Sustained-release Pellets Research Articles

Development of Sinomenine Hydrochloride Sustained-release Pellet With Multiple Release Characteristics.

Due to the gastrointestinal side effects, the clinical application of sinomenine hydrochloride (SH) in rheumatoid arthritis is limited. The elderly population constitutes the primary group affected by this disease, and within this demographic, there are significant variations in gastric emptying time. To reduce the influence of individual differences on drug efficacy and concurrently alleviate gastrointestinal side effects, the SH sustained-release pellets with multiple release characteristics were developed, which comprised both regular sustained-release pellets and enteric-coated sustained-release pellets. The drug-loaded layer formulation was optimized by full factorial design. With the optimal formulation, the drug-loaded pellets achieved a yield of 96.05%, an encapsulation efficiency of 83.36% for SH, a relative standard deviation of 3.26% in SH content distribution, an average roundness of 0.971 for the pellets, and the particle size span of 0.808. The pellets with a 4h SH release profile in an acidic environment and pellets displaying 4h acid resistance followed by an 8h SH release behavior in the intestinal environment were individually prepared through in vitro dissolution tests. The results demonstrated stable and compliant dissolution behavior of the formulation, along with excellent stability and physical appearance. This research offers novel insights and references for the innovative formulation of SH.

Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.

Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. Cmax and AUC(0-t) for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.

Formulation and in-vitro anticancer activity of nilotinib immediate release and ibrutinib sustained release pellets

Background: Blood cancer is a significant contributor to mortality rates worldwide, and its prevalence is projected to rise on a global scale. This trend places considerable strain on healthcare systems and necessitates the expedited development of innovative treatments by pharmaceutical firms to remain competitive. Conventional pellets produce rapid plasma drug levels, but they might cause side effects, decrease effectiveness, and lead to poor therapeutic management. Ibrutinib and Nilotinib are employed to treat leukemia patients. Methodology: The current research aims to formulate, characterize, and anticancer effect of Nilotinib immediate release (NIR) and Ibrutinib sustained release (ISR) seal sugar-coated pellets. Micrometric properties estimated the characterization of the drug pellets, and surface morphology was estimated using scanning electron microscopy. Drug excipient compatibility studies, stability studies, and in-vitro drug release were accessed. Result & Discussion: The results of pellet formulations FNI-1 to FNI-5 showed that FNI-5 formulations showed 100±6.0 µm size and possessed excellent mechanical strength for giving pellets a good self-life; also, due to the higher drug content up to 99%, FNI-5 was the best suited for pellet formulation and because NIR showed 99.18 ± 2.12 drug release at 2h and ISR 99.03±3.74% up to 12h so that anticancer concentration maintained for prolonged period. The standard dose for cytotoxicity against the THP-1 cell line of Nilotinib was found to be 200 mg, and the maintenance oral dose of Ibrutinib was 140mg, with four times the intake of the drug up to 560 mg. In an in vitro study in FNI-5 (final formulation), the dose of Ibrutinib was reduced to 420 mg. Conclusion: A synergistic effect of Ibrutinib and nilotinib drugs was observed in the inhibition of cancer cell growth, with an IC50 value of 4.585 µg/mL

Preparation and evaluation of lipid-based sustained release pellets of chlorpheniramine maleate by the wet extrusion-spheronization method

