New insights into the potential cardioprotective effects of telmisartan and nanoformulated extract of Spirulina platensis via regulation of oxidative stress, apoptosis, and autophagy in an experimental model.

Background: Cardiotoxicity is one of the limiting side effects of the commonly used anticancer agent cyclophosphamide (Cyclo). Materials and methods: The possible protective effects of telmisartan and nanoformulated Spirulina platensis (Sp) methanolic extract against Cyclo-induced cardiotoxicity were examined in this study. Experimental groups of rats were randomly divided into nine groups as control vehicle, control polymer, telmisartan (TEL, 10 mg/kg), free Sp extract (300 mg/kg), nano Sp extract (100 mg/kg), Cyclo (200 mg/kg), TEL + Cyclo, free Sp + Cyclo, and nano Sp + Cyclo. The groups with Cyclo combinations were treated in the same manner as their corresponding ones without Cyclo, with a single dose of Cyclo on day 18. Results: The results indicate that Cyclo causes significant cardiotoxicity, manifesting in the form of notable increases of 155.49%, 105.74%, 451.76%, and 826.07% in the serum levels of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), and cardiac troponin I (cTnI) enzyme activities, respectively, as compared to the control. In addition, the cardiac glutathione (GSH) content and activity of glutathione peroxidase-1 (GPX-1) enzyme decreased by 65.94% and 73.85%, respectively. Treatment with nano Sp extract showed the most prominent restorations of the altered biochemical, histopathological, and immunohistochemical features as compared with those by TEL and free Sp; moreover, reductions of 30.64% and 43.02% in the p-AKT content as well as 60.43% and 75.30% of the endothelial nitric oxide synthase (eNOS) immunoreactivity were detected in the TEL and free Sp treatment groups, respectively. Interestingly, nano Sp boosted the autophagy signal via activation of beclin-1 (36.42% and 153.4%), activation of LC3II (69.13% and 195%), downregulation of p62 expressions (39.68% and 62.45%), and increased gene expressions of paraoxonase-1 (PON-1) (90.3% and 225.9%) compared to the TEL and free Sp treatment groups, respectively. Conclusion: The findings suggest the protective efficiency of telmisartan and nano Sp extract against cardiotoxicity via activations of the antioxidant, antiapoptotic, and autophagy signaling pathways.

Antivirulence Effects of Trans-Resveratrol and Curcumin on Methicillin-Resistant Staphylococcus aureus (MRSA) from Saudi Arabia.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common resistant bacterium, whose resistance has expanded to commonly used antibiotics. It is crucial to create novel treatments to tackle bacterial resistance. Trans-resveratrol and curcumin are naturally occurring phenolic compounds, whose effects on MRSA virulence are the subject of this investigation. Sub-MICs of trans-resveratrol and curcumin were tested on the virulence factors of 50 MRSA clinical isolates (CIs), including biofilm, hemolysin, hemagglutination, protease, and lecithinase. The distribution of the virulence factors of the CIs was as follows: hemolysin: 98%, hemagglutination: 70%, protease: 62%, biofilm: 56%, and lecithinase: 52%. The sub-MIC that could reduce the effect of the tested virulence factors by 50% or more (IC50) was observed in the strains that showed susceptibility to the individual administration of trans-resveratrol at 50 µg/mL and curcumin at 20 µg/mL. Hemagglutination and hemolysin activity were inhibited by at least 50% in the majority of CIs (57-94%). Meanwhile, the IC50 for protease and biofilm was observed in 6.5-17.8% of the CIs. A few of the CIs were susceptible to lecithinase inhibition, but all showed a full inhibition. This research supports the possibility of the use of these compounds to reduce the bacterial virulence that can reduce antibiotic utilization, and eventually, they can become a potential alternative treatment in combating bacterial resistance.

Hyperlipidemia Increases Nalbuphine Brain Accumulation with Multiple Dosing without Affecting Its Analgesic Response-Its Respiratory Depression Potential Should Be Investigated in Future Studies.

