Effects of Enteric-Coated Formulation of Sodium Bicarbonate on Bicarbonate Absorption and Gastrointestinal Discomfort.

Sodium bicarbonate is used as an ergogenic supplement to enhance people's performances in various exercises. This study aimed to evaluate the effects of intestinal delivery of sodium bicarbonate on bicarbonate absorption and associated side effects in an experimental human trial. After preparing and assessing enteric-coated and uncoated sodium bicarbonate tablet formulations, pharmacokinetic analysis and gastrointestinal symptom tests were performed after oral administration in the human body. The dose required to increase blood bicarbonate concentration over 5 mmol∙L-1 for the purpose of improving performance during high-intensity exercise was also determined. Enteric-coated tablet formulation protects sodium bicarbonate under acidic conditions and releases bicarbonate in the intestine. Enteric-coated tablet formulation also reduced the oral dose required to achieve a blood bicarbonate concentration over 5 mmol∙L-1 from 300 mg∙kg-1 of uncoated tablet formulation to 225 mg∙kg-1. Gastrointestinal discomfort was significantly decreased for the group given 225 mg∙kg-1 enteric-coated tablets compared to that given 300 mg∙kg-1 uncoated tablets. These results suggest that enteric-coated tablet formulation could reduce the oral dose required in order to achieve a blood bicarbonate concentration over 5 mmol∙L-1 by 25%, from 300 mg∙kg-1 to 225 mg∙kg-1, along with its ability to reduce gastrointestinal discomfort associated with the dosage.

Bicarbonate buffer dissolution test with gentle mechanistic stress for bioequivalence prediction of enteric-coated pellet formulations.

This study aimed to develop a dissolution test that can predict the bioequivalence (BE) of enteric-coated pellet formulations. The original duloxetine hydrochloride capsule (reference formulation (RF); Cymbalta® 30 mg capsule) and four generic test formulations (two capsules (CP) and two orally disintegrating tablets (OD)) were used as model formulations. Clinical BE studies were conducted on 24-47 healthy male subjects under fasting conditions. Dissolution tests were performed using a compendial paddle method (PD) (paddle speed: 50 rpm) and a flow-through cell method (FTC) (flow rate: 4 mL/min). For a further test, cotton balls were added to the vessel to apply gentle mechanistic stress to the formulations, and paddle speed was reduced to 10 rpm (paddle with cotton ball method (PDCB)).All the dissolution tests were conducted with 0.01 M HCl (pH 2.0) for 0.5 h followed by 10 mM bicarbonate buffer solutions (pH 6.5) for 4 h. One each of the two CP and two OD showed BE with RF. PDCB was able to discriminate between BE and non-BE formulations, while this was not possible with PD and FTC. In PDCB, the cotton balls intermittently moved the pellets near the vessel bottom. PDCB is useful for predicting BE during formulation development.

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough.

INTRODUCTION: Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test. DISCUSSION: This study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition. TRIAL REGISTRATION: Our study was registered in the Chinese Clinical Trials Register ( www.chictr.org.cn/ ) (ChiCTR2000037429) in 28/08/2020.

Bioequivalue of two mycophenolate sodium enteric-coated tablets and the drug monitoring based on limited sampling strategy: A single-center, randomized, open-label, three-period, reference-replicated, crossover study.