Introduction: This study aimed to investigate the feasibility of preparation of sustained-release chlorpheniramine maleate (CPM) pellets based on Compritol® as a lipid matrix and evaluation of the affecting factors on pellet properties. Methods: Using the D-optimal experimental design, different pellet formulations containing various amounts of CPM, Compritol® and Avicel were prepared by the wet extrusion-spheronization method. Then the pellets were cured at 40, 65 and 90 ̊C for 4 and 8 h to study the effect of the thermal process. The physicomechanical properties of the pellets were investigated in terms of particle size distribution, pelletization yield, mechanical strength, aspect ratio and sphericity. To investigate the possible interaction of CPM and Compritol®, as well as to evaluate the morphology and surface characteristics of the pellets DSC and SEM were used, respectively. Also, to investigate the drug release rate from pellets the dissolution test was carried out and mean dissolution time (MDT) was calculated to compare different formulations. Results: The results showed that the curing process up to 65 °C improves the strength of the pellets. However, increasing the curing temperature from 65 to 90 °C and also increasing the curing time from 4 to 8 h did not have a significant effect on the strength of the pellets but increased the drug release rate of pellets. Increasing the amount of the drug or decreasing Compritol® in the matrix of pellets leads to a larger particle size with greater mechanical strength. All formulations of the pellets had an aspect ratio and sphericity of about 1.1 and 0.9 respectively, which indicates the spherical shape of the pellets as shown by SEM. DSC thermograms indicate the reduction of the crystallinity or the change of the crystalline form of the drug to amorphous during the pelletization process. Conclusion: The results revealed the feasibility of preparing lipid-based sustained-release matrix pellets using the wet extrusion-spheronization method. The optimal formulation in terms of physicomechanical properties and release rate was the formulation containing 8% CPM, 67% Compritol® and 25% Avicel, which were dried at 40 ° C for 4 h and released about 90% of the drug within 12 h.

Preparation and evaluation of lipid-based sustained release pellets of chlorpheniramine maleate by the wet extrusion-spheronization method

Background: This study aimed to investigate the feasibility of preparation of sustained-release chlorpheniramine maleate (CPM) pellets based on Compritol® as a lipid matrix and evaluation of the affecting factors on pellet properties. Method: Using the D-optimal experimental design, different pellet formulations containing various amounts of CPM, Compritol® and Avicel were prepared by the wet extrusion-spheronization method. Then the pellets were cured at 40, 65 and 90 ̊C for 4 and 8 h to study the effect of the thermal process. The physicomechanical properties of the pellets were investigated in terms of particle size distribution, pelletization yield, mechanical strength, aspect ratio and sphericity. To investigate the possible interaction of CPM and Compritol®, as well as to evaluate the morphology and surface characteristics of the pellets DSC and SEM were used, respectively. Also, to investigate the drug release rate from pellets the dissolution test was carried out and mean dissolution time (MDT) was calculated to compare different formulations. Results: The results showed that the curing process up to 65 °C improves the strength of the pellets. However, increasing the curing temperature from 65 to 90 °C and also increasing the curing time from 4 to 8 h did not have a significant effect on the strength of the pellets but increased the drug release rate of pellets. Increasing the amount of the drug or decreasing Compritol® in the matrix of pellets leads to a larger particle size with greater mechanical strength. All formulations of the pellets had an aspect ratio and sphericity of about 1.1 and 0.9 respectively, which indicates the spherical shape of the pellets as shown by SEM. DSC thermograms indicate the reduction of the crystallinity or the change of the crystalline form of the drug to amorphous during the pelletization process. Conclusion: The results revealed the feasibility of preparing lipid-based sustained-release matrix pellets using the wet extrusion-spheronization method. The optimal formulation in terms of physicomechanical properties and release rate was the formulation containing 8% CPM, 67% Compritol® and 25% Avicel, which were dried at 40 ° C for 4h and released about 90% of the drug within 12 h.

