Physiologically Based Biopharmaceutics Modeling (PBBM): Best Practices for Drug Product Quality, Regulatory and Industry Perspectives: 2023 Workshop Summary Report.

Physiologically based biopharmaceutics modeling (PBBM) is used to elevate drug product quality by providing a more accurate and holistic understanding of how drugs interact with the human body. These models are based on the integration of physiological, pharmacological, and pharmaceutical data to simulate and predict drug behavior in vivo. Effective utilization of PBBM requires a consistent approach to model development, verification, validation, and application. Currently, only one country has a draft guidance document for PBBM, whereas other major regulatory authorities have had limited experience with the review of PBBM. To address this gap, industry submitted confidential PBBM case studies to be reviewed by the regulatory agencies; software companies committed to training. PBBM cases were independently and collaboratively discussed by regulators, and academic colleagues participated in some of the discussions. Successful bioequivalence "safe space" industry case examples are also presented. Overall, six regulatory agencies were involved in the case study exercises, including ANVISA, FDA, Health Canada, MHRA, PMDA, and EMA (experts from Belgium, Germany, Norway, Portugal, Spain, and Sweden), and we believe this is the first time such a collaboration has taken place. The outcomes were presented at this workshop, together with a participant survey on the utility and experience with PBBM submissions, to discuss the best scientific practices for developing, validating, and applying PBBMs. The PBBM case studies enabled industry to receive constructive feedback from global regulators and highlighted clear direction for future PBBM submissions for regulatory consideration.

[Formulation Studies and Application of Their Experimental Techniques to Drug Discoveries].

In my first experience as a researcher, I isolated and performed structural predictions of the novel compounds, cis- and trans-palythenic acids, from Noctiluca milialis. I then worked for a pharmaceutical company in a research laboratory of pharmaceutics. I examined an inclusion complex of cinnarizine with ß-cyclodextrin, and found that the inclusion complex did not improve the oral bioavailability of cinnarizine. However, the bioavailability of the inclusion complex after its oral administration was improved by a competing agent. This was the first study to show the potential of a competing agent to improve bioavailability. I subsequently joined a laboratory performing drug discovery research and used experimental techniques from pre-formulation studies. A screening system of solubility for drug design and discovery was constructed to increase the solubilities of compounds synthesized in the laboratory. This screening system contributed to the discovery of a phosphodiesterase type 5 inhibitor with sufficient solubility. As a visiting lecturer at a university, I prepared amoxicillin intragastric buoyant sustained-release tablets for the eradication of Helicobacter pylori and applied cinnarizine as a competing agent. I established a laboratory of pharmaceutics at a university in Tochigi. To develop an enema with fluticasone propionate for ulcerative colitis, I investigated its physicochemical properties and methods to improve its solubility. After moving to another university in Kagawa, I developed a method to reduce the amount of drugs remaining on the surfaces of a pestle and mortar following the grinding of tablets, and new cleaning agents for an automatic dividing packaging machine were discovered.

Bufalin serves as a pharmaceutic that mitigates drug resistance.

Intrinsic or acquired drug resistance of tumor cells is the main cause of tumor chemotherapy failure and tumor-related death. Bufalin (BF) is the main active monomer component extracted from the Traditional Chinese Medicine Toad venom (secretions of glands behind the ears and epidermis of bufo gargarizans and Bufo Melanostictus Schneider). It is a cardiotonic steroid with broad-spectrum anti-cancer effects and has been widely used against various malignant tumors in clinical practice. Pharmacological studies also found that BF has the effect of reversing drug resistance, which provides a new perspective for the application of Traditional Chinese Medicine as a chemosensitizer in cancer therapy. This article provides an extensive search and summary of published research on mitigating drug resistance to BF and reviews its potential mechanisms.

[Origin, development, and modern application value of Chinese herbal lozenges].

