Comparative study on the methods to determine disintegration time of oral soluble films / 药学学报

Disintegration time is a key parameter that affects the palatability and compliance of oral soluble films. At present, there is no standard method to determine the disintegration time of oral soluble films. In this study, we compared the six methods (pharmacopoeial disintegration method, petri dish method, sponge surface method, slide frame and ball method, partially immersed into liquid (without weight attached) and partially immersed into liquid (with weight attached)) to determine the in vitro disintegration time of oral soluble films with different thickness, and evaluated the correlation with the in vivo disintegration time. The results showed that the repeatability and correlation of pharmacopoeial disintegration method and the partially immersed into liquid method (with weight attached) were excellent, with the endpoint of disintegration testing easy to determine. Partially immersed into liquid method (with weight attached), properly simulating the physiological condition in oral cavity, showed strong operability, good repeatability and in vitro-in vivo correlation, and was suitable for in vitro disintegration evaluation of oral soluble film dosage form. The adult sensory evaluation study was a research-based clinical trial conducted with informed consent from all subjects in accordance with the ethical requirements of Good Clinical Practice.

Application of physiologically based pharmacokinetic model in drug development and several questions being thought / 中国临床药理学与治疗学

Physiologically based pharmacokinetic (PBPK) model is based on physiology, anatomy, enzymes for drug metabolism, characteristic of drug transport, physicochemical property of drug and drug-body interaction. Thus, PBPK model may quantitatively predict: concentration-time profiles of drug and its metabolites in plasma and tissues; pharmacokinetics of drug under disease status; pharmacokinetics of drug in special population; pharmacokinetics of drugs in human derived from experimental animals; in vivo pharmacokinetics of drugs based on in vitro parameters for metabolism and transport; pharmacokinetics of drugs from different formations; pharmacodynamics or toxicity of drugs based on in vitro parameters for metabolism, transport, activity or toxicity of drug; drug-drug interaction; individual contributions of enzymes and transporters to in vivo drug disposition. Here, we would review applications of PBPK model in drug development and several questions which should be thought through a series of examples.

Biphasic dissolution test and its application in the evaluation of poorly soluble drug preparations / 药学学报

Biphasic dissolution test, consisting of immiscible aqueous and organic phase, is an in vitro dissolution method that simultaneously measures the dissolution and partition of drugs. Due to the advantages of simulating in vivo absorption and overcoming the influence of surfactants on dissolution, it has been widely used to evaluate the poorly soluble drugs in vitro dissolution. Based on the relevant research in this field in recent years, this review summarizes the history, dissolution device, theoretical model and application of the biphasic dissolution test. Finally, the prospects in the development of biphasic dissolution test are also outlined.

Research progress of in vitro-in vivo correlation of injectable polylactide-polyglycolide microspheres / 药学学报

As a depot drug delivery system, injectable polylactide-polyglycolide (PLGA) sustained-release microspheres have been successfully used to treat many diseases since the first microsphere product Lupron depot was approved for marketing in the United States in 1989. It has the ability of long-term release in the body for several days to several months, which can not only reduce the times of administration, but also reduce the drug blood concentration fluctuations, significantly improve the safety and patient compliance. In vitro-in vivo correlation (IVIVC) makes the development of microspheres more possible. It can describe the dynamic information of drug release in vivo through the in vitro release behavior of microspheres, and can reduce the workload of each stage and shorten the time span while characterizing the performance of microspheres. IVIVC can provide guidance or support for drug development, production changes, supervision and management. This article summarizes the release mechanism of injectable PLGA sustained-release microspheres, common measurement methods and theories of in vitro and in vivo release. And we also focus on the establishment and application of IVIVC, especially A level IVIVC in the field of microsphere preparations, to provide a reference for further study on in vitro-in vivo correlation of microspheres.