OBJECTIVE: A mycophenolate sodium enteric-coated tablet has shown a satisfying anti-rejection effect in patients receiving solid organ transplantation. The current study evaluated the bioequivalence between the test (Ruiyirong®) vs. reference (Myfortic®) formulations by exploring equations for predicting their area under the concentration-time curve (AUC) using a limited sampling strategy in healthy subjects. METHODS: Forty-eight healthy Chinese subjects were randomized into three administration sequences (test-reference-reference, reference-reference-test, and reference-test-reference) to receive the Ruiyirong or Myfortic treatment on days 1, 8, and 15. RESULTS: The 90% confidential interval (CI) of the geometric mean ratios (test/reference) of maximum plasma concentration (Cmax), the AUC from time 0 to the last timepoint (AUC0-t), and the AUC from 0 to infinity (AUC0-∞) was 92.90%-110.57%, 96.91%- 101.80%, and 96.71%-101.84%, respectively. All these values fell into the bioequivalence criteria of 80.00%-125.00% (based on the criteria of the Food and Drug Administration). The adverse events were 10.4% in Ruiyirong test group and 14.6% in Myfortic reference group. Eight equations for estimating the AUC of the Ruiyirong test and Myfortic reference formulations were evaluated; most of them worked well with the R-value >0.8. Among the four chosen equations, the intragroup verification exhibited a high agreement with the R-value ranging from 0.857 to 0.971 and with the low predictive error (PE > 5% with absolute PE > 15%). Meanwhile, the intergroup verification indicated a high inter-agreement with the R-value ranging from 0.896 to 0.974 (all P < 0.001). CONCLUSION: The Ruiyirong test vs. Myfortic reference formulations meet the bioequivalent criteria and are well tolerated. The further linear regression analysis explores eight equations predicting the AUC value and the chosen four equations for the Ruiyirong test and Mayfortic reference formulations are interchangeable.

Pharmacokinetic Study of Enteric-Coated Sustained-Release Aspirin Tablets in Healthy Chinese Participants.

Purpose: To study and compare the pharmacokinetic characteristics of enteric-coated sustained-release (EcSr) aspirin tablets with enteric-coated (Ec) aspirin tablets (Bayer S.p.A) in healthy Chinese participants. Patients and Methods: In this open, randomized, single-dose, three-way, crossover study, 18 healthy participants randomly received 100 mg EcSr tablets pre-prandially (a.c.), EcSr tablets post-prandially (p.c.), or Ec tablets a.c. in each period. The concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in plasma were determined by the LC-MS/MS method, and the pharmacokinetic parameters were calculated using WinNonlin (version 8.1). Results: The essential PK parameters under the three treatment conditions (ie Ec a.c., EcSr a.c. and EcSr p.c.) were as follows: Cmax, ASA: 758.38±455.34, 222.77±98.04 and 194.54±61.19 ng, Tmax, ASA: 6.75(2,16), 4.5(2,11) and 8.25(5,11) h, T1/2, ASA: 0.43±0.08, 1.44±0.59 and 4.32±10.04 h, AUC0-t, ASA: 1008.88±452.27, 918.04±238.40 and 845.55±183.25 h·ng/mL; Cmax, SA: 6409.38±2098.52, 2863.53±679.73 and 2913.75±853.27ng/mL, Tmax, SA: 7.25(2,24), 10(3.5-14) and 10(7,14) h, T1/2, SA: 2.21±0.46, 2.69±0.72 and 3.51±2.06h, AUC0-t, SA: 29,131.41±9376.23, 27,243.97±7465.16, 27,240.25±7444.67 h·ng/mL. When taking EcSr aspirin tablets, the 90% confidence intervals of the geometric mean ratios (pre-prandial/post-prandial) of AUC0-t, ASA and AUC0-∞, ASA, Cmax, SA, AUC0-t, SA and AUC0-∞, SA were within the range of 80.00%-125.00%. Conclusion: EcSr aspirin tablets showed less inter-individual variation in release and absorption than Ec aspirin tablets, which was well reflected by comparing essential PK parameters. Furthermore, meals had no significant effect on the pharmacokinetics of EcSr aspirin tablets.

The effect of particle size on the sublimation behavior of butylhydroxytoluene as antioxidant in tablets during storage and coating.

The effect of particle size on the sublimation behavior of butylhydroxytoluene (BHT) was investigated when BHT was included as antioxidant in tablets. Sublimation of pure BHT was found to be independent of its particle size, with pore formation on the surface of all tablets after storage at room temperature and above. Moreover, a higher residual BHT content after storage was detected in tablets containing a larger size fraction. X-ray µCT scans revealed the formation of peripherally larger pores at higher BHT particle sizes, implying a slower sublimation rate in the tablet core. A stability study indicated an increase in the extent of BHT sublimation at higher temperature and longer exposure time for all size fractions. The influence of BHT particle size was more pronounced when the tablets were stored at higher temperature, but the effect receded with longer exposure time. Similar trends were seen in film-coated tablets. Due to the short exposure time to elevated temperatures, a gradient in pore size was also observed at smaller particle sizes, with peripheral pores being larger in uncoated tablets. Superficial pores disappeared when a film coating was deposited onto the tablets. After storage of the film-coated tablets, less BHT had sublimated compared to the uncoated tablet. The coating layer did not prevent sublimation, but the process was slowed down.

