Gelatin Capsules Research Articles

Case Study on Regulatory Approaches for New Degradation Impurity Exceeding ICH Thresholds in Solubilized Ibuprofen Capsules During Stability Testing

The article discusses the identification, isolation, characterization, and toxicology study of a new degradation impurity found in stability samples of Ibuprofen soft gelatin capsules. An unknown impurity was detected during stability analysis, reaching 0.28% level, which prompted further investigation. A preparative method was developed to isolate the impurity quickly, followed by its identification and characterization using spectroscopic techniques. The impurity, named 2,3-dihydroxxypropyl 2-(4-isobutylphenyl)propanoate, was confirmed through various analyses, including HPLC, LC-MS, NMR, and FT-IR. Forced degradation studies suggested that the impurity formation might be due to the reaction of Ibuprofen with Glycerin present in the product. Toxicology studies were conducted to evaluate the safety of Ibuprofen with the impurity, concluding that it posed no significant toxicity concerns. Based on the findings, a specification limit of not more than 0.3% for the impurity was proposed, supported by justification from various studies and guidelines. To the best of our knowledge, this impurity has not been reported in pharmaceuticals elsewhere; it can be helpful in the pharmaceutical industry for regulatory considerations. This would enhance the pharmaceutical industry's perspectives on unknown impurities and knowledge of degradation impurities, which would positively impact pharmaceutical companies' approaches.

Preparation and evaluation of soft gelatin capsules loaded with astaxanthin, niacin and garlic oil for removal of plague in atherosclerosis

Atherosclerosis, a chronic inflammatory disease, is the leading cause of cardiovascular diseases. In atherosclerosis, the arterial walls are characterized by plaque deposits on the inside of arteries. This study focuses on preparing a fill formulation to remove plaque in atherosclerosis, then analyse the pharmaceutical ingredients used and later produce soft gelatin capsules. Soft gelatin capsules are hermetically sealed, one-piece capsule which has a suspension or semi-solid as fill. Oxidative stress and inflammation are factors responsible for the development of atherosclerosis. Hence, the active pharmaceutical ingredients (APIs) chosen for fill formulation need to possess effective anti-oxidant and anti-inflammatory properties. A novel combination of APIs: Astaxanthin, Niacin and Garlic oil were chosen for the removal of plaque in atherosclerosis. Each of these APIs is known to possess a specific function in the control of plaque development. The fill formulation prepared was analysed for its recovery using various analytical techniques like UV spectrophotometry, high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). This fill formulation was encapsulated within the gelatin shell prepared to produce soft gelatin capsules. The encapsulated soft gelatin capsules were evaluated based on various parameters which include average net weight, disintegration test, loss on drying and dissolution.

Suppression of the postprandial hyperglycemia in patients with type 2 diabetes by a raw medicinal herb powder is weakened when consumed in ordinary hard gelatin capsules: A randomized crossover clinical trial.

Contradictory claims about the efficacy of several medicinal plants to promote glycemic control in patients with type 2 diabetes mellitus (T2DM) have been explained by divergences in the administration form and by extrapolation of data obtained from healthy individuals. It is not known whether the antidiabetic effects of traditional herbal medicines are influenced by gelatin capsules. This randomized crossover trial aimed to evaluate the acute effect of a single dose of raw cinnamon consumed orally either dissolved in water as a beverage or as ordinary hard gelatin capsules on postprandial hyperglycemia (>140 mg/dL; >7.8 mmol/L) in T2DM patients elicited by a nutritionally-balanced meal providing 50 g of complex carbohydrates. Fasting T2DM patients (n = 19) randomly ingested a standardized meal in five experimental sessions, one alone (Control) and the other after prior intake of 3 or 6 g of crude cinnamon in the form of hard gelatin capsules or powder dissolved in water. Blood glucose was measured at fasting and at 0.25, 0.5, 0.75, 1, 1.5 and 2 hours postprandially. After each breakfast, its palatability scores for visual appeal, smell and pleasantness of taste were assessed, as well as the taste intensity sweetness, saltiness, bitterness, sourness and creaminess. The intake of raw cinnamon dissolved in water, independently of the dose, decreased the meal-induced large glucose spike (peak-rise of +87 mg/dL and Δ1-hour glycemia of +79 mg/dL) and the hyperglycemic blood glucose peak. When cinnamon was taken as capsules, these anti-hyperglycemic effects were lost or significantly diminished. Raw cinnamon intake did not change time-to-peak or the 2-h post-meal glycaemia, but flattened the glycemic curve (lower iAUC) without changing the shape that is typical of T2DM patients. This cinnamon's antihyperglycemic action confirms its acarbose-like property to inhibit the activities of the carbohydrate-digesting enzymes α-amylases/α-glucosidases, which is in accordance with its exceptionally high content of raw insoluble fiber. The efficacy of using raw cinnamon as a diabetes treatment strategy seems to require its intake at a specific time before/concomitantly the main hyperglycemic daily meals. Trial registration: Registro Brasileiro de Ensaios Clínicos (ReBEC), number RBR-98tx28b.

