

This study was aimed to develop an ascending release push-pull osmotic pump (APOP) system with a novel mechanism and an easy manufacture process. Theoretical analysis showed that the key to obtain the non-zero order drug release was to break the balance between the drug suspension release rate in the drug layer and the swelling rate of the core, and an ascending drug release rate was achieved when the former was slower than the latter. A polymer (Polyox WSR N-12K) was introduced as a suspension agent in drug layer to slow down the hydration rate of drug layer. Influence of the composition of drug layer (PEO category, total amount, drug loading and fraction of NaCl), push layer (NaCl amount), and also the level of coating weight gain on the drug release profiles was investigated. Observation of hydration state was estimated by taking photos, and also was confirmed by the theories. Paliperidone was delivered successfully by APOP at an ascending release rate up to 20 h in vitro. The in vivo plasma concentration of paliperidone in beagle dogs increased gradually up to 19 h. The APOP with an easy manufacture process was a promising strategy to deliver drug at an ascending rate.

Design and statistical optimization of osmotically driven capsule based on push-pull technology

In present investigation attempt was made to develop and statistically optimize osmotically active capsule tailor made from the concept of bilayer (push–pull) osmotic tablet technology. The capsule was comprised of active (drug) and push (osmogen) layer. Active layer was compressed in form of tablet by mixing known amount of drug and formulation excipients. Similarly push layer was made by compressing Mannitol with formulation excipients. Finally, both layers were packed in hard gelatin capsule having small aperture at top and coated with semipermeable membrane to form osmotically active capsule. Formulated and optimized capsules were characterized for Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC), scanning electron microscopy, In-vitro drug release study and Release models and kinetics. Statistically optimized formulation showed good correlation between predicted and experimented results, which further confirms the practicability and validity of the model.

Simultaneous delivery of Nifedipine and Metoprolol tartarate using sandwiched osmotic pump tablet system

The sandwiched osmotic tablet system that could deliver Nifedipine and Metoprolol tartarate simultaneously for extended period of time was developed in order to reduce the problems associated with multidrug therapy of hypertension. This system composed of a middle push layer and attached drug layers of Nifedipine and Metoprolol. The advantage of the sandwiched osmotic tablet system over the commercialized push–pull osmotic tablet system is its simplicity of preparation, as the surface identification was avoided. Polyethylene oxide 600,000 and 8,000,000 g/mole were used as thickening agent of drug layer and the expandable hydrogel of push layer, respectively. It has been observed that amount of polyethylene oxide (PEO) and KCL of the drug and push layer had profound influence on Nifedipine and Metoprolol release. Further, the release of drugs was optimized by the size of the delivery orifice, level of plasticizer and membrane thickness. The optimal osmotic pump tablet was found to deliver both drugs at a rate of approximately zero order for up to 16 h independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. The formulations were found to be stable after 3 months of accelerated stability studies. Prediction of steady-state levels showed the plasma concentrations of Nifedipine and Metoprolol to be within the desired range. Further sandwiched system had a good sustained effect in comparison with the conventional product. Hence the prototype design of the system could be applied to other combinations of drugs used for cardiovascular diseases, diabetes, etc.

Benchtop-magnetic resonance imaging (BT-MRI) characterization of push–pull osmotic controlled release systems

The mechanism of drug release from push–pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push–pull osmotic systems, which enable a more efficient optimization of such formulations.