Pharmacokinetics, Bioequivalence, and Safety of Esomeprazole Magnesium Enteric-Coated Capsules in Healthy Chinese Subjects.

This bioequivalence study is critically important for drug production. Recently, a local pharmaceutical company produced esomeprazole magnesium enteric-coated capsules, a major drug to help to eradicate Helicobacter pylori, but the bioequivalence is not well known. The present study aimed to evaluate the bioequivalence of the 2 esomeprazole magnesium enteric-coated capsules and their pharmacokinetics and safety in 3 biological equivalence trials: fasting, feeding, and mixing. The fasting and mixing trials used single-centered randomized, open-label, single-dose, 2-treatment, 2-period, and 2-sequence crossover design, while the fed trials used single-centered, randomized, open-label, single-dose, 2-treatment, 3-period, 3-sequence partial crossover design. For the fasting and mixing trials, each of the 32 subjects was fasted overnight prior to taking the test preparations or reference preparations. In the fed trial, 54 subjects were given a high-fat meal 1 hour before the drugs were administered. Blood specimens from all subjects were collected against the light within 14 hours, with the plasma drug concentration being detected by the validated ultra-performance liquid chromatography-tandem mass spectrometry analysis method. Geometric mean ratio of maximum concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and area under the concentration-time curve from time zero to infinity with 90% confidence interval were calculated. The data from fasting, mixing, and fed trials met the bioequivalence criteria. No serious adverse reactions were found, suggesting that the test and reference preparations of esomeprazole magnesium enteric capsules have similar safety profile.

A Novel Alginate Film Based on Nanocoating Approach for Enteric-Release Tablets.

The objective of this study was to propose a new coating film for biodegradable polymers and environmentally friendly processing. Here, a novel implementation of solid lipid nanoparticles (SLN) into a biodegradable alginate (ALG) film composition created a new gastric-resistant film for an enteric-release tablet. Experiments were performed on a water-soluble substance (thiamine nitrate) to characterize the effects of SLN upon the addition of the ALG coating formulation. The coated tablets or cast films were characterized based on delayed-release properties, surface morphology, moisture resistance, and chemical interactions. The SLN-ALG film displayed gastric-resistant properties (< 10% drug substance dissolved at pH 1.2) and rapid disintegration in the intestinal medium (pH 6.8). Morphological analysis using a microscope and scanning electron microscope confirmed the uniformity and smoothness of the SLN-ALG film, which improved the mechanical properties of the film. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated that SLN contributed to the formation of the film, which maintained free carboxylic groups, making the SLN-ALG film a higher acid resistance, but soluble in pH 6.8 buffer. These promising results suggest a novel nanotechnology-based coating formulation for various enteric-release dosage forms. Because of their biodegradability, the proposed ingredients and processes are safe and environment-friendly.

Safety, tolerability, pharmacokinetic/pharmacodynamic characteristics of bersiporocin, a novel prolyl-tRNA synthetase inhibitor, in healthy subjects.