Nalbuphine is associated with a significant risk of respiratory depression. Its central nervous system entry is hindered by P-glycoproteins, and lower P-glycoprotein activity is a risk factor for respiratory depression. We assessed the effect of hyperlipidemia on nalbuphine pharmacokinetics, brain and liver uptake, and analgesic response following single (2.5 mg/kg) and multiple (2.5 mg/kg/day for three days) doses in normolipidemic and hyperlipidemic rats. Trends of reduction and increase in nalbuphine Cmax and Vdss/F were observed, respectively, in hyperlipidemic rats. Negative correlations were observed between Cmax and serum lipoproteins. Serum-normalized brain and liver levels at 1 h post-dose were lower in hyperlipidemic rats, with brain and liver levels being negatively and positively correlated with TG and HDL, respectively. At steady state, marked nalbuphine accumulation was observed in hyperlipidemic rat brains (R = 1.6) compared with normolipidemic rats (R = 1.1). Nalbuphine analgesic response was not altered by hyperlipidemia at steady state. Caution should be exercised since greater brain accumulation in hyperlipidemic patients treated with nalbuphine could increase their risk of respiratory depression. Our study highlights an unexpected role of lipoproteins in drug absorption and tissue uptake. We also propose a model for reduced nalbuphine absorption based on interaction with intestinal HDL-3.

Insight of the Biopharmaceutical Implication of Sleeve Gastrectomy on Levothyroxine Absorption in Hypothyroidism Patients.

PURPOSE: The growing rate of obesity led to an increased number of bariatric surgeries (BS) as a treatment option for obesity. The gastrointestinal tract (GIT) changes following BS can impact many drugs' absorption. Levothyroxine (LT4) is a synthetic thyroxine (T4) replacement used commonly as tablets to manage hypothyroidism disorder, which is more prevalent among patients with obesity. This study aims to examine the LT4 oral tablet form therapy after sleeve gastrectomy. MATERIALS AND METHODS: A retrospective cohort study was conducted in multi-center. The LT4 doses and TSH and T4 levels were compared before and after BS. The post-surgery readings were categorized into three periods: (one to three months), (four to six months), and (> six ) months after surgery. ANOVA test was used for analysis. RESULTS: A total of 14374 patients who underwent BS from (1/2019 to 3/2022) were screened for eligibility, and n = 101 participants matched the inclusion criteria. The TSH and T4 were not statistically significant differences before and after surgery (P-values of 0.4864 and 0.5970, respectively). However, the doses significantly differed before and after surgery in all the follow-up time point periods (P < 0.002). CONCLUSION: The LT4 required doses significantly reduced after sleeve gastrectomy, which can be related to the improved endogenous thyroid production in patients with obesity. However, the abnormality of the GIT induced by the sleeve gastrectomy may affect the exogenous LT4 absorption. Using liquid forms of LT4 while monitoring the thyroid function parameters can optimize the treatment after the procedure.

A pH-sensitive silica nanoparticles for colon-specific delivery and controlled release of catechin: Optimization of loading efficiency and in vitro release kinetics.

Catechin is a naturally occurring flavonoid of the flavan-3-ol subclass with numerous biological functions; however, these benefits are diminished due to several factors, including low water solubility and degradation in the stomach's harsh environment. So, this study aimed to develop an intelligent catechin colon-targeting delivery system with a high loading capacity. This was done by coating surface-decorated mesoporous silica nanoparticles with a pH-responsive enteric polymer called Eudragit®-S100. The pristine wormlike mesoporous silica nanoparticles (< 100 nm) with high surface area and large total pore volume were effectively synthesized and modified with the NH2 group using the post-grafting strategy. Various parameters, including solvent polarity, catechin-carrier mass ratio, and adsorption time, were studied to improve the loading of catechin into the aminated silica nanoparticles. Next, the negatively charged Eudragit®-S100 was electrostatically coated onto the positively charged aminated nanocarriers to shield the loaded catechin from the acidic environment of the stomach (pH 1.9) and to facilitate site-specific delivery in the acidic environment of the colon (pH 7.4). The prepared nanomaterials were evaluated using several methods, including The Brauner-Emmett-Teller, surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope, Powder X-Ray Diffraction, Fourier Transform Infrared Spectroscopy, Energy-Dispersive X-ray Spectroscopy, and Differential Scanning Calorimetry. In vitro dissolution studies revealed that Eudragit®-S100-coated aminated nanomaterials prevented the burst release of the loaded catechin in the acidic environment, with approximately 90% of the catechin only being released at colonic pH (pH > 7) with a supercase II transport mechanism. As a result, silica nanoparticles coated with Eudragit®-S100 would provide an innovative and promising approach in targeted nanomedicine for the oral delivery of catechin and related medicines for treating diseases related to the colon, such as colorectal cancer and irritable bowel syndrome.

Effect of Resveratrol and Curcumin on Gene Expression of Methicillin-Resistant Staphylococcus aureus (MRSA) Toxins.