Esophageal transit of solid oral dosage forms – impact of different surface materials characterized in vitro and in vivo by MRI in healthy volunteers

Acceptable swallowability and complete esophageal transit are decisive for the safe and effective administration of solid oral dosage forms. This applies in particular to the main user group of medicines, older adults, who often suffer from swallowing difficulties. It is well known that surface properties play an important role in this respect. In the past, this has led to the development of numerous coating formulations for tablets with improved swallowability. However, in vitro and especially in vivo data investigating a positive effect of different coating materials is limited. Therefore, we investigated coating materials being based on polyvinyl alcohol, hydroxypropyl methylcellulose, and a copolymer of methacrylate in respect to their influence on swallowability and esophageal transit of a tablet formulation. They were compared to uncoated tablets as well as to hard gelatin capsules. Three in vitro assays suitable for routine use in pharmaceutical development were performed: i.) Wettability test in artificial saliva; ii.) Swelling measurement in artificial saliva; iii.) Measurement of the adhesion between surface materials and a simulated mucosa surface. All three assays resulted in a differentiation of the surface materials. The coated tablets showed favorable behavior compared to uncoated tablets and hard gelatin capsules. To test the effect of the different materials in vivo, an intervention study was conducted. 36 adults were included and the likeliness of prolonged esophageal transit of (un-)coated tablets as well as a hard gelatin capsule of the same weight was objectively evaluated by means of magnetic resonance imaging. While hard gelatin capsules showed highest rates for prolonged esophageal transit, the tendency for adhesion was reduced for uncoated tablets, and least for coated tablets, i.e., prolonged esophageal transit in 22.2 %, 11.1 %, and ≤5.6 % of the cases, respectively. Further differentiation of the coating materials was not possible. Subjective evaluations of each participant with respect to subjective swallowability and esophageal transit did not correlate well with the objective measurements by means of magnetic resonance imaging. The use of coatings in general has a positive influence on esophageal transit. However, the selection of coating type seems to be of greater importance in respect to patients' oral perception of the dosage forms compared to their influence on the probability for prolonged esophageal transit.

Influence of Polymer Film Thickness on Drug Release from Fluidized Bed Coated Pellets and Intended Process and Product Control.

Coated drug pellets enjoy widespread use in hard gelatine capsules. In heterogeneous pellets, the drug substance is layered onto core pellets. Coatings are often applied to generate a retarded release or an enteric coating. In the present study, the thickness of a polymer coating layer on drug pellets was correlated to the drug release kinetics. The question should be answered whether it is possible to stop the coating process when a layer thickness referring to an intended drug release is achieved. Inert pellets were first coated with sodium benzoate and second with different amounts of water insoluble polyacrylate in a fluidized bed apparatus equipped with a Wurster inlet. The whole process was controlled in-line and at-line with process analytical technology by the measurement of the particle size and the layer thickness. The in-vitro sodium benzoate release was investigated, and the data were linearized by different standard models and compared with the polyacrylate layer thickness. With increasing polyacrylate layer thickness the release rate diminishes. The superposition of several processes influencing the release results in release profiles corresponding approximately to first order kinetics. The coating layer thickness corresponds to a determined drug release profile. The manufacturing of coated drug pellets with intended drug release is possible by coating process control and layer thickness measurement. Preliminary investigations are necessary for different formulations.