Bersiporocin, a novel first-in-class prolyl-tRNA synthetase (PRS) inhibitor currently under clinical development, was shown to exert an antifibrotic effect through the downregulation of collagen synthesis in various pulmonary fibrosis models. The aim of this first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-dose, dose-escalation study was to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bersiporocin in healthy adults. A total of 40 and 32 subjects were included in a single- (SAD) and multiple-ascending dose (MAD) study, respectively. No severe or serious adverse events were observed after a single oral dose up to 600 mg and multiple oral doses up to 200 mg twice daily for 14 days. The most common treatment-emergent adverse events were gastrointestinal adverse events. To improve the tolerability, initial bersiporocin solution was changed to the enteric-coated formulation. Afterward, the enteric-coated tablet was used in the last cohort of SAD and in the MAD study. Bersiporocin showed dose-proportional PK characteristics after a single dose up to 600 mg and multiple doses up to 200 mg. Upon reviewing the safety and PK data, the final SAD cohort (800 mg enteric-coated tablet) was canceled by the Safety Review Committee. The levels of pro-peptide of type 3 procollagen were lower after treatment with bersiporocin than after the placebo in the MAD study, whereas no significant change was observed in other idiopathic pulmonary fibrosis (IPF) biomarkers. In conclusion, the safety, PK, and PD profile of bersiporocin supported its further investigation in patients with IPF.

Predicting mini-tablet dissolution performance utilizing X-ray computed tomography.

Mini-tablets (MTs) have been utilized as an alternative to monolithic tablets due to their ease of use for pediatric populations, dose flexibility and tailoring of drug release profiles. Similar to monolithic tablets, MTs can develop film coat and internal core defects during manufacturing processes that may adversely affect their dissolution performance. The use of x-ray computed microtomography (XRCT) is well documented for monolithic tablets as a means of identifying internal defects, but applications to MTs have not been well studied. In this study, we have developed a workflow that analyzes reconstructed XRCT images of enteric-coated mini-tablets using deep learning convolutional neural networks. This algorithm was utilized to extract key physical features of individual MTs, such as micro-crack volume and enteric coat thickness. By performing dissolution studies on individual MTs, correlations were established based on the physical parameters obtained by XRCT and the dissolution performance, enabling prediction of dissolution performance utilizing non-destructive imaging data. This workflow provides insight into the physical variability of MT populations that are generated during manufacturing, enabling optimization of critical tableting and coating parameters to achieve the target dissolution criteria. Through this mechanistic understanding, quality is built into the final drug product through rational development of formulation and process parameters.

New HPLC pattern-oriented approach for quality control of enteric coated tablets containing aescin from Aesculus hippocastanum.

From the seed of Aesculus hippocastanum L., a complex mixture of triterpene saponin glycosides known as aescin was isolated, purified and characterized to be an active pharmaceutical ingredient for preparing of drug products. A reversed phase high performance liquid chromatographic method with UV detection was developed for the determination of total triterpene glycosides in enteric coated tablets containing aescin in a pattern-oriented manner. The mobile phase consisted of a mixture of acetonitrile and 0.1 % phosphoric acid solution (40: 60). UV detection was performed at 220 nm. The chromatographic column was Gemini C18 column, 5 µm 250 mm × 4.6 mm, which was maintained at 25 ◦C, connected with a precolumn (C18, 4.0 × 3.0 mm, 5 µm). The linear range was from 53.4 to 160.1 µg·mL-1. The RSD of intra-and inter-day precision variations were less than 1 % and the mean recovery was (100.66 ± 0.49) % (RSD = 0.64 %). The method showed its suitability, simplicity, rapidity and precision. Accordingly, it was proven adequate for quality control of this herbal drug product either for registration with the regulartory authority or routine analysis.

Effects of Quadruple Therapy Combined with Probiotics on Helicobacter Pylori-Related Peptic Ulcer.

The present study was designed to observe the effect of quadruple therapy combined with probiotics on Helicobacter pylori-related peptic ulcer. The patients in the control group (n = 90) were given regular quadruple therapy including proton pump inhibitor ilaprazole enteric-coated tablet + two antibiotics amoxicillin dispersible tablet and metronidazole tablet + colloidal bismuth pectin capsule for 2 weeks. Patients in the study group (n = 90) were given abovementioned quadruple therapy combined with probiotics live combined Bifidobacterium, Lactobacillus, and Enterococcus Capsules, oral for 2 weeks. Then Hp clearance rate, recurrence rate, levels of gastrointestinal hormone makers, and advance reactions between two groups were compared. At the 2nd week after the treatment, the Helicobacter pylori clearance rate in the study group (87.79%) was significantly higher than the control group (78.89%), and the total recurrence rate in the study group (6.67%) was significantly lower than the control group (13.33%) (P < 0.05). Serum gastrin and motilin expression were lower, and somatostatin expressions was significantly higher than those in the control group (P < 0.05). There was no significant difference in the total incidence of adverse reactions between the two groups (P > 0.05). In summary, quadruple therapy combined with probiotics in the treatment of Helicobacter pylori-related peptic ulcer can improve the Helicobacter pylori clearance rate, reduce the Helicobacter pylori recurrence rate, and is beneficial to improving the level of gastrointestinal hormones, with certain safety.