In vitro-in vivo correlation of goserelin acetate microspheres / 药学学报

The objective of this paper was to establish a level A in vitro-in vivo correlation (IVIVC) for goserelin acetate extended release microspheres for injection. Three kinds of goserelin acetate microspheres with different release rates were prepared and the critical physicochemical properties, such as drug loading, particle size, glass transition temperature and morphology were characterized. In vitro dissolution test of the prepared goserelin acetate microspheres was performed using sample-and-separate method at 45 ℃ in 5% (v/v) methanol. The morphology of the microspheres and the molecular weight of poly (lactic-co-glycolic acid) (PLGA) of the prepared goserelin acetate microspheres were investigated to research the release mechanism of microspheres. The plasma concentration of goserelin was detected after intramuscular injection of goserelin acetate microspheres to SD rats, and correlated with the in vitro release profiles after processing by percent AUC method. The pharmacokinetic experimental protocol of goserelin acetate microspheres for injection in SD rats was approved by the Animal Ethics Committee of Shandong Luye Pharmaceutical Co., Ltd. The results indicated that the developed sample and separate method was able to detect differences in the release characteristics of the prepared goserelin acetate microspheres, and the in vitro-in vivo correlation of goserelin acetate microspheres was excellent (r > 0.98) and had good predictive ability in SD rats.

In vitro accelerated release of triptorelin acetate microspheres and the in vivo/in vitro correlation / 国际药学研究杂志

Objective To establish an in vitro accelerated release method of triptorelin acetate microspheres with good in vi-tro/in vivo correlation(IVIVC). Methods The in vivo release of triptorelin acetate from microspheres was obtained by residual method in rats. Influences of pH value,concentration of ethanol,temperature,rotation speed and concentration of antiseptic on the in vitro accel-erated release were studied,then the correlation between in vitro accelerated release and in vivo release of the microspheres was estab-lished by adjusting the release conditions. Results The in vitro accelerated release medium of triptorelin acetate microspheres composed of 15%ethanol solution(containing 0.06%Tween 80 and 0.1%benzalkonium chloride)at 55℃with rotating rate of 200 r/min. The cumulative release of triptorelin acetate from microspheres was 87.35%at 30 h under accelerated release condition,equivalent to in vivo release for 30 days. The established in vitro accelerated release had a good correlation with that of in vivo(y=0.8845x+12.4510, R2=0.9938). Conclusion The in vitro accelerated release of triptorelin acetate microspheres could correlate well with in vivo release and has a potential application in rapid and effective evaluation of triptorelin acetate microspheres.

Evaluating on correlation between in vivo absorption kinetics and in vitro release kinetics of multiple components contained in gbe sustained-release pellets / 中草药

Objective The relationship between the in vivo absorption kinetics and the in vitro release kinetics of various components (including flavonoids and terpenoids) contained in Ginkgo biloba extract (GBE) sustained-release pellets were evaluated using multi-component integration kinetics which could provide a reference for more accurate assessment of in vitro and in vivo correlation. Methods The release rates in vitro of main ingredients (quercetin, isorhamnetin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C) were detected by HPLC-MS/MS. The integrated drug concentration was calculated, and the release rates in vitro of integrated components were then depicted according to the results. Plasma was collected at different time points after oral administration of GBE sustained-release pellets, multiple components contained in GBE sustained-release pellets were then determined. A novel approach of self-defined weighting coefficient (Wj) based on the area under the curve from zero to infinity AUC0—∞ had been created to obtain the holistic pharmacokinetic profiles of GBE sustained-release pellets. To evaluation the in vitro-in vivo correlation of GBE sustained-release pellets, the percent of integrated in vivo absorption calculated by the Wagner-Nelson methodwas plotted versus the percent of integrated in vitro drug release at the same time. Results The components contained in sustained- release pellets had a good release, the Wj of each component in GBE sustained-release pellets were as follows: quercetin, 0.248 1; isorhamnetin, 0.009 2; bilobalide, 0.228 2; ginkgolide A, 0.296 4; ginkgolide B, 0.132 4; ginkgolide C, 0.090 3. The in vivo-in vitro correlation equation was Y = 0.930 8 X + 12.84, r = 0.962 9, indicated that the correlation between in vivo absorption kinetics and in vitro release kinetics is good. Conclusion The efficacy of the herbal medicines depends on a variety of components combined effect, using the integrated pharmacokinetic to analyze IVIVC could take the characteristic of each component into account, which is helpful for the study of the correlation between in vivo absorption kinetics and in vitro release kinetics.