Staphylococcus aureus is an opportunistic pathogen that can lead to a number of potentially terrible community- and hospital-acquired illnesses. Among the diverse set of virulence factors that S. aureus possesses, secreted toxins play a particularly preeminent role in defining its virulence. In this work, we aimed to facilitate the development of novel strategies utilizing natural compounds to lower S. aureus's toxin production and consequently enhance therapeutic approaches. Two natural polyphenols, resveratrol (RSV) and curcumin (CUR), were tested for their effect on reducing toxin gene production of MRSA isolates. Fifty clinical MRSA isolates were gathered from Riyadh and Jeddah. Molecular screening of toxin genes (sea, seb, sec, sed, seh, lukF, and lukS) harbored by MRSA was performed. Sub-inhibitory concentrations of RSV (50 µg/ml) and CUR (20 µg/ml) were determined to study their effect on the gene expression MRSA's toxin genes. Our findings revealed the presence of the tested genes in MRSA isolates, with lukF being the most prevalent gene and seh the least detected gene. We found that RSV reduced the relative expression of toxin genes, sea, seb, lukF, and lukS, respectively, while CUR decreased the relative expression of sea and seb genes in the examined isolates. Regarding lukF and lukS, CUR downregulated the expression of both genes in some isolates and upregulated the expression in other isolates. From these results, we concluded that RSV and CUR could be used as alternative therapeutic approaches to treat MRSA infections through reducing toxin production.

New Insight on the Cytoprotective/Antioxidant Pathway Keap1/Nrf2/HO-1 Modulation by Ulva intestinalis Extract and Its Selenium Nanoparticles in Rats with Carrageenan-Induced Paw Edema.

Currently, there is growing interest in exploring natural bioactive compounds with anti-inflammatory potential to overcome the side effects associated with the well-known synthetic chemicals. Algae are a rich source of bioactive molecules with numerous applications in medicine. Herein, the anti-inflammatory effect of Ulva intestinalis alone or selenium nanoparticles loaded with U. intestinalis (UISeNPs), after being fully characterized analytically, was investigated by a carrageenan-induced inflammation model. The pretreated groups with free U. intestinalis extract (III and IV) and the rats pretreated with UISeNPs (groups V and VI) showed significant increases in the gene expression of Keap1, with fold increases of 1.9, 2.27, 2.4, and 3.32, respectively. Similarly, a remarkable increase in the Nrf2 gene expression, with 2.09-, 2.36-, 2.59-, and 3.7-fold increases, was shown in the same groups, respectively. Additionally, the groups III, IV, V, and VI revealed a significantly increased HO-1 gene expression with a fold increase of 1.48, 1.61, 1.87, and 2.84, respectively. Thus, both U. intestinalis extract and the UISeNPs boost the expression of the cytoprotective/antioxidant pathway Keap1/Nrf2/HO-1, with the UISeNPs having the upper hand over the free extract. In conclusion, U. intestinalis and UISeNPs have proven promising anti-inflammatory activity through mediating different underlying mechanisms.

Saliva Sampling in Therapeutic Drug Monitoring and Physiologically Based Pharmacokinetic Modeling: Review.

Therapeutic drug monitoring investigations based on saliva samples can be utilized as an alternative to blood sampling for many advantages. Moreover, the development of physiologically based pharmacokinetic (PBPK) modeling tools can further help to estimate drug exposure from saliva. This review discusses the use of saliva samples and illustrates the applications and examples of PBPK modeling systems for estimating drug exposure from saliva.

Insight into Fucoidan-Based PEGylated PLGA Nanoparticles Encapsulating Methyl Anthranilic Acid: In Vitro Evaluation and In Vivo Anti-Inflammatory Study.

A potential fucoidan-based PEGylated PLGA nanoparticles (NPs) offering a proper delivery of N-methyl anthranilic acid (MA, a model of hydrophobic anti-inflammatory drug) have been developed via the formation of fucoidan aqueous coating surrounding PEGylated PLGA NPs. The optimum formulation (FuP2) composed of fucoidan:m-PEG-PLGA (1:0.5 w/w) with particle size (365 ± 20.76 nm), zeta potential (-22.30 ± 2.56 mV), % entrapment efficiency (85.45 ± 7.41), drug loading (51.36 ± 4.75 µg/mg of NPs), % initial burst (47.91 ± 5.89), and % cumulative release (102.79 ± 6.89) has been further investigated for the anti-inflammatory in vivo study. This effect of FuP2 was assessed in rats' carrageenan-induced acute inflammation model. The average weight of the paw edema was significantly lowered (p ≤ 0.05) by treatment with FuP2. Moreover, cyclooxygenase-2 and tumor necrosis factor-alpha immunostaining were decreased in FuP2 treated group compared to the other groups. The levels of prostaglandin E2, nitric oxide, and malondialdehyde were significantly reduced (p ≤ 0.05) in the FuP2-treated group. A significant reduction (p ≤ 0.05) in the expression of interleukins (IL-1ß and IL-6) with an improvement of the histological findings of the paw tissues was observed in the FuP2-treated group. Thus, fucoidan-based PEGylated PLGA-MA NPs are a promising anti-inflammatory delivery system that can be applied for other similar drugs potentiating their pharmacological and pharmacokinetic properties.