Lozenge is one of the traditional dosage forms of Chinese medicine. It has been recorded in traditional Chinese medical classics of all dynasties since the Eastern Han Dynasty and has been developing and evolving continuously. The unique pharmaceutical methods and application scope are the driving force of its emergence, existence, and development. Up to now, lozenge has been included in the Chinese Pharmacopoeia as an independent dosage form. Lozenge has been endowed with new meaning by modern Chinese medicine pharmaceutics, which is worth tracing origin and exploring value. The present study reviewed the origin and development of lozenge, compared lozenge with other similar dosage forms, analyzed the characteristics of modern and ancient dosage forms of lozenge, and discussed the development prospect and potential of lozenge in combination with the demand development of modern Chinese medicine preparation, so as to provide references for expanding the modern application of lozenge.

The pulmonary biopharmaceutics and anti-inflammatory effects after intratracheal and intravenous administration of Re-Du-Ning injection.

BACKGROUND: Re-Du-Ning injection (RDN) is a renowned heat-clearing traditional Chinese medicine for the treatment of respiratory diseases owing to its anti-inflammatory effects. However, very little is known about the pulmonary distribution and lung exposure-efficacy relationships. This study aimed to investigate the pulmonary distribution and biopharmaceutics concerning lung penetrability and affinity and the local anti-inflammatory effects after intravenous and pulmonary administration of RDN. METHODS: Two iridoids and seven phenolic acid components were selected as the chemical markers in RDN. The in vitro pulmonary distribution and biopharmaceutics were conducted by evaluating the binding and disassociation kinetics of chemical markers in lung tissue explants whereas the in vivo evaluation was performed by determining the time-dependent concentrations of chemical markers in plasma, lung epithelial lining fluid (ELF), lung tissues and immune cells in the ELF after intratracheal and intravenous administrations of RDN. The inhibitory effects on tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production were used to evaluate the anti-inflammatory effect of RDN on lung tissues in vitro and on mice with LPS-induced lung inflammation. RESULTS: The chemical markers of RDN exhibited excellent lung penetrability but poor lung affinity in vitro and in vivo. After intravenous administration, the chemical markers appeared to rapidly penetrate through the lung tissue to reach the ELF, leading to markedly higher drug exposure to ELF and immune cells in the ELF than to lung tissues. Compared to intravenous injection, the intratracheal instillation of RDN increased drug exposure to lung tissue and immune cells in the ELF by up to > 80-fold, leading to improved anti-inflammatory potency and prolonged duration of action. CONCLUSION: The drug exposure to immune cells in the ELF was correlated with the lung-targeted anti-inflammatory effects of RDN and pulmonary delivery has the potential to replace intravenous injection of RDN for the treatment of respiratory diseases.

Origin, development, and modern application value of Chinese herbal lozenges / 中国中药杂志

Lozenge is one of the traditional dosage forms of Chinese medicine. It has been recorded in traditional Chinese medical classics of all dynasties since the Eastern Han Dynasty and has been developing and evolving continuously. The unique pharmaceutical methods and application scope are the driving force of its emergence, existence, and development. Up to now, lozenge has been included in the Chinese Pharmacopoeia as an independent dosage form. Lozenge has been endowed with new meaning by modern Chinese medicine pharmaceutics, which is worth tracing origin and exploring value. The present study reviewed the origin and development of lozenge, compared lozenge with other similar dosage forms, analyzed the characteristics of modern and ancient dosage forms of lozenge, and discussed the development prospect and potential of lozenge in combination with the demand development of modern Chinese medicine preparation, so as to provide references for expanding the modern application of lozenge.

The anti-cancer properties of neem (Azadirachta indica) through its antioxidant activity in the liver: its pharmaceutics and toxic dosage forms. A literature review.