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area.

Objective: Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods: Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30-60 mg·h/L). Results: A total of 96 pediatric patients aged at 13.3 (range 4.3-18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6-18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22-0.46 m2, 180 mg every 24 hours with BSA of 0.47-0.67 m2, 180 mg every 24 hours with BSA of 0.68-0.96 m2, 360 mg every 24 hours with BSA of 0.97-1.18 m2, 540 mg every 24 hours with BSA of 1.19-1.58 m2, and 360 mg every 12 hours with BSA of 1.59-2.03 m2. Conclusion: BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m2 is warranted.

Development of a particle swarm optimization-backpropagation artificial neural network model and effects of age and gender on pharmacokinetics study of omeprazole enteric-coated tablets in Chinese population.

BACKGROUND: The effects of age and gender were explored on pharmacokinetics study of omeprazole enteric-coated tablets in Chinese population and a plasma concentration prediction model was developed. All the data (demographic characteristics and results of clinical laboratory tests) were collected from healthy Chinese subjects in pharmacokinetics study using 20 mg omeprazole enteric-coated tablets. A noncompartmental method was used to calculate pharmacokinetic parameters, and 47 subjects were divided into two groups based on the calculation of the median age. Pharmacokinetic data from the low-age and high-age groups or male and female groups were compared by Student t-test. After a total of 12 variables were reconstruct and convert into independent or irrelative variables by principal component analysis, particle swarm optimization (PSO) was used to construct a backpropagation artificial neural network (BPANN) model. RESULT: The model was fully validated and used to predict the plasma concentration in Chinese population. It was noticed that the Cmax, AUC0-t, AUC0-∞ and t1/2 values have significant differences when omeprazole was administered by low-age groups or high-age groups while there were slight or no significant differences of pharmacokinetic data were found between male and female subjects. The PSO-BPANN model was fully validated and there was 0.000355 for MSE, 0.000133 for the magnitude of the gradient, 50 for the number of validation checks. The correlation coefficient of training, validation, test groups were 0.949, 0.903 and 0.874. CONCLUSION: It is necessary to pay attention to the age and gender effects on omeprazole and PSO-BPANN model could be used to predict omeprazole concentration in Chinese subjects to minimize the associated morbidity and mortality with peptic ulcer. TRIAL REGISTRATION: The study was registered in China Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn ), the registration number was CTR20170876, and the full date of registration was 04/AUG/2017.

Population pharmacokinetics and IVIVC for mesalazine enteric-coated tablets.

Although in-vivo bioequivalence (BE) study serves as a golden standard for establishing interchangeability of oral dosage forms, it remains challenging for products with high inter-subject variability such as mesalazine enteric-coated tablet to fulfil the BE criteria set by regulatory authorities. Mesalazine, as a BCS class IV drug, targets to be delivered to distal ileum or colon with a pH-sensitive polymer coating for the remission of ulcerative colitis. Through population pharmacokinetic (PK) analysis and in-vitro in-vivo correlation (IVIVC) modeling on the dissolution and BE data of a generic enteric-coated product (EM) and its reference Salofalk® 250 mg tablet (SM), we for the first time revealed the underlying mechanism of the high inter-subject variability for such delayed-release formulation. It was also noted that the in-vivo start time of absorption (Ts) for EM and SM was positively correlated with their in-vitro lag time (Tlag) under the USP three-stage dissolution condition and reversely correlated with their in-vivo bioavailability. The varied oral bioavailability of mesalazine enteric-coated tablet was mainly due to the varied N-acetyltransferase activities along GI tract. Although such extensive intestinal first-pass metabolism with large individual differences led to a significant variation of mesalazine Cmax (coefficient of variation: 60-63.5%) and AUC0-t (coefficient of variation: 37.5-46.9%), the corresponding variations in the total absorbed mesalazine (mesalazine and its metabolite N-acetyl mesalazine) were significantly reduced by 12 to 45%. Since the BE purpose for mesalazine enteric-coated tablet focused on their comparable safety profiles, total absorbed mesalazine was recommended to be adopted for the development of the IVIVC model and BE evaluation for EM. All in all, our model-based approach has not only successfully identified the key factors that affect the BE of EM to guide its further formulation optimization, but also demonstrated the indispensable role of modeling in the development of generic pharmaceutical product at its early stages.