FORMULATION AND BIOPHARMACEUTICAL EVALUATION OF SUSTAINED RELEASE PELLETS OF BOSENTAN BY PANCOATING METHOD

Objective: The aim of the present study was to formulate sustained-release pellets of bosentan by eudragit RL 100 and RS 100, which are the polymers used in the pan coating technique. Methods: The sustained release pellets of bosentan were formulated by pan coating method. The drug was coated on nonpareil seeds along with EudragitRL100 by solution layering technique. Drug-loaded pellets were coated with EudragitRS100. The prepared pellets were evaluated for moisture content, drug content, particle size, and in vitro drug release. Stability studies were carried out on the optimised formulations for a period of 6 mo. Results: The drug content was in the range of 98.89±0.32. The mean particle size of the drug-loaded pellets was in the range of 835 μm. The drug release rate decreased as the concentration of eudragit increased in the pellet formulations. Among the prepared formulations, PC 4 showed 89.35±0.52 drug release in 12 h from a good linear relationship was established between model-independent approaches (T25%, T50%, and T100%) and weight gain in coating. This indicated the possibility of extending the drug release by increasing the weight gain in the coating, and hence, it was proposed to extend the drug release for 24 h. From the prepared pellets, the optimised formulation PC 12 showed a 100.02±0.03 drug release in 24 h. Furthermore, these pellets were filled into capsules and compared the dissolution studies. The compatibility between drugs and polymers in the drug-loaded pellets was confirmed by DSC and FTIR studies. Stability studies indicated that the pellets were stable. Conclusion: The prepared pellets were capable of releasing the drug for 24 h to treat the Pulmonary Arterial Hypertension.

Use of strongly acting sustained-release opioids in pediatrics : Pitfalls and solutions for morphine and hydromorphone

In pediatrics, adequate treatment with potent opioids requires the administration of sustained-release preparations for many patients; however, the dosing and administration of sustained-release morphine and hydromorphone preparations via gastrointestinal tubes confronts providers with amajor hurdle, especially as the company Mundipharma GmbH has discontinued the production and distribution of the preparation MST retard granules in 2019, which has been proven for these purposes in pediatrics. The aim of this study was to establish aproduction technique for available sustained-release opioid preparations, which are particularly suitable for use in the low-dose range required in pediatrics and which can also be administered via gastrointestinal tubes. Low-dose preparations were produced by opening of morphine and hydromorphone capsules and weighing of the sustained-release pellets. To evaluate the partition, an analysis of the drug content via high performance liquid chromatography (HPLC) was conducted. Moreover, the administration via gastrointestinal tubes (charrière, Ch 8-Ch10) was examined by an ex vivo experiment. The examination showed apracticable method to produce low dosages of sustained-release morphine and hydromorphone. The preparations are in accordance with the test for content uniformity of the European Pharmacopoeia (Ph. Eur.). Furthermore, the pellets were administered to gastrointestinal tubes Ch8 (morphine) and Ch10 (hydromorphone) by asyringe application technique and passed the tubes completely. The production technique can be considered as safe and enables the off-label oral application or application via gastrointestinal tubes of sustained-release opioids in pediatrics.

Design and Development of Cyclobenzaprine HCl Sustained Release Pellets by Wurster Coating Method

Background Cyclobenzaprine is structurally related to the tricyclic antidepressants. Cyclobenzaprine may be slightly different than the other musculoskeletal agents because it is believed to decrease skeletal muscle spasm through atropine-like effects directly on the cerebral motor neurons. Cyclobenzaprine may also have analgesic properties that may add to its therapeutic effects. This research encompasses all oral dosage forms and strengths.Objective Even though Cyclobenzaprine HCl tablets are available in market we can formulate pellets because pellets demonstrate good flow properties in the intestine and require less cost for the production of formulation. The main aim of the present study was to produce the extended-release Cyclobenzaprine HCl capsules of 16 hours release to reduce the dosing frequency as a skeletal muscle relaxant when compared with the innovator drug Amrix. Cyclobenzaprine HCL is a muscle relaxant that works on the central nervous system by altering the signals from the brain causing muscle to tighten.Methodology Cyclobenzaprine hydrochloride sustained release SR pellets were prepared by Wurster coating method using different excipients and polymers to release the drug slowly for an extended period of time. The method of preparation of Cyclobenzaprine hydrochloride SR pellets involves two steps drug coating and polymer coating. In the drug coating process the drug was coated in a suspension form on the dummy pellets dried and sieved. Drug coated pellets were coated with SR polymer to form SR pellets. These SR pellets were dried sieved and sent for quality control.Results After 12th hour the percentage drug release from the formulations were 89.6 87.4 85.8 85.6 83.9 75.1 for the formulation containing EC N14 2.5 5 7.5 and EC N50 10 12.5 and 15 respectively. The dissolution profile was shown and the mean dissolution time of pellets was noted to be 6.19 hrs. Formulation F5 was identified to be the most superior formulation.Conclusion Accordingly it can be concluded that the F5 12.5 ww EC N50 is a robust one and the performance is less likely to be affected by the various factors studied. The formulations were subjected to stability studies according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH guidelines for three months which demonstrated all the tested formulations to be stable.