OBJECTIVES: The neem (Azadirachta indica) have been used in herbal medicine for the treatment of multiple diseases, particularly cancer. The mechanism of anti-cancer properties of neem are far from clear. However, it is well accepted that anti-cancer effects of neem is mediated via its hepatic anti-oxidant activity. In the present review, we are going to classify in vitro and in vivo studies about anti-cancer activity of neem via its hepatic anti-oxidant activity. We also summarize its active ingredients and some therapeutic and toxic dosage forms. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for neem, A. indica, anti-cancer, anti-tumor, carcinogen, liver, antioxidant activity, neem ingredients, and glutathione. Electronic database searches combined and duplicates were removed. RESULTS: The neem plant have been used in herbal medicine for the treatment of various diseases, particularly cancer. The mechanisms of anti-cancer effects of neem are far from clear. Cancerous cells growth can induce imbalance the oxidant and anti-oxidant activity in various organs particularly in the liver. Therefore, it seems that neem have anti-cancer effects via restore of the antioxidant disturbances close to the control ones in the liver. Additionally, administration of neem extract can induce oncostatic potential via several mechanism including; suppression of the NF-κß pathway, increased expression of tumor suppressor (such as p53 and pTEN), decreased expression of oncogenes (such as c-Myc), and increased apoptosis in cancerous cells. The median lethal dose (LD50) value for extracts of neem was higher than 2,500 mg/kg. CONCLUSIONS: It is suggested that neem plays pivotal role in the prevention and treatment of cancer via its hepatic antioxidant activity. Indeed, application of neem extract can decreased tumor growth via restore of the antioxidant disturbances close to the control ones in the liver.

Erding formula and bioactive markers in hyperuricemia: towards rational scientific approaches for the modernization of Traditional Chinese Medicine

Introduction: Traditional Chinese Medicine (TCM) represents one of the first holistic approaches in the world to treat and prevent disease. Herbal medicine is one of the major therapeutic remedy in TCM. It often involves multi-herb therapies instead of single herb preparations. Parallel to western medicine, hundreds of herbal formulas have been made available as finished products. Currently, the use of herbal products is popular as treatment option or to complement western medicine. Indications of the herbal formulas were established by TCM terms such as heat-clearing and/or detoxifying which lack modern pharmacological meanings. It is difficult for people without relevant background to understand such terms and their implications for treatments. Furthermore, due to the quality control issues of herbal medicines which contain multiple constituents, consumers may be confronted with the risk of using unstandardized products. Hence, in this thesis, the modernization of TCM is discussed through employing scientific pharmaceutical approaches to a traditional formula, called Erding formula (EF). The aim was to investigate if a new indication, hyperuricemia, can be assigned to a heat-clearing and detoxifying formula. Our hypothesis was: Can Erding formula be used for hyperuricemia treatment and is esculetin a bioactive marker for this new indication? Methods: A hypoxanthine and potassium oxonateinduced hyperuricemic mouse model, a xyleneinduced inflammatory mouse model, and an acetic acidinduced pain model were used to investigate EF and its constituent herbs. The quantity of esculetin was measured by high-performance liquid chromatography. The therapeutic effect of esculetin was assessed using potassium oxonate induced hyperuricemic mouse model, and esculetin and its metabolites were characterized in serum via ultra-performance liquid chromatographyquadrupole time-of-flight mass spectrometry. To develop a modern dosage form, a laboratory-scale wet bead milling approach was employed to prepare esculetin nanocrystals. The formulation was further optimized by design of experiment, and an optimized formulation was then characterized for its saturation solubility and short-term stability. Results: The study showed that EF and Viola yedoensis Makino (Viola) lowered uric acid (UA) levels, while EF and all four individual herbs had antiinflammatory and analgesic activities. These findings revealed that EF was able to treat hyperuricemia and suggested that Viola was the main herb in EF on reducing UA levels. The study showed that esculetin significantly reduced UA levels and six metabolites of esculetin were identified in serum. This confirms that esculetin was absorbed and is a suitable bioactive and quality control marker for EF in hyperuricemia treatment. An esculetin-Povacoat nanocrystal formulation with a 200 nm particle size was successfully prepared. The formulation presented up to a 1.5-fold increase in saturation solubility compared to the bulk esculetin and it was stable for 180 days. Conclusion: The studies proved that Erding formula can be used for hyperuricemia treatment with esculetin as bioactive quality control marker. As well, a new nano-sized formulation of the bioactive marker, esculetin, was created. This presented the possibility to develop an innovative nanotechnological product of the active substances derived from herbal medicine. The findings facilitated a better understanding of TCM terms and concept through mechanistic scientific experiments. This study revealed a potential pathway and an idea to modernize TCM without setting aside its unique concepts. This might increase the global acceptance of TCM products. Furthermore, the TCM concept might be useful in the development of multi-component drug products