Moisture content determination along production line of ibuprofen soft gelatin capsule manufacturing by near infrared spectroscopy and ensemble deep neural networks

AbstractIn the manufacturing process of ibuprofen soft gelatin capsules, controlling moisture content at each production line stage, including in their components—gelatin, fill content, and shell—is vital to ensure quality and stability. This study developed and assessed an analytical method for rapid and non‐destructive moisture determination using near‐infrared spectroscopy (NIRS) coupled with deep neural networks (DNN) on all stages of the ibuprofen production line. The NIRS‐DNN classifier models were able to distinguish between the three components, achieving accuracy scores of up to 99%. The DNN models for moisture quantification also demonstrated high accuracy, with R2 values exceeding 0.997 across all production stages and prediction errors to those of previously reported models. A significant advantage of the NIRS‐DNN approach was its ability to maintain accuracy over a wide moisture concentration range, from 7% to 48%. The ensemble model, NIRS‐EDNN, seamlessly integrated classification and quantification, revealing its potential for real‐time process control in soft gel manufacturing. The comprehensive sampling approach ensured a diverse representation of moisture content, thereby enhancing the understanding of its impact on the final product stability, demonstrating that this methodology is potentially applicable to any soft gelatin capsule tracking worldwide.

The anti-inflammatory effect of a magnoliae cortex and Zea mays L. extract mixture in a canine model of ligature-induced periodontitis

BackgroundPeriodontitis is common in dogs. It is characterized by destruction of the supporting tissues of the teeth due to the host-immune response triggered by plaque. Magnoliae cortex and Zea mays L. extract showed anti-inflammatory and anti-microbial effects, respectively. This study aimed to evaluate improvement in periodontitis following the administration of Magnoliae cortex and Zea mays L. extract in dogs. Periodontitis was experimentally induced in 10 beagle dogs. Five dogs were administered 40 mg of Magnoliae cortex extract and 20 mg of Zea mays L. extract orally once per day for 2 months (MZ group), whereas the other group received empty gelatin capsules (control group). Periodontal clinical parameters, complete blood count, serum chemistry parameters, and tissue inflammatory cytokines and chemokine expression were assessed before and after combined oral extracts administration.ResultsThe complete blood count and serum chemistry results of all dogs were within normal ranges. Gingival inflammation in MZ group was significantly better than that in the control group at 4 and 8 weeks post-medication (PM; p < 0.05). The periodontal pocket depth and clinical attachment loss at 8 weeks PM in the MZ group were significantly lower than the baseline values (p < 0.05). The incidence of bleeding on probing in the MZ group was significantly lower than that in the control group at 4 weeks PM (p < 0.05). Throughout the medication period, the percentages of CD4 + and CD8 + T cells were higher and lower, respectively, in the MZ group. However, these differences were only significant at 8 weeks PM. The expression of the inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α and the chemokine IL-8 in the inflamed tissues was lower in the MZ group, and the two groups showed a significant difference in TNF-α expression.ConclusionsCombined administration of Magnoliae cortex and Zea mays L. extract improved the clinical symptoms of periodontal disease in dogs. This beneficial effect may be partly due to the inhibitory effects of these extracts on the inflammatory response.

Determining the Levels of Cortisol, Testosterone, Lactic Acid and Anaerobic Performance in Athletes Using Various Forms of Coffee.

Coffee is considered one of the most preferred and consumed beverage types in the world, and caffeine is known to increase physical performance due to its ergogenic properties. The aim of this study is to examine the effects of coffee consumption in different forms on cortisol, testosterone, lactic acid and anaerobic performance levels. A total of 15 licensed male football players participated in the research voluntarily. The research was implemented in a single-blind, counterbalanced, randomized and crossover study design. Participants were given caffeinated coffee (CK), decaffeinated coffee (placebo) (DK), powdered caffeine (in a gelatin capsule) (PC) and powdered placebo (maltodextrin in a capsule) (PM) on different days, and the Wingate test protocol was performed after the warm-up protocol. Blood samples were collected post-test. Cortisol, testosterone and lactic acid levels in the serum samples taken were determined by the ELISA method. As a result, it was revealed that caffeinated coffee given to participants who exercise increased anaerobic power. However, it was observed that lactic acid levels were higher in placebo and decaffeinated coffee. The highest level of cortisol was found in caffeinated coffee and powdered caffeine compared to the placebo. Testosterone values were observed to be highest in caffeinated coffee and decaffeinated coffee compared to a placebo. The study suggests that the type of caffeine is a factor that affects absorption rate, which impacts performance and hormone levels.