Determinação das curvas de absorção, perfis de dissolução e estabelecimento de correlação in vitro-in vivo por métodos in silico utilizando o GastroPlusTM e o DDDPlusTM / Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

O uso de programas de computador para prever a absorção de fármacos em humanos e simular perfis de dissolução tem se tornado uma ferramenta bastante valiosa na área farmacêutica. O objetivo deste trabalho foi utilizar métodos in silico por meio dos programas de computador GastroPlusTM e DDDPlusTM para simular curvas de absorção de fármacos, perfis de dissolução e estabelecer correlações in vitro-in vivo (CIVIVs). O material aqui apresentado é constituído por cinco capítulos incluindo os fármacos cetoprofeno, pirimetamina, metronidazol, fluconazol, carvedilol e doxazosina. No capítulo 1 são apresentadas curvas plasmáticas simuladas para comprimidos matriciais de cetoprofeno, sendo estabelecida a CIVIV. A utilização de simulações de ensaios de dissolução intrínseca para os fármacos pirimetamina e metronidazol como uma ferramenta para classificação biofarmacêutica é detalhada no capítulo 2. No capítulo 3, a simulação de curvas plasmáticas a partir de cápsulas de fluconazol contendo diferentes perfis de dissolução é demonstrada como uma ferramenta para bioisenção. Estudos de CIVIV foram também realizados para comprimidos de liberação imediata de carvedilol a partir dos perfis de dissolução no capítulo 4. Já o capítulo 5 trata da aplicação de simulações de ensaios de dissolução para o desenvolvimento de formulações de liberação prolongada de doxazosina. As simulações das curvas plasmáticas, assim como a CIVIV, obtidas com o auxílio do programa GastroPlusTM, além dos ensaios de dissolução intrínsica e os perfis de dissolução obtidos por meio do uso do programa DDDPlusTM apresentaram-se como ferramentas de grande aplicação na previsão de características biofarmacêuticas sobre os fármacos e formulações, permitindo redução de tempo e custo com trabalho experimental em laboratório

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work

Evaluation of pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancer following transdermal administration / 中国中药杂志

The study was carried out to investigate the pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancers (PE) following transdermal administration. With Azone as the positive control, ibuprofen hydrogels containing Chuanxiong oil, Angelica oil or Cinnamon oil as PE were prepared and administered to the rat abdominal skin. Then the pharmacokinetics of ibuprofen following transdermal administration were investigated and compared. In comparison with negative control (no PE was added), the relative bioavailability values with the addition of Chuanxiong oil, Angelica oil, Cinnamon oil and Azone as PE were determined to be 161.87%, 171.05%, 151.37% and 148.66%, respectively. In vitro/in vivo correlation analysis was performed by deconvolution method and the results demonstrated a good correlation between in vitro and in vivo percutaneous absorption studies. The correlation coefficients were measured to be 0.999 7, 0.995 2 and 0.999 4 for Chuanxiong oil, Angelica oil and Cinnamon oil respectively. In summary, Chuanxiong oil, Angelica oil and Cinnamon oil as PE could significantly enhance the bioavailability of ibuprofen following transdermal administration. A satisfactory in vitro/in vivo correlation could be obtained by using hydrogel as the dosage form.