Medicina Tradicional Chinesa (MTC) representa uma das primeiras abordagens holísticas em âmbito global para tratar e prevenir doenças. A fitoterapia consiste na principal terapia na MTC. Frequentemente, envolve terapias com múltiplas ervas em vez de preparações individuais. Paralelamente à medicina ocidental, centenas de fórmulas herbais foram disponibilizadas como produtos acabados. Atualmente, o uso de produtos fitoterápicos é popular como opção de tratamento ou para complementar a medicina ocidental. As indicações das fórmulas fitoterápicas foram estabelecidas pelos termos da MTC, tais como "limpeza pelo calor e / ou desintoxicante", que não têm significados farmacológicos modernos. É difícil para a população em geral e mesmo para profissionais sem histórico relevante na área entender tais termos e suas implicações para os tratamentos. Além disso, devido às questões de controle de qualidade dos medicamentos fitoterápicos que contêm múltiplos constituintes, os pacientes podem ser confrontados com o risco de usar produtos não padronizados. Assim, nessa tese, a modernização da MTC é discutida por meio da utilização de abordagens farmacêuticas científicas para uma fórmula tradicional, denominada fórmula de Erding (FE). O objetivo foi o de investigar se uma nova indicação, a hiperuricemia, pode ser atribuída a uma fórmula desintoxicante e de compensação de calor. Nossa hipótese foi: a fórmula de Erding pode ser usada para tratamento de hiperuricemia e a esculetina é um marcador bioativo para essa nova indicação? Foi empregado modelo de camundongo hiperuricêmico induzido por hipoxantina e oxonato de potássio, outro modelo de camundongo inflamatório induzido por xileno e, adicionalmente, modelo de dor induzida por ácido acético. Esses modelos foram usados para investigar a FE e suas ervas constituintes. A quantidade de esculetina foi determinada por cromatografia líquida de alta eficiência. O efeito terapêutico da esculetina foi avaliado utilizando modelo de camundongo hiperuricêmico induzido por oxonato de potássio, e a esculetina e seus metabólitos foram caracterizados no soro por cromatografia líquida de alto desempenho - espectrometria de massa. Para desenvolver forma farmacêutica moderna, uma abordagem de moagem em escala úmida reduzida foi empregada tendo em vista a preparação de nanocristais de esculetina. A formulação foi ainda otimizada empregado planejamento experimental. Essa fórmula foi caracterizada quanto à sua solubilidade de saturação e estabilidade a curto prazo. O estudo mostrou que a FE e a Viola yedoensis Makino (Viola) reduziram os níveis de ácido úrico (AU), enquanto a FE e as quatro plantas individuais apresentaram atividades antiinflamatória e analgésica. Esses resultados revelaram que a FE foi capaz de tratar a hiperuricemia e sugeriu que a viola foi a principal erva da FE na redução dos níveis de AU. O estudo mostrou também que a esculetina reduziu significativamente os níveis de AU e os seis metabólitos da esculetina foram identificados no soro. Tal resultado confirma que a esculetina foi absorvida e pode ser usada como marcador de controle bioativo e de qualidade para FE, no tratamento da hiperuricemia. A formulação de nanocristais de esculetin-povacoat® apresentou tamanho de partícula de 200 nm. A formulação apresentou aumento de 1,5 vezes na solubilidade de saturação em comparação com a esculetina em escala micrométrica e manteve-se estável durante 180 dias. Os estudos comprovaram que a fórmula de Erding pode ser utilizada no tratamento da hiperuricemia empregando a esculetina como marcador bioativo de controle de qualidade. Além disso, foi desenvolvida formulação inovadora, em escala nanométrica, do marcador bioativo, a esculetina. Esse resultado permitiu desenvolver produto com base nanotecnológica das substâncias ativas derivadas do fitoterápico, assim comol permitiram melhor compreensão dos termos e dos conceitos da MTC por meio de experimentos científicos mecanicistas. Esse estudo revelou potencial para a modernização da MTC sem excluir seus conceitos únicos. Isso pode aumentar a aceitação global dos produtos MTC. Além disso, o conceito de MTC pode ser útil no desenvolvimento de medicamentos de múltiplos componentes