СРАВНИТЕЛЬНАЯ ОЦЕНКА ВЛАГОСОРБЦИОННЫХ СВОЙСТВ ЖЕЛАТИНОВЫХ И ГИПРОМЕЛЛОЗНЫХ ТВЕРДЫХ КАПСУЛ

Aim. Comparative evaluation of the shells of solid capsules made of gelatin and hypromelose of hygroscopicity and disintegration indicators. Materials and Methods. Solid gelatin and hypromellose capsules produced by Capsugel (Belgium), as well as pharmaceutical compositions with bifidobacterium lyophilisate were used as objects of research. Hygroscopicity was determined according to FEES methods. Hygroscopicity is determined by the weight method according to the GF RF XV according to the OFS.1.1.0042 "Determination of hygroscopicity". The water-absorbing properties of capsule shells were evaluated by the rate of moisture gain of empty and filled solid capsules. Tests on the disintegration index were conducted according to the GF of the Russian Federation XV, OFS.1.4.2.0013 "Disintegration of solid dosage forms", OFS.1.7.1.0003.15 "Bifido-containing probiotics". Results. Comprehensive pharmaceutical-technological studies of empty hard capsules and model samples with encapsulated composition with bifidobacterium lyophilisate in hard capsules produced by Capsugel® (Belgium) were carried out. As a result of comparative analysis of characteristics of empty hard capsules Coni-Snap and Vcaps Plus, it was revealed that Vcaps Plus capsules have faster disintegration, higher rate of moisture gain, low hygroscopicity of the capsulated composition with preservation of the shape and structure of the capsule shell. Conclusion. Comparative studies of the water-absorption properties of gelatin and hypromellose capsules have shown the rationality of using hypromellose capsules for encapsulating hygroscopic AFS, in particular lyophilizates.

Prepartum anti-inflammatory therapies in Holstein dairy cows blocked by parity and body condition score group: Effects on metabolic stress, systemic inflammation, performance, and health

The objective of this study was to assess the effects of prepartum administration of anti-inflammatory therapies on body condition score (BCS), β-hydroxybutyrate (BHB) concentration, haptoglobin (HP) concentration, milk yield, milk components, rumination time, clinical health events and reproductive performance in Holstein dairy cows. At 14 d before the expected calving date, cows (PAR; n = 170) and heifers (nulliparous [NUL]; n = 63) were blocked by BCS group (optimal = 3-3.5 [OPT]; over-conditioned cows [OVERC; BCS ≥ 3.75 pts.]) and parity (NUL; PAR) and randomly allocated to one of 3 treatment groups: 1) ASA (n = 78): receive one oral administration of acetylsalicylic acid (4 boluses; 480 grain/bolus); 2) MEL (n = 76): receive one oral administration with meloxicam (1mg/kg of BW), or 3) PLC (n = 77): receive one oral treatment with gelatin capsules filled with water. Body condition score was assessed, and blood samples were collected, weekly starting one week before treatment until 3 weeks after calving. Daily milk yields and daily rumination times were collected from on-farm computer records. Dairy Herd Improvement Association (DHIA) monthly test data were collected to assess milk yield, somatic cell counts, and milk components. Furthermore, health events, culling rate, and reproductive performance data were collected from on-farm computer records. The data were analyzed using MIXED, GLIMMIX, and LIFETEST procedures of SAS as a randomized complete block design. On average, MEL-NUL cows produced 4.77 ± 0.93 kg/d and 4.81 ± 0.92 kg/d more milk from wk 6 to wk 21 of lactation compared with ASA-NUL and PLC-NUL cows, respectively. Similarly, there was a week by treatment by body condition group interaction (P = 0.01), where OVERC cows treated with MEL produced more milk from wk 10 to wk 15 of lactation compared with ASA- OVERC and PLC-OVERC cows. Parous cows treated with ASA had lower BCS compared with PAR cows treated with MEL or PLC. A lower percentage of OVERC cows treated with ASA became sick in the first 60 DIM compared with MEL- OVERC and PLC- OVERC cows (ASA = 23.88 ± 7.26%, MEL = 46.36 ± 8.57%; PLC = 46.74 ± 8.53%; P = 0.04). Parous cows treated with ASA had (P = 0.03) a higher hazard ratio to become pregnant by 300 DIM compared with PAR MEL cows. Although the study was not sized for finding treatment differences in blocking criteria groups, these results suggest that treatment with prepartum anti-inflammatory therapies may have positive effects on milk yield and postpartum health in specific groups of cows, such as NUL and OVERC cows, while it may not be recommended for other animal categories, such as parous cows and cows with optimal BCS. Larger studies are needed to strengthen the associations observed in this study.