Retrospective growth kinetics and radiosensitivity analysis of various human xenograft models / 한국실험동물학회지

The purpose of this study was to delineate the various factors that affect the growth characteristics of human cancer xenografts in nude mice and to reveal the relationship between the growth characteristics and radiosensitivity. We retrospectively analyzed 390 xenografts comprising nine different human cancer lines grown in nude mice used in our institute between 2009 and 2015. Tumor growth rate (TGR) was calculated using exponential growth equations. The relationship between the TGR of xenografts and the proliferation of the cells in vitro was examined. Additionally, we examined the correlations between the surviving fractions of cells after 2 Gy irradiation in vitro and the response of the xenograft to radiation. The TGR of xenografts was positively related to the proliferation of the cells in vitro (r(P)=0.9714, p<0.0001), whereas it was independent of the histological type of the xenografts. Radiation-induced suppression of the growth rate (T/C%) of xenografts was positively related to the radiosensitivity of the cells in vitro (SF₂; r(P)=0.8684, p=0.0284) and TGR (r(P)=0.7623, p=0.0780). The proliferation of human cancer cells in vitro and the growth rate of xenografts were positively related. The radiosensitivity of cancer cells, as judged from the SF₂ values in vitro, and the radiation-induced suppression of xenograft growth were positively related. In conclusion, the growth rate of human xenografts was independent of histological type and origin of the cancer cells, and was positively related to the proliferation of the cancer cells in vitro.

In vitro- In vivo Correlation Studies of Modified Release Tolterodine Tablet Dosage form in Rabbits.

Tolterodine is an antimuscarnic drug that is used for sympathetic treatment of urinary incontinence. Tolterodine modified release tablet, was investigated in rabbit for pharmacokinetic and in vitro–in vivo correlation studies. Tablets were prepared and in vitro release was studied in simulated gastric fluid at 150RPMs. New Zealand albino male rabbits have been used as animal model for in vivo study. A sensitive and simple HPLC method was developed for the determination of Tolterodine content in rabbit plasma. In vitro release studies showed that release patterns followed zero order for around 24h. The in vivo–in vitro correlation coefficients obtained from point-to-point analysis were greater than 99% between concentrations at certain time points obtained from release study in simulated gastric fluid and HPLC analysis of rabbit’s plasma. From the in vitro–in vivo correlation prediction it was evident that the Tolterodine matrix assisted tablet is a good for controlled delivery of Tolterodine.

Progress in research of biorelevant dissolution media / 中国药学杂志

OBJECTIVE: To summarize and analyze the physiological parameters of the gastrointestinal tract, as well as the progress in research of biorelevant dissolution media. METHODS: Related literatures in recent years were reviewed. RESULTS: The biorelevant dissolution media based on physiological relevant information were used to establish the methods of dissolution evaluation in vitro. CONCLUSION: With depth understanding of the physiological parameters of the gastrointestinal tract, in vitro dissolution of dosage form in biorelevant dissolution media could predict in vivo dissolution performance. In addition, biorelevant media were utilized to investigate the food effect on dissolution. Therefore, the liability of evaluating in vitro-in vivo correlation is further improved.

Enhanced Bioavailability of Nimodipine from Bioadhesive Buccal Bilayered Patches in Human Volunteers.