Análisis temático desde el Observatorio Métrico de Coronavirus de las investigaciones publicadas en PubMed / Thematic analysis from the Coronavirus Metric Observatory of the research published in PubMed

La experiencia científica de los últimos meses contra la pandemia de la COVID-19 muestra una celeridad nunca vista, así mismo, es inédita la velocidad en la publicación de los resultados de tales investigaciones. El contexto revela la carrera sostenida que tiene la ciencia contra la expansión de este letal virus. En el presente estudio se documentan evidencias bibliográficas para reconocer a PubMed como uno de los principales recursos de información científica sobre medicina que existen en el mundo. Es una necesidad del gremio científico médico e investigativo en el contexto de la COVID-19 conocer las temáticas que abordan los principales artículos de la base de datos. El objetivo de esta investigación es analizar el comportamiento temático de los artículos publicados por PubMed sobre coronavirus en el primer semestre del año 2020 utilizando como herramienta de análisis al Observatorio Métrico de Coronavirus de la Universidad de Pinar del Río. El interés científico del estudio se concentra en las variables materia, MeSH y palabras clave; las que son analizadas con diferentes técnicas métricas que facilitan la visualización e interpretación de los resultados. Se demostró que PubMed, entre los temas más recurrentes, ha socializado investigaciones en virología, microbiología, farmacéutica, medicina general integral y sus relaciones con la oncología, neurología, pediatría, psicología, psiquiatría, oftalmología, nutrición, telemedicina y dispositivos médicos(AU)

The scientific experience of recent months against the COVID-19 pandemic shows a speed never seen before, likewise, the speed in the publication of the results of such investigations is unprecedented. The context reveals the sustained race in science against the spread of this deadly virus. In this study, bibliographic evidence is documented to recognize PubMed as one of the main sources of scientific information on medicine that exist in the world. In the context of COVID-19, it is a necessity for the scientific, medical and research union to know the issues addressed by the main articles in the database. The objective of this research is to analyze the thematic behavior of the articles published by PubMed on coronavirus in the first half of 2020, using the Coronavirus Metric Observatory of the University of Pinar del Río as an analysis tool. The scientific interest of the study is concentrated in the variables subject, MeSH and keywords; those that are analyzed with different metric techniques that facilitate the visualization and interpretation of the results. It was shown that PubMed, among the most recurrent topics, has socialized research in virology, microbiology, pharmaceuticals, comprehensive general medicine and their relationships with oncology, neurology, pediatrics, psychology, psychiatry, ophthalmology, nutrition, telemedicine and medical devices(AU)

Eremantholide C from aerial parts of Lychnophora trichocarpha, as drug candidate: fraction absorbed prediction in humans and BCS permeability class determination.