Ascertain a minimum coating thickness for acid protection of enteric coatings by means of optical coherence tomography.

Enteric coatings are designed to protect active pharmaceutical ingredients (APIs) against untimely release in the stomach. Acid protection of such coatings depends on the coating layer thickness and integrity, which must be determined in an accurate and reliable way to ensure the final product's desired performance. Our work addresses the use of optical coherence tomography (OCT) for characterizing the coating thickness and variability of an enteric-coated drug product and linking them to resistance against gastric fluid. In this study, three batches of enteric-coated tablets drawn during the manufacturing process were investigated. An industrial OCT system was used to establish the coating thickness variability of single tablets (intra-tablet), all tablets in a batch (inter-tablet) and between the batches (inter-batch). Based on the large amount of OCT data, we calculated a critical coating thickness for the investigated film coating, which was found to be 27.4 µm. The corresponding distribution has a mean coating thickness of 44.3 µm ± 7.8 µm. The final coated product has a final mean coating thickness of 63.4 µm ± 8.7 µm, guaranteeing that all tablets meet the quality criterion (i.e., acid protection). Based on the measured thickness distributions, already known distribution functions were considered and an additional, new function was proposed for characterizing the coating thickness distributions in the early stages of industrial coating processes. The proposed approach can be transferred to in-line monitoring of the tablet coating processes, which could drastically improve the production efficiency by ultimately allowing real-time release testing (RTRT).

Visualising liquid transport through coated pharmaceutical tablets using Terahertz pulsed imaging.

Dissolution of pharmaceutical tablets is a complex process, especially for coated tablets where layered structures form an additional barrier for liquid transport into the porous tablet matrix. A better understanding of the role of the coating structure in the mass transport processes that govern drug release, starting with the wetting of the coating layer by the dissolution medium, can benefit the formulation design and optimisation of the production. For this study, terahertz pulsed imaging was used to investigate how dissolution medium can penetrate coated tablets. In order to focus on the fundamental process, the model system for this proof-of-principle study consisted of tablet cores made from pure microcrystalline cellulose compacted to a defined porosity coated with Opadry II, a PVA-based immediate release coating blend. The coating was applied to a single side of flat-faced tablets using vacuum compression moulding. It was possible to resolve the hydration of the coating layer and the subsequent liquid ingress into the dry tablet core. The analysis revealed a discontinuity in density at the interface between coating and core, where coating polymer could enter the pore space at the immediate surface of the tablet cores during the coating process. This structure affected the liquid transport of the dissolution medium into the core. We found evidence for the formation of a gel layer upon hydration of the coating polymer. The porosity of the tablet core impacted the quality of coating and thus affected its dissolution performance (r =  0.6932 for the effective liquid penetration rate RPeff and the core porosity). This study established a methodology and can facilitate a more in-depth understanding of the role of coating on tablet dissolution.

Pharmacokinetics and food impact assessment of ademetionine enteric-coated tablet as an endogenous substance drug in healthy Chinese volunteers.