Temperature effects on ribbon characteristics in soft gelatin capsule manufacture

In the manufacture of soft gelatin capsules using a rotary-die encapsulation machine, the formation of ribbons at the cooling drums and their subsequent mechanical performance are key attributes for a smooth machinability. In this paper we present the results of a comprehensive investigation of the intricate impact of the cooling drum temperature in the range between 5 and 25 °C on the mechanical and the microstructural properties of a highly concentrated gelatin formulation (40% w/w) typically used in soft capsule manufacture.The study demonstrates that the temperature at the cooling drums strongly affects the gelation kinetics, the gel elasticity and the tensile strength of the ribbons. The temperature correlates linearly with the storage modulus G′ under low shear deformation, i.e. the lower the temperature of the gel, the higher the gel elasticity. A reverse linear relationship was found for the temperature-dependent ultimate tensile strength (UTS) of the gelatin ribbons, i.e. a higher drum temperature leads to a higher UTS. This inverse effect of the ageing temperature on G′ and UTS can be explained by temperature-induced microstructural differences within the gel network, as indicated by FTIR spectroscopy and Differential Scanning Calorimetry (DSC) measurements. Lower ageing temperatures result in a higher number of triple helical junction zones with fewer and/or weaker hydrogen bonds, which translate into a higher gel elasticity under low shear deformation, but a lower resilience of the ribbons against rupture in tensile testing. At higher temperatures, fewer but longer and/or more thermostable triple helical links in the gel network enhance the stability of the ribbons against tensile stress.In summary, the results clearly reveal that a detailed understanding of the complex relationship between the drum temperature, the gel network structure and the mechanical properties of gelatin ribbons is essential for process optimization.

Three-Dimensional Printing of PVA Capsular Devices for Applications in Compounding Pharmacy: Effect of Design Parameters on Pharmaceutical Performance.

The creation of products with personalized or innovative features in the pharmaceutical sector by using innovative technologies such as three-dimensional (3D) printing is particularly noteworthy, especially in the realm of compounding pharmacies. In this work, 3D printed capsule devices (CDs) with different wall thicknesses (0.2, 0.3, 0.4, 0.6, and 0.9 mm) and sizes were designed and successfully fabricated varying printing parameters such as extrusion temperature, printing speed, material flow percent, and nozzle diameter. The physicochemical, pharmaceutical, and biopharmaceutical performance of these CDs was evaluated with the aim of achieving an immediate drug release profile comparable to hard gelatin capsules (HGC) for use in magistral compounding. It was observed that the disintegration time of the CDs increased with wall thickness, which correlated with a slower drug release rate. CDs with configurations presenting 0.4 mm wall thickness and sizes comparable to HGC n° 0, 1, and 2 demonstrated satisfactory weight uniformity, short disintegration times, and immediate drug release, indicating their potential as effective devices in future compounding pharmacy applications. In addition, a modified Weibull-type model was proposed that incorporates wall thickness as a new variable in predicting dissolution profiles. This model improves the process of selecting a specific wall thickness to achieve the desired dissolution rate within a specified time frame.