BACKGROUND: Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip has been used in folk medicine to treat pain, inflammation, rheumatism and bruises. Eremantholide C, a sesquiterpene lactone, is one of the substances responsible for the anti-inflammatory and anti-hyperuricemic effects of L. trichocarpha. OBJECTIVES: Considering the potential to become a drug for the treatment of inflammation and gouty arthritis, this study evaluated the permeability of eremantholide C using in situ intestinal perfusion in rats. From the permeability data, it was possible to predict the fraction absorbed of eremantholide C in humans and elucidate its oral absorption process. METHODS: In situ intestinal perfusion studies were performed in the complete small intestine of rats using different concentrations of eremantholide C: 960 µg/ml, 96 µg/ml and 9.6 µg/ml (with and without sodium azide), in order to verify the lack of dependence on the measured permeability as a function of the substance concentration in the perfusion solutions. RESULTS: Eremantholide C showed Peff values, in rats, greater than 5 × 10-5 cm/s and fraction absorbed predicted for humans greater than 85%. These results indicated the high permeability for eremantholide C. Moreover, its permeation process occurs only by passive route, because there were no statistically significant differences between the Peff values for eremantholide C. CONCLUSION: The high permeability, in addition to the low solubility, indicated that eremantholide C is a biologically active substance BCS class II. The pharmacological activities, low toxicity and biopharmaceutics parameters demonstrate that eremantholide C has the necessary requirements for the development of a drug product, to be administered orally, with action on inflammation, hyperuricemia and gout.

Contribución a la caracterización biofarmacéutica de un extracto de hojas de Passiflora ligularis (granadilla) optimizado en flavonoides / Contribution to the biopharmaceutical characterization of an extract of leaves of Passiflora ligularis (granadilla) optimized in flavonoids

Passiflora ligularis, comúnmente conocida como granadilla, es una especie que ha demostrado resultados prometedores de actividad hipoglicemiante/antidiabética. Con el presente trabajo, se aplicó la utilidad del Sistema de Clasificación Biofarmacéutica en el estudio de nuevos principios activos, para caracterizar y evaluar un extracto de hojas de P. ligularis, como matriz de partida útil en el de diseño y desarrollo de una formulación; y así, contribuir al desarrollo de un producto fitoterapéutico a partir de las hojas de esta especie. Inicialmente, se estandarizaron las condiciones de extracción de flavonoides (considerados como los marcadores activos) a partir de las hojas, mediante extracción asistida por ultrasonido, para lo cual, previamente se desarrolló y validó una metodología analítica por UHPLC-DAD. Se evaluó la actividad farmacológica del extracto optimizado según un modelo in vitro de actividad antiglicante y, en el modelo in vivo de tolerancia a la glucosa en ratones Swiss ICR. Adicionalmente, se determinó la estabilidad bajo condiciones de estrés, y las características biofarmacéuticas, solubilidad y permeabilidad intestinal, del extracto optimizado, en función de los marcadores activos. De acuerdo con el análisis de superficie de respuesta, las condiciones óptimas de extracción de flavonoides por ultrasonido fueron, etanol 63%, 70ºC, durante 33 minutos; el extracto optimizado demostró mayor actividad inhibitoria de la formación de los productos finales de glicación avanzada, y, mejor actividad anti-hiperglicemiante, que un extracto de las hojas obtenido por infusión, método de extracción de la medicina tradicional. Por otro lado, se catalogó el extracto optimizado como prácticamente estable, fotoestable, lábil y muy lábil, bajo condiciones oxidativas, fotolíticas, de hidrólisis neutra e hidrólisis ácida-básica, respectivamente. Por último, se comprendieron algunos de los factores que influencian el proceso de absorción intestinal de los flavonoides presentes en el extracto, como su alta solubilidad, y baja permeabilidad en el modelo in situ SPIP (Single Pass Intestinal Perfusion), que permitieron catalogarlo dentro de la clase III del sistema de clasificación biofarmacéutico (SCB). Con el fin de evaluar posibles efectos de la matriz vegetal sobre las propiedades biofarmacéuticas de los marcadores activos, se estudiaron dichas características en el flavonoide mayoritario (isoquercetina), al ser un componente dentro del extracto o un compuesto puro. En el primer caso, se clasificó también dentro de la clase III, y en el segundo, como clase II (baja solubilidad-alta permeabilidad); considerándose la baja solubilidad como uno de los mayores retos a superar en etapas de investigación y desarrollo Debido a todo lo anterior, se propone aprovechar el extracto optimizado y caracterizado de hojas de P. ligularis, aplicando estrategias de tecnología farmacéutica que favorezcan la permeabilidad de principios activos clase III, para el diseño y desarrollo de un potencial producto fitoterapéutico, que ayude en el tratamiento de la hiperglicemia y/o diabetes.