Quality and safety investigation of commonly used topical cosmetic preparations.

Cosmetic and personal care products are considered an essential part of our daily care routine; hence, these products must be stable and safe for human use. This study aimed to assess the quality and safety of the most common cosmetic preparations. To select the products to be tested, a cross-sectional survey was distributed featuring the most used types and brands of products. Based on 447 responses from both males and females with different ages and education levels, 21 products from different brands were selected and tested in terms of microbial load, heavy metal content, and organoleptic properties. Microbial contamination was investigated using the aerobic plate count method. Lead (Pb), aluminum (Al), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), zinc (Zn), iron (Fe), and arsenic (As) impurities were analyzed using an inductively coupled plasma mass spectrometer. The products included sunblock, lip balm, hand cream, hair cream, shampoo, cleanser, baby oil, baby powder, bar soap, hair dye, makeup, deodorant, hair serum, shaving gel, and toothpaste. Microbial contamination was found in 14 of the products, ranging between 1467.5 and 299.5 cfu/ml. The most commonly isolated microorganisms were Staphylococcus aureus and Bacillus species. Most of the tested products showed metal impurities, with toothpaste having the highest concentrations of Pb, Cr, As, Cu and Ni. The samples did not show lumps or discoloration, did not have characteristic odors, and had pH values ranging from 6.90 to 8.10. The continuous usage of such products could lead to serious negative consequences. As a result, ensuring the quality of cosmetic products is critical. Regulatory authorities are required to enforce strict legislation on cosmetic manufacturing to assess and ensure the quality and safety of the products before they reach consumers.

Co-delivery of gentiopicroside and thymoquinone using electrospun m-PEG/PVP nanofibers: In-vitro and In vivo studies for antibacterial wound dressing in diabetic rats.

Nanofibers (NFs) provide several delivery advantages like their great flexibility and similarity with extracellular matrix (ECM) which qualify them to be the unique model of a wound dressing. NFs could create mats of polymeric matrix loaded with an active agent enhancing its solubility and stability. In our study, Gentiopicroside (GPS) and Thymoquinone (TQ) loaded in NFs polymeric mats composed of coblended polyvinyl pyrrolidine (PVP) and methyl ether Polyethylene glycol (m-PEG) were fabricated via electrospinning technique. A morphological study using Scanning Electron Microscopy (SEM) was performed for all formulae as well as in vitro release study using High-performance Liquid chromatography (HPLC) for sample analysis. The optimized formula (F3) was chosen for further assays using Fourier-Transform Infrared Spectroscopy (FTIR), and Differential Scanning Calorimetry (DSC). Study of the antibacterial effect, and in vivo healing action for diabetic infected wounds to quantify Tumor necrosis factor-alpha and Cyclooxygenase-2 were also investigated. F3 achieved the highest % cumulative release (99.79 ± 6.47 for GPS and 96.89 ± 6.87 for TQ) at 60 min, and a smaller diameter (200 nm) showing significant anti-bacterial effects with well-organized skin architecture demonstrating great healing signs. Our results revealed that m-PEG/PVP NFs mats loaded with GPS and TQ could be considered an optimal wound care dressing.

Gentiopicroside PLGA Nanospheres: Fabrication, in vitro Characterization, Antimicrobial Action, and in vivo Effect for Enhancing Wound Healing in Diabetic Rats.