Biodegradable capsules as a sustainable and accessible container for vitrification of gonadal tissue using the zebrafish animal model

Cryopreservation of fish gonadal tissue is an important technique for preserving genetic variability. However, this technique involves the use of cryotubes, plastic containers with low degradability that are expensive and difficult to obtain in certain parts of the world. Therefore, this study aimed to evaluate the efficiency of gelatin and hypromellose hard capsules as a sustainable and accessible alternative container to the cryotube for vitrification of zebrafish (Danio rerio) gonadal tissue. The gonadal tissues (testicular or ovarian) were vitrified in cryotubes, hard-gelatin, and hard-hypromellose capsules. Gelatin capsules exhibited comparable efficacy to cryotubes in preserving spermatogonia viability (33.03 ± 10.03 % and 37.96 ± 8.35 %, respectively), whereas hypromellose capsules showed decreased viability (18.38 ± 2.09 %). Immature oocyte viability remained unaffected by the capsule materials, with no difference compared to cryotubes at all oocyte stages (Primary Growth: p < 0.0001; Cortical Alveolar: p < 0.0001; Vitellogenic: p < 0.0001). Mitochondrial activity and lipid peroxidation demonstrated no difference among cryotubes and capsules for both gonadal tissues. However, antioxidant activity was notably higher in gelatin capsules (Testes: 147.2 ± 32.32 μg; Ovary: 87.98 ± 10.91 μg) than in cryotubes (Testes: 81.04 ± 26.05 μg; Ovary: 54.35 ± 11.23 μg) and hypromellose capsules (Testes: 62.36 ± 17.10 μg; Ovary: 63.96 ± 7.51 μg), likely due to the inherent antioxidant properties of gelatin. The results obtained in this study demonstrate that the cryotube can be replaced by gelatin capsules for vitrification of both gonadal tissues of zebrafish, being a sustainable and accessible alternative as it is a low-cost and environmentally friendly container.

Does a single oral administration of amiloride affect spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults?

Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults.NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.

Relative availability of five inorganic magnesium sources in non-pregnant non-lactating Holstein cows.

Inorganic sources of Mg are commonly used in dairy cow diets, but their availability varies significantly. This study assessed the relative availability of 4 commonly used inorganic Mg sources and a novel alkalinizing proprietary mineral blend [PMB; Multesium (GLC Minerals, LLC, Green Bay, WI, USA)]. The study was a duplicated 6 × 6 Latin square, with 12 nonlactating, non-pregnant Holstein dairy cows assigned to a square based on BW and parity. Cows were fed 90% of their voluntary DMI (diet contained 0.21% Mg). Each experimental period lasted 7 d. On d 2 of each period, urinary catheters were fitted. Total urine collection started on d 3 for 48 h with samples collected and measured every 12 h. On d 4, 30 g of Mg were administered as boluses with gelatin capsules: negative control (one empty capsule), magnesium oxide (MgO), magnesium sulfate (MgSO4), calcium magnesium hydroxide [CaMg(OH)4], calcium magnesium carbonate [CaMg(CO3)2], and PMB [a blend of Ca and Mg sources that includes CaMg(CO3)2, CaMg(OH)4, and MgO]. Blood samples were collected at 0, 1, 2, 3, 12, and 24 h after treatment administration on d 4 of each treatment period. Urine and blood samples were analyzed for Mg and Ca concentration. Statistical analyses were conducted with PROC GLIMMIX including treatment, time, period, square, treatment × time, treatment × period, and time × period as fixed effects, and cow nested within square as a random effect in the model. Urinary Mg excretion for 4 of the Mg sources studied [PMB, MgO, CaMg(OH)4, and MgSO4] increased significantly, representing an increase of at least 40.8% relative to control. The supplementation of CaMg(CO3)2 did not significantly increase relative to control. There were no significant changes in blood Mg concentration with treatment; but, a significant treatment × time effect was observed. Calcium-rich sources [PMB, CaMg(OH)4, CaMg(CO3)2] had lower blood Mg concentrations at 12 or 24 h after treatment than control and CaMg(CO3)2. Based on urinary Mg excretion 24 h after treatment, 4 of the Mg sources evaluated (including PMB) showed a similar availability, however, the availability of the commercial CaMg(CO3)2 source included in our study was similar to the negative control (no-supplemented cows).