Pengaruh Desain Punch Terhadap Mutu Fisik dan Disolusi Tablet MUPS Metformin HCl

The compaction of multi-unit pellet system (MUPS) into tablets is a potential alternative for sustained release drugs. Tableting tools (punch and die) affect the compaction process and quality of MUPS tablets. The punch design intends to preserve the desired drug release of compacted pellets. This study aims to investigate the effect of two punch shapes, the flat face radius edge (FFRE) and concave-faced punch (concave), each at two different cup depths, on the physical properties and release profile of metformin HCl MUPS tablets. Drug release parameters, t50 values, showed that the metformin HCl released from MUPS tablets was faster than the uncompacted sustained release pellets. The similarity of the dissolution profile (f2) between MUPS tablets and uncompacted metformin HCl pellets was lower than 50 as the minimum acceptance value. The tablet tensile strength obtained was below the requirements (<1.7 MPa). Tablet disintegration time was approximately less than 2 minutes. In conclusion, drug release profile of the MUPS tablets showed damage of the pellets due to compaction process. Nevertheless, pellets compacted at low compaction pressure using FFRE with a deeper cup depth (size 0.80 mm) showed a slightly better protection compared to other punch shapes and cup depth sizes applied.

Design, Development and In-Vitro Characterization of of Cyclobenzaprine Hcl Sustained Release Pellets

The aim of the present studyisto formulate and evaluate the cyclobenzaprine hydrochloride extended release pellets by Wurster coating method using starch, PVP K-90, ethyl cellulose, isopropyl alcohol, talc and other polymers to release the drug slowly through an extend period of time. The method of preparation of Cyclobenzaprine Hydrochloride SR pellets involves in two steps, namely drug coating and polymer coating. In the drug coating process drug is coated as a suspension form to dummy pellets and dried and sieved. Drug loaded pellets are coated with SR polymer to form SR pellets. These SR pellets are dried, sieved and send to quality control.FTIR studies of the formulation indicating no chemical interaction between cyclobenzaprine HCl and excipients. In order to get the optimized formulation, the various process parameters were adjusted. The various evaluations for formulations were carried out, that to based on the in-vitro drug release studies of F5 formulation shows better drug releaseprofile than other formulations. The results conclude that trial F5 has met the objective of extended release, cost effective as once day of drug.

Biodegradation of microcystin using free and alginate-immobilized Stenotrophomonas geniculate DMC-X3 bacterium

The eutrophication of water bodies and global warming have led to frequent cyanobacterial blooms, producing large quantities of algal toxins, which are released into water bodies, posing a threat to human health. Among known algal toxins, microcystin (MC) is the most harmful and most commonly detected. Because of its stable chemical structure, it is difficult to degrade MC though chemical and physical methods. Hence, effectively removing MC from water and ensuring water safety have become urgent issues. In this study, strain DMC-X3, which could rapidly and efficiently degrade MC, was isolated from a reservoir affected by a Microcystis aeruginosa bloom and identified as Stenotrophomonas geniculate. Inoculated at OD600 = 0.1, strain DMC-X3 degraded 70 % of 1000 μg/L MC in 24 h, and over 90 % within 48 h. When the inoculation density was increased to OD600 = 0.35, this bacterial strain completely degraded 1000 μg/L MC in 16 h and 5000 μg/L MC in 96 h. DMC-X3 maintained its MC degradation ability under the environmental conditions of pH 5–11 and 15–35 °C. After 60 d of storage at room temperature, DMC-X3 embedded and immobilized on sodium alginate pellets showed 90 % degradation of 200 μg/L MC in 48 h, and the pellets could be used for at least three cycles. Sustained-release pellets made by embedding and immobilizing both the degradation bacteria DMC-X3 and algicidal substance prodigiosin on sodium alginate effectively eradicated M. aeruginosa cells and degraded MC, promising a good application prospect in controlling M. aeruginosa blooms.

Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies

Lisinopril (LIS) is antihypertensive drug, classified as a class III drug with high water solubility and low permeability. To overcome the low permeability, 32 factorial designs aimed to formulate LIS as a sustained-release (LIS-SR) matrix pellet by extrusion/spheronization. Matrix pellets were composed of wet mass containing Avicel® and polymeric matrix polymers (sodium alginate (SA) and chitosan (CS)). Evaluation of the effect of two independent variables, matrix-forming units (SA and CS) on mean line torque, on pellet size, dissolution rate after 6 h, and mucoadhesion strength of the pellets were assessed using Statgraphics software. The tested formulations (F1-F9) showed that mean line torque ranged from 1.583 to 0.461 Nm, with LIS content in the LIS-SR pellets ranged from 87.9 to 103%, sizes varied from 1906 to 1404 µm and high percentages of drug released from pellets formulations (68.48 to 74.18 %), while the mean zeta potential value of mucoadhesive range from −17.5 to –22.9 mV.The selection of optimized formulation must have the following desirability: maximum peak torque, maximum pellets’ particle size, and minimum % LIS release after 6hr. LIS optimized sustained release pellet formula composed of 2,159 % SA and 0.357 % CS was chosen as optimized formula. It’s showed a 1.055 Nm mean line torque was responsible for the increased pellet size to 1830.8 μm with decreased release rate 56.2 % after 6 hr, and −20.33 mV average mucin zeta potential.Ex-vivo mucoadhesion studies revealed that that the optimize formulation, exhibited excellent mucoadhesive properties, after 1 h, about 73% of the pellets were still attached to the mucus membrane. Additionally, ex-vivo permeation determination of LIS from the optimized LIS-SR formulation was found to be significantly higher (1.7-folds) as compared to free LIS.In conclusion: LIS-SR matrix pellets, prepared with an extrusion/spheronization have desirable excellent characteristics in-vitro and ex-vivo sustained-release pellet formulation of LIS-SR was able to sustain the release of LIS for up to 8 h.

Abstract P4-01-24: Targeting receptor tyrosine kinases in overcoming tamoxifen resistance and dormancy in invasive lobular cancer