Chemical and Physical Characterization of the Hackberry (Celtis australis) Seed Oil: Analysis of Tocopherols, Sterols, ECN and Fatty Acid Methyl Esters.

For the very first time, the nutritional and physicochemical properties of the oil extracted from hackberry Celtis australis fruit were investigated with the aim of possible applications of such wild fruit oil. The physicochemical properties such as peroxide value, acidity, saponification, iodine value and total fat content of the extracted oil were examined extensively. The obtained results showed that peroxide value, acidity, saponification, iodine value and total fat content of the extracted oil were found to be 4.9 meq O2/kg fat, 0.9 mg KOH/g fat, 193.6 mg KOH/g fat, 141.52 mg I2/g fat and ~5%, respectively. The predominant fatty acid found in this wild fruit is linoleic acid which was calculated to be 73.38%±1.24. In addition, gamma-tocopherol (87%) and ß-sitosterol (81.2%±1.08) were the major tocopherol and sterol compositions found in Celtis australis seed oil. Moreover, equivalent carbon number (ECN) analysis has indicated that the three linoleic acids are the main composition of the triacylglycerols extracted from Celtis australis. Also, the high value of omega 6 and ß-sitosterol make this oil applicable in cosmetics and pharmaceutical applications.

[Present and Future of the Japanese Pharmacopoeia in the Clinical Setting and Pharmacy Education].

The Japanese Pharmacopoeia (JP) has played a major role in ensuring the quality of drugs used in Japan as the ultimate source of information on pharmaceuticals. Physicians and pharmacists can reliably use drugs in the clinical setting because they trust the quality when medical treatment progresses smoothly. When there is a problem or challenge, they can refer to the JP. For pharmacists, both the quality of the drug and information on its efficacy and safety are indispensable. Twelve years have passed since the introduction of a 6-year course in pharmacy education, but the weight placed upon the JP has not increased in the educational curriculum. A specific behavioral objective of describing the significance and structure of the JP is included in the revised model core curriculum for pharmacy education. However, fewer than 60% of pharmacy schools have courses specifically focusing on the JP. Professors of physical chemistry, analytical chemistry, pharmaceutics, and pharmacognosy often teach the relevant sections of the JP in their lectures. The foundations of the Japanese manufacturing industry have been questioned because data falsification and inspection fraud have been disclosed in numerous fields. Therefore, ethical education for those who use the JP is a prerequisite for ensuring the reliability of pharmaceuticals.

Intravenous Admixture Preparation Considerations, Part 3: Methods and Techniques to Decrease Incompatibilities.

The study of intravenous admixture compatibility is an excellent application of "clinical pharmaceutics." Clinical pharmaceutics involves the study and application of pharmaceutics and pharmaceutic (physical pharmacy/ chemistry) principles to clinical compounding situations to aid in the evaluation of each intravenous admixture. This series includes compatibility and stability considerations in intravenous admixture compounding. Part 2 of this series of articles discussed many factors that should be considered that may give rise to compatibility concerns, as well as drug sorption issues. In this issue (Part 3), there is a discussion on the methods and techniques that can be used to decrease the occurrence and incidence of incompatibilities, along with some alternate techniques to consider when some approaches do not seem feasible.

Matrix effects of the hydroethanolic extract and the butanol fraction of calyces from Physalis peruviana L. on the biopharmaceutics classification of rutin.