Elemental Impurities in Gelatine Capsules: Human Health Risk Assessment

INTRODUCTION. This work continues the authors’ earlier study on gelatine capsule contamination with elemental impurities, which resulted in proposing a list of elements for standardisation. To ensure the safe use of medicinal products in this dosage form, it is necessary to develop criteria for the quantitative assessment of potential human health risks associated with elemental impurities in gelatine capsule shells.AIM. This study aimed to determine the permitted daily concentration (PDC) limits for elemental impurities in gelatine capsules from a risk-based pharmaceutical quality control perspective.MATERIALS AND METHODS. The authors analysed their previous experimental data, the relevant Russian State Standard (GOST), the requirements of the State Pharmacopoeia of the Russian Federation and leading world pharmacopoeias (USA, UK, EU, China, Japan, and India), and the scientific literature published from 1980 to 2023 on the content of elemental impurities (Al, As, Cd, Cu, Cr, Cr, Fe, Hg, Mn, Pb, and Zn) in gelatine capsule shells and medical gelatine.RESULTS. When standardising the content of elemental impurities in gelatine capsule shells, it is necessary to consider not only the toxicity of impurities but also their potential to compromise the quality of gelatine. Complexing elements (Cd, Cu, Hg, Cr, and Zn) can affect the quality of gelatine at subtoxic concentrations. For Cd, Cu, and Hg, the authors recommended using the PDC limits specified in GOST 23058-89 Gelatine. Raw materials for the medical industry. Specifications. For Cr and Zn, the authors recommended adhering to the PDC limits specified in the State Pharmacopoeia of the Russian Federation, edition XIV, Monograph 2.1.0099.18 Gelatine. Lead affects the quality of gelatine at concentrations above the toxicity threshold, and arsenic does not cause clustering of gelatine molecules. For Pb and As, the authors recommended using the PDC limits specified in the State Pharmacopoeia of the Russian Federation, edition XV, General Monograph 1.1.0040 Elemental impurities. The authors proposed a conversion factor to account for the complexing potential of Al when limiting its content in gelatine capsule shells. The authors recommended assessing the risks to human health associated with Mn intake with gelatine capsule shells indirectly by listing total heavy metals as a quality attribute to be controlled at the level of medical gelatine. The content of Fe should also be standardised at the raw material level.CONCLUSIONS. The content of elemental impurities in gelatine capsule shells should not exceed the following limits: 45 µg/g for Al, 1.5 µg/g for As, 0.03 µg/g for Cd, 10 µg/g for Cr, 15 µg/g for Cu, 0.05 µg/g for Hg, 0.5 µg/g for Pb, and 30 µg/g for Zn. The standardisation of these elements in gelatine capsule shells will prevent negative effects on the human body and shell quality.

Liquid- and Semisolid-Filled Hard Gelatin Capsules Containing Alpha-Lipoic Acid as a Suitable Dosage Form for Compounding Medicines and Dietary Supplements.

Liquid-filled hard gelatin capsules may have pertinent advantages both for therapeutic effect and extemporaneous preparations of medicines. Alpha lipoic acid is a substance used in medicines and dietary supplements and there is a need for creating an appropriate formulation which would be suitable for each individual patient or consumer. Based on its biopharmaceutical and physical chemical characteristics, eight different capsule formulations were designed and characterized. Silicon dioxide was added to form a semisolid content and prevent leakage. The formulation filled with alpha lipoic acid solution in polyethylene glycol 400 showed the best performance. Although the addition of silicon dioxide to the formulation with polyethylene glycol 400 led to a change in both flow character and viscosity, the release rate did not show a statistically significant decrease (more than 85% of content was released after 5 min testing). Applied technique is a simple and an appropriate approach for compounding and could be used for other substances with similar properties.

In vivo assessment, formulation, characterization and enhancing pharmacotherapy of encapsulated mini tablets for immediate release Sildenafil citrate and sustained release Bosentan

The purpose of this study was to prepare and evaluate multiple unit mini tablets (MTs) of prolonged released (PR) bosentan (BSN) and fast release (FR) sildenafil citrate (SDC) on the basis of encapsulation method for the effective management of pulmonary artery hypertension. The system consists of MTs are in the form of uncoated tablets containing the superdisintegrating agents where as the PRMTs contains the polymer with film coating. All the units are prepared by direct compression method and encapsulated using size 1 hard gelatin capsule shells. The formulations were evaluated for differential scanning calorimetry, dissolution test and post compression studies for their quality attributes and it was found that all the parameters were in the acceptable limits. The optimized formulation for BSN PRMTs i.e BS3 which contains 5 % HPMC K15M shows a promising sustained release profile of 82.31 % in 24 h similarly FRMTs of SDC of formulation SD6 that having 3 % of magnesium aluminium silicate shows about 90 % of drug release within 15 min. The in-vivo pharmacokinetic characterization of the system was carried out using wister rats where the AUC value for SDC FRMTs and BSN PRMTs was found to be 94256.88625 ± 123.65 ng h/mL and 142438.084 ± 324.11 ng h/mL respectively. The other pharmacokinetics are also determined and found to be satisfactory. The six months stability samples showed no significant change in the drug content, hardness and uniformity of the content of the optimized formulations.