Abstract Objective: The molecular hallmark of invasive lobular cancer (ILC) is the loss of E-cadherin, resulting in the unique morphology, low mitotic index and unusual metastatic spread to ovaries, gut, and peritoneum. Patients with ILC face delayed, and higher stage at diagnosis, worse disease-free and overall survival1. The most frustrating challenge is the delayed recurrence, likely due to resistance and induction of dormancy2. Despite these unique features, ILC is lumped with hormone receptor-positive invasive ductal cancers (IDC); consequently, management strategies are based on data from IDC. Hence there is an unmet need to address the unique challenges of ILC. We generated Tamoxifen-resistant (TAMR) ILC cell lines with the aim to study the distinct characteristics, dormancy, differentially activated pathways, and response to drugs targeting such pathways in the resistant cells. Methods: We used MDA-MB-134-VI and SUM44-PE cells to study the effect of tamoxifen in combination with multi-targeted receptor tyrosine kinase inhibitor, Lenvatinib. TAMR cells from both MB-134 and SUM44PE cells were generated by growing them in increasing concentrations of 4-hydroxy tamoxifen (4-HT) up to 500nM, for 6 months. Total RNA from parental and TAMR cells were subjected to RNA-seq. Whole cell extracts were analyzed for specific phospho proteins by Western Blot analysis. Growth kinetics and effect of drugs on cell viability was measured using MTT assay (Roche). Cell migration was measured using Transwell migration assay. Novel engineered 2D and 3D cultures were used to study dormancy and the effect of the drug combination. Orthotopic tumor induction in NSG mice is ongoing to determine the effect of drug combination in vivo. Results: The TAMR cell lines show distinct morphological features, small but significant increase in growth rate (p=0.05) and remarkably higher migration (MB-134TAMR:11.5-fold, p< 0.005 and SUM44TAMR:>100-fold, p< 0.005). The IC50 for tamoxifen increased from 8.1M (MB-134) to 16.8M (MB-134TAMR) and from 11.3 M (SUM44) to 26.6 M (SUM44TAMR). RNA seq analysis revealed enrichment of PI3K-AKT, MAPK, cAMP, Rap1 signaling pathways, ECM-receptor interaction, Focal adhesion, and steroid hormone biosynthesis pathways in the TAMR cells. Upon stimulation by endothelial growth factor, the MB-134TAMR but not the parental cells showed dose dependent increase in phospho-AKT and phospho-MAPK levels. Using novel 2D/3D cultures, we show differential morphologies between IDC (MCF7) cells, MB-134TAMR, and the parental cells. MCF7 and MB-134TAMR cells are more adherent to fibronectin (p< 0.0001), whereas the parental ILC cells are more adherent to COL3A1 (p< 0.0001), a feature observed in dormancy3. Further, the administration of 5 M 4-HT induced a cessation of growth in the parental cell line, with a sub-population of apparent dormant cells. The combination of Lenvatinib (5 M) and 4-HT (7.5 M) synergistically inhibited both the parental cell lines by ~60%. Lenvatinib (5 M) and 4-HT (15 M) inhibited the MB-134TAMR and SUM44TAMR cell lines synergistically by 65% and 45% respectively. In vivo, the growth of MB-134 induced tumors were completely suppressed when 5mg sustained release pellet of TAM citrate was injected in the subscapular region of tumor bearing mice (tumor @100cm3). The results of the combination using in vivo models and 2D/3D cultures will be reported. Conclusion and significance: Lenvatinib with tamoxifen is active and synergistic against parental and TAMR ILC cell lines. Our novel 2D/3D cultures show distinct pattern of growth for ILC cells and a possible induction of a dormant subpopulation upon 4-HT treatment. Overcoming resistance to conventional therapies and preventing induction of dormancy will improve long-term outcomes of patients with ILC. 1. PMID:33641217 2. PMID: 34388695 3. PMID: 35121989 Citation Format: Bhuvaneswari Ramaswamy, Nikhil Pramod, Anagh Kulkarni, Xilal Y. Rima, Eduardo Reátegui, Eswar Shankar, Sarmila Majumder. Targeting receptor tyrosine kinases in overcoming tamoxifen resistance and dormancy in invasive lobular cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-24.

Optimization of Preparation Process and Pharmacokinetics of APAP Double-Release Pellet Capsules

In order to develop a kind of APAP double-release pellet capsules, which was prepared with the manual filling method, the immediate and sustained release pellets of a certain proportion were prepared by the fluidized bed coating and the extrusion spheroidization process, respectively. It was founded that both the prepared immediate-release pellets and sustained-release pellets had smooth and round surfaces. The particle size distribution ranged evenly from 16 to 35 mesh. Response surface plots showed that the optimal preparation prescription for immediate-release pellets were that ethanol concentration (X1) 70%, APAP 20%, MCC (X2) 40%, PVP K30 (X3) 20%, and sucrose pellet core 20%; and the optimal preparation prescription for sustained-release pellets were that HPMC concentration (X*3) 6.5%, APAP 30%, EC (X*1) 20%, MCC (X*2) 40%, PVP K30 4%, and lactose 6%. The results of pharmacokinetic analysis revealed that, after the APAP double-release pellet was orally administered, compared with that of conventional tablets, the plasma APAP levels in the blood circulation dramatically rose to significant peaks as a result of the quick and slow release of APAP from the capsules, which significantly prolonged the effective time of drugs in blood. Finally, immediate and sustained antipyretic-analgesic effects were obtained.