Purpose: Gentiopicroside (GPS), an adequate bioactive candidate, has a promising approach for enhancing wound healing due to its antioxidant and antimicrobial properties. Its poor aqueous solubility negatively affects oral absorption accompanied by low bioavailability due to intestinal/hepatic first-pass metabolism. Our aim in this study is to fabricate GPS into appropriate nanocarriers (PLGA nanospheres, NSs) to enhance its solubility and hence its oral absorption would be improved. Methods: Normal and ODS silica gel together with Sephadex LH20 column used for isolation of GPS from Gentiana lutea roots. Crude GPS would be further processed for nanospheres fabrication using a single o/w emulsion solvent evaporation technique followed by in vitro optimization study to examine the effect of two formulation variables: polymer (PLGA) and stabilizer (PVA) concentrations on the physical characterizations of prepared NSs. Possible GPS-PLGA chemical and physical interactions have been analyzed using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The optimum GPS-PLGA NSs have been chosen for antimicrobial study to investigate its inhibitory action on Staphylococcus aureus compared with unloaded GPS NSs. Also, a well-designed in vivo study on streptozotocin-induced diabetic rats has been performed to examine the wound healing effect of GPS-PLGA NSs followed by histological examination of wound incisions at different day intervals throughout the study. Results: The optimum GPS PLGA NSs (F5) with well-controlled particle size (250.10±07.86 nm), relative high entrapment efficiency (83.35±5.71), and the highest % cumulative release (85.79±8.74) have increased the antimicrobial activity as it exhibited a higher inhibitory effect on bacterial growth than free GPS. F5 showed a greater enhancing impact on wound healing and a significant stimulating effect on the synthesis of collagen fibers compared with free GPS. Conclusion: These findings demonstrate that loading GPS into PLGA NSs is considered a promising strategy ensuring optimum GPS delivery for potential management of wounds.

Investigation of the effects of different beverages on the disintegration time of over-the-counter medications in Saudi Arabia.

Full disintegration of Oral solid dosage forms is critically important to achieve reliable clinical performance of the drug. Tablets/capsules are supposed to be taken with a full glass of water; however, many patients do not follow this recommendation as they administer their medications with beverages other than water. This study aims to assess the impact of different commonly consumed beverages in Saudi Arabia on the disintegration times of common over-the-counter (OTC) medication tablets and capsules in the Kingdom of Saudi Arabia. Five immediate release OTC drugs were chosen: Fevadol®, Solpadeine®, Ralaxon®, Artiz ®, and Brufen®. The disintegration times of these medications were assessed using a disintegration test in five beverages: Coca-cola, arabic coffee, orange juice, buttermilk and an energy drink. Times were compared to the disintegration time in water under two temperature conditions (37 °C and 5 °C). All beverages significantly increased the disintegration times of fevadol, solpadeine, and relaxon in comparison with water. The same was found for burfen, except that arabic coffee did not significantly increase disintegration time (p > 0.05). The disintegration time of artiz tablets was also significantly influenced by all beverages, except for Coca-cola and the energy drink, which had no significant impact on the disintegration time. The tested beverages should not be used as substitutes for water when ingesting medications. Patients should be advised to avoid consuming beverages other than water with therapeutic products. Increasing public awareness of drug-beverage interactions is needed.

Medication use patterns in the visually impaired in Saudi Arabia and the importance of applying Braille labeling.

BACKGROUND: A visually impaired person typically faces countless challenges throughout their daily activities. These challenges can include medication safety and efficacy. Few studies have addressed the issues of safety and pattern of medication usage in visually impaired patients, or the need to apply Braille labeling to medications dispensed to these patients. OBJECTIVE: To explore the medication use pattern in severely visually impaired and blind patients living in Saudi Arabia, and to evaluate the need for Braille labeling on medication dispensed to these patients. METHOD: The merits of the proposal and its alignment with national regulations were evaluated and the study was approved by the Institutional Review Board (IRB). This cross-sectional study was conducted through open- and closed-ended questionnaires that were distributed to 215 visually impaired people, aged 18 years and above, dispersed throughout different cities within the kingdom. RESULT: The sample population was equally distributed in terms of sex. The majority of the participants were young with a college degree. More than half of the participants were unable to identify the name, dose, expiry date, instructions and interactions of their medication, and the respondents usually relied on their caregivers. 91% of the respondents agreed that application of Braille labeling on their medications would improve the quality of their therapy and help them overcome some of their difficulties. CONCLUSION: This study investigated medication usage patterns in the visually impaired in Saudi Arabia. These patients face considerable challenges to any efforts to self-administer their own medication and are heavily reliant on caregivers. The current methods for dispensing medications to this population, (and current regulations) do not sufficiently meet their health information needs. The study highlighted the necessity of applying Braille labeling to medicines prescribed to the visually impaired. A reconsideration of the current regulations regarding the application of Braille labeling to medications is warranted. The use of Braille labeling on medications may improve drug treatment regimes, minimize medications errors, and promote independence in these individuals (through self-administration of medications). The addition of technology to the printed Braille labeling can advance the pharmaceutical care services provided and improve the life quality of patients.