WHAT IS KNOWN AND OBJECTIVES: Ademetionine 1,4-Butanedisulfonate (SAMe) enteric-coated tablets are widely used for treatment of pre-cirrhotic and cirrhotic intrahepatic cholestasis, as well as intrahepatic cholestasis of pregnancy (ICP), but incomplete clinical data and interference from endogenous substances pose numerous challenges for clinical trial of ademetionine. The objective of this study was to evaluate the pharmacokinetic profile of SAMe enteric-coated tablets and to assess its food impact and safety in healthy Chinese subjects. METHODS: A randomized, open-label, single-dose study was carried out to determine the pharmacokinetics of SAMe enteric-coated tablets administered in both fasted and postprandial conditions. Baseline collection and data adjustment were required to reduce the effect of endogenous substances. Relevant pharmacokinetic data from subjects administered the reference formulation will be disclosed and utilized in this thesis. RESULTS: Twenty-four subjects with a body mass index (BMI) of 19-24 kg/m2 were enrolled in the study and all completed the trial. The impact of food on the drug was noticeable, with faster absorption in the fasting group (Tmax , 4.50 ± 1.07 and 7.50 ± 1.58 for the fasting and postprandial groups, respectively) but higher exposure in the postprandial group (AUC0-inf , 4021.02 ± 3377.13 and 5087.28 ± 3539.26 for the fasting and postprandial groups, respectively). No serious adverse effects were observed in the fasted and postprandial conditions. WHAT IS NEW AND CONCLUSIONS: The pharmacokinetic profile of SAMe enteric-coated tablets in healthy Chinese subjects was partially complemented in this study. SAMe enteric-coated tablets showed promising safety in fasted and postprandial conditions. However, the impact of food on the drug was significant and might access to the absorption site and affect biochemical reactions.

Going green: Development of a sustainable lipid-based enteric coating formulation for low-dose aspirin multiparticulate systems.

There is a rising awareness of pharmaceutical industry of both patient-centric and sustainable product development. Manufacturing of multiparticulate systems (MPS) with functional coating via solvent-free hot melt coating (HMC) can fulfill both requirements. An innovative lipid-based formulation was developed with the composition of palmitic acid and Grindsted® citrem BC-FS (BC-FS) for enteric coating of acetylsalicylic acid (ASA). The ASA crystals were directly hot melt coated to produce user-friendly low-dose ASA MPS for thromboembolism prophylaxis. Prior to HMC, rational boundaries for the process temperature were defined based on the melting and crystallization behavior of coating blend. Stability of coating in terms of resistance to heat stress and solidstate stability were screened via Fourier-transform infrared spectroscopy and x-ray diffraction. Exposure of coating blend to 100 °C for two hours did not cause any chemical degradation. Crystal growth of palmitic acid and polymorphic transformation in BC-FS were observed after storage under accelerated conditions, however did not significantly affect the ASA release from coating. The developed formulation is a unique solvent-free, lipid-based enteric composition and paves the way for sustainable green pharmaceutical manufacturing.

Pharmacokinetic and Pharmacodynamic Profile of a Novel Phospholipid Aspirin Formulation.

Aspirin is one of the most widely used medicines. Although aspirin is commonly utilized for the treatment of several medical conditions, its broadest uptake is for the prevention of recurrent ischemic events in patients with atherosclerotic disease. Its mechanism of action of inhibiting platelet activation via blockade of thromboxane A2 production is unique and is not covered by any other antiplatelet agents. While plain, uncoated, immediate-release aspirin is used in acute settings to help assure rapid absorption, enteric-coated aspirin formulations dominate current chronic use, particularly in North America, including for secondary prevention of cardiovascular events. The unmet needs with current aspirin formulations include a high risk of gastrointestinal (GI) adverse events with plain aspirin, which enteric-coated formulations are not able to overcome, and subject to erratic absorption leading to reduced drug bioavailability. These observations underscore the need for aspirin formulations with a more favorable safety and efficacy profile. Phospholipid-aspirin complex (PL-ASA) is a novel formulation designed to address these needs. It is associated with reduced local acute GI injury compared with plain aspirin, and predictable absorption resulting in more reliable platelet inhibition compared with enteric-coated tablets. This review explores the rationale and pharmacologic profile of PL-ASA intended to address the unmet needs for aspirin therapy.