PS-BPB05-3: SERINE PROTEASE INHIBITION EXERTS AQUARETIC EFFECT AND DECREASES URINARY EXOSOMAL AQP2 LEVELS

Objective: Serine proteases (SPs) play pivotal roles in various physiological processes. In the kidney, it is reported that the epithelial sodium channel (ENaC) is activated via the proteolytic cleavage of α and γ subunits by SPs. We previously reported that a synthetic SP inhibitor camostat mesilate (CM) suppressed the cleavage of γENaC, thereby decreasing sodium reabsorption and blood pressure in aldosterone-infused rats. These results suggest the important roles of SPs within the kidney in the regulation of sodium homeostasis and blood pressure. Here, we aimed to identify novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors by administering CM into healthy rats. Design and method: Six-week-old male Sprague-Dawley rats were divided into control and CM groups. CM group rats were subcutaneously implanted with sustained-release pellets of CM (14 mg/day). After 24 h urine collection was performed, rats were sacrificed at day 7 to obtain blood and kidney samples. Urine volume was measured during the experimental period, and blood and urinary electrolytes, blood vasopressin, and renal tissue osmolality were measured. Protein expression of SPs and aquaporin-2 (AQP2) was analyzed by Western blotting. Results: CM significantly increased urine volume by approximately two-fold throughout the experimental period [urine volume (mL/day): control, 15.5 ± 2.4; CM, 30.6 ± 5.8], in a urinary sodium and osmolyte excretion-independent manner, which indicated that free water excretion had occurred. The vasopressin, potassium, and calcium levels in the blood and osmolality in the inner medulla, which affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting that the AQP2 activity was suppressed in the collecting duct. These changes were reversed by the infusion of desmopressin. Such water diuretic action caused by CM was independent of its action on prostasin and TMPRSS4, which are serine proteases associated with sodium and water homeostasis, respectively. Conclusion: Our results revealed the association of SP inhibition with free water diuresis in the kidney and demonstrated that CM administration resulted in the downregulation of AQP2. The current findings suggest that SP inhibitors could become a new class of aquaretic drugs.

Development of sinomenine hydrochloride sustained-release pellet using a novel whirlwind fluidized bed

The clinical application of Sinomenine hydrochloride (SH) oral solid formulation is limited due to its short half-life and gastrointestinal side effects. The novel whirlwind fluidized bed was first applied to develop the sustained-release pellet of SH, so as to mitigate the side effects. The formulation of drug-loaded layer was optimized by full factorial design. Additionally, Box–Behnken experimental design was used to optimize the operating parameters and the formulation of sustained-release layer. Compared to the conventional fluidized bed, the whirlwind fluidized bed significantly improved the quality of pellets. According to the design spaces, the yield of pellets and SH encapsulation efficiency were greater than 96% and 90%, respectively. The in vitro release results demonstrated the sustained-release time was over 12 h and the dissolution behavior of different batches of samples was stable. Findings in current study suggest that the whirlwind fluidized bed is a promising approach to develop pellets.

Formulation and Evaluation of Sustained Release Pellets of Verapamil HCL

Verapamil Hydrochloride, an antihypertensive agent which is used as a calcium channel blocker. The aim of the present study was to formulate and evaluate Verapamil HCL sustained release pellets. The work is to obtain Verapamil HCL sustained release pellets by using HPMC based polymers i.e., HPMC AN6, HPMC E5, HPMC E15 in the sustained release layer. The verapamil Hydrochloride has pH-dependent solubility. To overcome the pH dependent solubility Fumaric acid was used that which provides micro-acidic environment. Different Ratios of Ethyl-cellulose and HPMC polymers were used to optimise and evaluate the formulation for the sustained release of the drug. It uses the Pelletization technology. This technique is practised to produce pellets of uniform size with high drug loading capacity and also to prevent the segregation and dust.