OBJECTIVES: The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic extract of calyces from Physalis peruviana L. (HEE) and its butanol fraction (BF), on the biopharmaceutics classification of their major compound, quercetin-3-O-rutinoside (rutin, RU). METHODS: Rutin was quantified by HPLC-UV, and Caco-2 cell monolayer transport studies were performed to obtain the apparent permeability values (Papp ). Aqueous solubility was determined at pH 6.8 and 7.4. KEY FINDINGS: The Papp values followed this order: BF > HEE > RU (1.77 ± 0.02 > 1.53 ± 0.07 > 0.90 ± 0.03 × 10-5  cm/s). The lowest solubility values followed this order: HEE > RU > BF (2.988 ± 0.07 > 0.205 ± 0.002 > 0.189 ± 0.005 mg/ml). CONCLUSIONS: According to these results, rutin could be classified as BCS classes III (high solubility/low permeability) and IV (low solubility/low permeability), depending on the plant matrix. Further work needs to be done in order to establish how apply the BCS for research and development of new botanical drugs or for bioequivalence purposes.

[Pharmaceutics research advances in oral administration of puerarin].

Puerarin is a naturally occurring isoflavone C-glycoside,isolated from the root of Pueraria lobata,which has attracted extensive attention in the medical circles because of its various pharmacological effects,such as vasodilation,cardioprotection,neuroprotection,antioxidant,anticancer,anti-inflammation,alleviating pain,promoting bone formation,inhibiting alcohol intake,and attenuating insulin resistance. However,its low oral bioavailability has limited its clinical application. This review gives a comprehensive summary of the researches on physicochemical properties,pharmacokinetics( absorption,distribution,metabolism and excretion,pharmacokinetic parameters) in oral administration,and pharmaceutics research strategies of puerarin in recent years,and the in vivo behavior difference between multicomponent and single component environment was also summarized. The reasons( low water solubility,poor membrane permeability,short half-life,inhibition of P-gp efflux and first-pass metabolic effects of intestinal enzymes,etc.) for low bioavailability were concluded and the idea that multicomponent enviroment would affect the bioavailability was clarified. The aim of this review is to provide literature basis for the development of new dosage forms and new technologies for multivariate compound drug delivery system to improve the bioavailability of oral puerarin,and to propose ways to improve the bioavailability of BCS Ⅳ drugs derived from traditional Chinese medicine by fully enlarging the synergistic effect of multi-components or reasonably using the inhibitory effect between components.

[Research and development thought on biopharmaceutics classification system of Chinese materia medica].

The biopharmaceutics classification system( BCS) is a scientific framework or method for classifying drugs based on drug solubility and permeability,which can be used to provide drug bioavailability-absorption correlation analysis. Based on the characteristics of multi-component and multi-target of traditional Chinese medicine( TCM) as well as the concept,method and technology of BCS,the research group proposed biopharmaceutics classification system of Chinese materia medica( CMMBCS) and carried out research and data accumulation of classical prescriptions. Based on the previous research results,further development ideas under the CMMBCS concept and framework were further proposed in this study. In the course of research,the influence of the intermediate links of the complex interactions of the multi-component environment was omitted,and the component absorption studies on the main clinical effects of prescription ingredients were directly concerned,or the components and data were reversely extracted from the aspects of metabolism,pharmacodynamic pathways and absorption principles. Studies were conducted from two aspects( single component and compound prescription) to comprehensively evaluate the absorption properties of TCM compound. In the research path,the different ways in which Chinese medicine could exert its efficacy were fully considered,and CMMBCS classification and establishment rules were clarified mainly by focusing on the absorption pathway into the blood. Specifically,the network pharmacology and molecular docking technology were used to screen the compound index components of TCM; the absorption rules were studied by the physiologically based pharmacokinetic models and the absorption parameters of CMMBCS were calculated by reverse reasoning. Then the CMMBCS classification of TCM prescription was corrected by studying the efficacy or absorption pathway. In this paper,the theoretical framework and research methodology of CMMBCS were systematically improved based on the establishment of CMMBCS basic theory,the supplementary of drug-oriented research ideas and the application of modern mature Chinese medicine methodology.