Unveiling the Preparation and Characterization of Lercanidipine Hydrochloride in an Oral Solid Self-Nanoemulsion for Enhancing Oral Delivery.

Chronic kidney disease (CKD) is becoming increasingly prevalent worldwide, particularly among the elderly, along with an increase in the incidence of hypertension and cardiovascular disorders. Developing lipid-based oral dosage forms with a higher expected bioavailability of antihypertensive drugs with nephroprotective effects poses a challenge. Lercanidipine hydrochloride (LRCH) is a newer type of third-generation dihydropyridine calcium channel blocker that functions as an antihypertensive and has significant nephroprotective effects. Due to its extensive first-pass metabolism, its bioavailability is about 10% and increases to 3-4 times when taken with a high-fat meal. Targeting this drug to the lymphatic system using the solid self-nano-emulsifying drug delivery system (SSNEDDS) is a promising approach for improving LRCH's bioavailability and dispersion rate. SSNEDDS combines the benefits of both liquid self-emulsifying and solid dosage forms, improving drug stability and extending storage time. In this study, liquid SNEDDS composed of 10% peppermint oil, 67% Tween 20, and 22.5% propylene glycolwas solidified using two adsorbent agent mixtures (SSNEDDS1: Avicel PH 101 and Aerosil 200) and (SSNEDDS2: Avicel PH 102 and Aerosil 200) separately. The prepared formulations were evaluated for powder flow, drug content, and an in-vitro dispersion test in comparison to the brand-marketed tablet as a standard or pure drug. DSC and X-ray diffraction analysis were also used. The SSNEDDS2 shows excellent flowability, a higher drug content (99.761%), and a significantly higher and faster dispersion rate of 100% within 10 minutes compared to 92% of the marketed LRCH tablet and 18.1% of the pure drug for 60 minutes. The solid-state characterization of the formulation composed of SSNEDDS2 confirmed that the LRCH was in an amorphous form inside the solidified nano system without interacting with the excipient. This study successfully prepared LRCH using the promising strategy of SSNEDDS as a hard gelatin capsule with a higher dispersion rate. It improved its stability and expected bioavailability compared to the brand-marketed tablet as the standard.

A Quality by Design Approach for Optimizing Solid Lipid Nanoparticles of Bedaquiline for Improved Product Performance.

Bedaquiline (BQ) solid lipid nanoparticles (SLNs), which have previously been formulated for parenteral administration, have a risk of patient non-compliance in treating tuberculosis. This research presents a strategy to develop BQ SLNs for oral delivery to improve patient adherence, The upper and lower levels for the formulation excipients were generated from screening experiments. Using 4 input factors (BQ, lecithin, Tween 80, and PEG), a full factorial design from 3 × 2x2 × 2 experiments was randomly arranged to investigate 3 response variables: Particle size distribution (PSD), polydispersity index (PdI), and zeta potential (ZP). High shear homogenization was used to mix the solvent and aqueous phases, with 15% sucrose as a cryoprotectant. The response variables were assessed using a zeta sizer while TEM micrographs confirmed the PSD data. Solid-state assessments were conducted using powdered X-ray diffraction and scanning electron microscopy (SEM) imaging. A comparative invitro assessment was used to determine drug release from an equivalent dose of BQ free base powder and BQ-SLN, both packed in hard gelatin capsules. The sonicated formulations obtained significant effects for PSD, PdI, and ZP. The p-values (0.0001 for PdI, 0.0091 for PSD) for BQ as an independent variable in the sonicated formulation were notably higher than those in the unsonicated formulation (0.1336 for PdI, 0.0117 for PSD). The SEM images were between 100 - 400nm and delineated nanocrystals of BQ embedded in the lipid matrix. The SLN formulation provides higher drug levels over the drug's free base; a similarity factor (f2 = 18.3) was estimated from the dissolution profiles.