Studies on Almond Gum and Gelucire-Based Pellets Prepared by Extrusion and Spheronization for Sustained Release.

The aim of the investigation was to prepare sustained release (SR) pellets of diltiazem hydrochloride employing almond gum and gelucire. The study was performed to explore the suitability of almond gum in the preparation of pellets of diltiazem hydrochloride without the use of microcrystalline cellulose and role and effectiveness of hydrophobic gelucire (43/01) in controlling the drug release. Pellets were prepared by extrusion-spheronization of the blend previously obtained by incorporation of the drug in a mixture of melted gelucire 43/01 and almond gum. A 32 factorial design was employed to study the effect of two independent variables, almond gum and gelucire, on the size, friability and drug release from pellets. Scanning electron microscopy, differential scanning calorimetry and infrared spectroscopy were performed to characterize pellets. Free flowing spherical pellets could be prepared. The 32 factorial study revealed that as the proportion of almond gum increased, the size of pellets increased, while increasing gelucire had opposite effect. The yield of pellets prepared in different formulations is in the range of 86 to 92%. The size of the pellets varied from 1128 to 1458 μ. Higher amounts of gelucire resulted in pellets with greater friability, whereas increasing the amount of almond gum yielded pellets with low friability. The pellets exhibited SR of diltiazem and the presence of gelucire in the matrix of the pellets had an enhanced sustaining effect on release. Dispersion of the drug in gelucire before it was converted to pellets resulted in extended release of drug. The drug release rate changed with changes in the proportion of pellet composition. The results of the study suggest that employing gelucire (43/01) in the preparation of pellets is a useful approach in the design of SR products of highly water-soluble drug such as diltiazem hydrochloride.

Camostat mesilate, a serine protease inhibitor, exerts aquaretic effects and decreases urinary exosomal AQP2 levels

Serine proteases (SPs) play physiological roles in the kidney. We previously reported that a synthetic SP inhibitor, camostat mesilate (CM), suppressed sodium reabsorption in the renal tubule and showed natriuretic effects in aldosterone-infused rats. Here, we aimed to explore novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors, by administering CM to healthy rats. Sprague–Dawley rats were classified into control and CM (subcutaneous sustained-release pellet) groups and sacrificed on day 7. CM significantly increased urine volumes by approximately two-fold in a urinary sodium- and osmolyte excretion-independent manner, indicating the occurrence of free water excretion. Serum vasopressin, potassium, and calcium levels and the osmolality in the renal medulla, which all affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting suppression of AQP2 activity in the collecting duct. These changes were reversed by desmopressin infusion. Water diuresis caused by CM was independent of its action on prostasin or TMPRSS4. Our results revealed the association of SP inhibition with free water handling and demonstrated that CM administration exerted diuretic effects with AQP2 downregulation, suggesting SP inhibitors as a new class of aquaretic drugs.

Formulation Development of Sustained Release Matrix Pellets Compressed into Unit Dosage Form

>Any drug delivery system’s main objective is to consistently deliver the desired drug concentration in the blood or tissues, which is therapeutically beneficial and non-toxic. The spherical, free-flowing granules known as pellets increase bioavailability, lower the risk of dose dumping and local gastrointestinal discomfort, regulate drug release, and boost absorption of the medicine. A second-generation sulfonylurea called gliclazide is used to treat non-insulin-dependent diabetic mellitus (NIDDM). This study’s objectives were to construct a flexible dosage form with controlled release and look into how process parameters affected the procedure. To find the batch of pellets that provided a sustained release pattern for the drug gliclazide, several batches of pellets manufactured using the extrusion spheronization process and the design of experiment (DoE) approach were used. Due to their roundness, the pellets had excellent flow characteristics, which affected the dosage production rate. They also had small particles that could be easily dispersed and helped prevent dosing. The release rate of the pellets was 99.3% after 12 hours. With superior medication release control, the study completes the development of sustained-release pellets, minimizing issues with the conventional tablet administration form.