The Irrelevance of In Vitro Dissolution in Setting Product Specifications for Drugs Like Dextromethorphan That are Subject to Lysosomal Trapping.

The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX.

Disease specific modeling: Simulation of the pharmacokinetics of meloxicam and ibuprofen in disease state vs. healthy conditions.

PURPOSE: Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences. METHOD: Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlus™. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models. RESULT: For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans. CONCLUSIONS: Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption.

Simulation of in vitro dissolution behavior using DDDPlus™.

Dissolution testing is a performance test for many dosage forms including tablets and capsules. The objective of this study was to evaluate if computer simulations can predict the in vitro dissolution of two model drugs for which different dissolution data were available. Published montelukast sodium and glyburide dissolution data was used for the simulations. Different pharmacopeial and biorelevant buffers, volumes, and rotations speeds were evaluated. Additionally, a pH change protocol was evaluated using these buffers. DDDPlus™ 3, Beta version (Simulation Plus, Inc.), was used to simulate the in vitro dissolution data. The simulated data were compared with the in vitro data. A regression coefficient between predicted and observed data was used to assess the simulations. The statistical analysis of Montelukast sodium showed that there was a significant correlation between the in vitro release data and the predicted data for all cases except for one buffer. For glyburide, there was also a significant correlation between the experimental data and the predicted data using single pH conditions. Using the dynamic pH protocol, a correlation was significant for one biorelevant media. The simulations showed that both in vitro drug releases were sensitive to solubility effects which confirmed their BCS class II category. Computer simulations of the in vitro release using DDDPlus™ have the potential to estimate the in vivo dissolution at an early stage in the drug development process. This might be used to choose the most appropriate dissolution condition to establish IVIVC and to develop biorelevant in vitro performance tests to capture critical product attributes for quality control procedures in quality by design environments.

Provisional biopharmaceutical classification of some common herbs used in Western medicine.

The aim of this study was to classify some markers of common herbs used in Western medicine according to the Biopharmaceutical Classification System (BCS). The BCS is a scientific approach to classify drug substances based upon their intestinal permeability and their solubility, at the highest single dose used, within the physiologically relevant pH ranges. Known marker components of twelve herbs were chosen from the USP Dietary Supplement Compendium Monographs. Different BCS parameters such as intestinal permeability (P(eff)) and solubility (C(s)) were predicted using the ADMET Predictor, which is a software program to estimate biopharmaceutical relevant molecular descriptors. The dose number (D0) was calculated when information from the literature was available to identify an upper dose for individual markers. In these cases the herbs were classified according to the traditional BCS parameters using P(eff) and D0. When no upper dose could be determined, then the amount of a marker that is just soluble in 250 mL of water was calculated. This value, M(x), defines when a marker is changing from highly soluble to poorly soluble according to BCS criteria. This biopharmaceutically relevant value can be a useful tool for marker selection. The present study showed that a provisional BCS classification of herbs is possible but some special considerations need to be included into the classification strategy. The BCS classification can be used to choose appropriate quality control tests for products containing these markers. A provisional BCS classification of twelve common herbs and their 35 marker compounds is presented.

Investigation of the performance of the disintegration test for dietary supplements.

The aim of this study was to investigate how beaker size, basket assembly, use of disk, and immersion medium impact the disintegration time of dietary supplements. The disintegration times were determined for five tablet and two capsule products. A two-station disintegration tester was used with Apparatus A or Apparatus B as described in the United States Pharmacopeia (USP) chapters, <701> and <2040>. Two beakers complying with the harmonized specifications were used, one with a volume of 1,000 mL and one with a 1,500-mL volume. The disintegration data were analyzed using ANOVA for the following factors: beaker size, equipment (App A and B) and condition (with/without disk). Two tablet products were not sensitive to any changes in the test conditions or equipment configurations. One product was only partially sensitive to the test conditions. The other products showed impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or fail current USP disintegration requirements depending on the equipment configuration. Similar results were obtained for the two investigated capsule formulations. One product might fail current USP disintegration requirements if the large beaker was used, but might pass the disintegration requirements when the small beaker was used. Hydroxy propyl methyl cellulose capsules were mostly influenced if sodium instead of a potassium buffer was used as the immersion medium. The results demonstrate that the current harmonized ICH specifications for the disintegration test are insufficient to make the disintegration test into reliable test for dietary supplements.