Aims: The objective of the present study was to develop a bioadhesive bilayered buccal patch of Nimodipine (15 mg) using Eudragit Rs 100 as secondary layer and a primary layer with Hydroxy propyl methyl cellulose and Hydroxy propyl cellulose JF. Methodology: Bilayered buccal patches were prepared by solvent casting technique. The absence of physiochemical interactions between NMDP and the polymer were investigated by differential scanning calorimetry (DSC). Bilayered buccal patches of NMDP were evaluated for in vitro drug permeation through porcine buccal membrane, in vitro drug release, moisture absorption, surface pH, mechanical properties and in vitro bioadhesion. Results: The results indicated that suitable bioadhesive bilayered buccal patches with desired permeability could be prepared. The bioavailability study was performed in healthy humans in a crossover experimental design. Bioavailability studies revealed that nimodipine possessed good buccal absorption. The relative bioavailability of the optimized buccal patch was found to be 205% in comparison to 30 mg marketed oral tablet. The formulation CC3 showed 68.84 ± 1.4% release and 46.85 ± 5.1% of drug permeated through porcine buccal membrane in 4 hr. A good correlation was seen between percentage in vitro release the extent of bioavailability for nimodine buccal patch. Conclusion: An improvement of bioavailability was obtained by buccal route to the extent of 2.05 times higher than that of oral route for NMDP. Hence, the development of a bioadhesive bilayered buccal patch for NMDP might be a promising one, as the necessary dose of drug could be decreased, resulting less side effects. Good ex vivo - in vivo correlation was obtained for NMDP.

Formulation and in vitro/in vivo Evaluation of Zidovudine Contained in Solidified Reverse Micellar Delivery System of Immune Compromised Rats.

Aim of the study was to study the in vitro and in vivo evaluation and correlation of zidovudine (AZT) loaded solidified reverse micellar microparticles (SRMMs). The SRMMs composed of goat fat and Phospholipon® 90H in various ratios (1:1, 2:1, 3:1 and 2:3) were prepared by melt dispersion method. AZT (1 %w/w, 2 %w/w, 3 %w/w and 5 %w/w) were incorporated into the SRMMs and preliminary analysis of the preparations on their stability were done visually. The 1:1 formulation was evaluated for the particle size, percentage yield and in vitro studies which was done using SGF and SIF. The in vivo study was done using Wistar albino rats and the in vitroin vivo correlation (IVIVC) was determined by plotting a graph of the fraction of drug absorbed in vivo versus the fraction of drug released in vitro. The yield of the goat fat extraction was 58 %. The particle size and yield of the solid lipid microparticle (SLM) containing 1 %w/w of AZT were 5.10 ± 0.10m and 86.3 ± 4.70% respectively. The fraction of drugs absorbed in vivo were 0.102 μg, 0.114 μg, 0.115 μg, 0.134 μg and 0.123 μg for 1 h, 3 h, 5 h, 8 h and 12 h respectively. A 1:1 ratio of goat fat and Phospholipon® 90H with a high value of correlation coefficient (r2 = 0.909) suggested good level-A correlation between the in vitro-in vivo data of the SLM obtained in the study.

Correlação in vitro-in vivo para formas farmacêuticas sólidas de liberação modificada contendo diclofenaco de sódio / In vitro-in vivo correlation for sodium diclofenac modified release tablet formulations

A correlação in vitro-in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre as propriedades biológicas, ou parâmetros derivados destas, produzidos por uma forma farmacêutica e suas propriedades ou características físico-químicas. O estabelecimento desse tipo de correlação de dados pode possibilitar a substituição dos estudos in vivo, necessários à demonstração da bioequivalência, pelos estudos in vitro, no caso de alterações no processo de fabricação pós-registro. Os sistemas matriciais apresentam, como principal exemplo de material controlador da liberação, substâncias poliméricas formadoras de matrizes hidrofílicas. Hidroxipropilmetilcelulose (HPMC) é um excipiente de escolha para o preparo de matrizes hidrofílicas, devido à capacidade de formação de gel e controle da liberação. O diclofenaco de sódio (DCL) é um antiinflamatório não esteroidal com ação analgésica e antipirética. Considerando suas características físico-químicas e farmacológicas, é objetivo deste trabalho o estabelecimento de uma CIVIV para DCL incorporado em sistemas matriciais. Os comprimidos de DCL com HPMC foram desenvolvidos e submetidos aos ensaios de dissolução utilizando os aparatos 1, 2, 3 e 4 conforme as especificações farmacopeicas. Foi realizado o estudo de biodisponibilidade, seguindo as normas éticas, com as formulações selecionadas. A partir dos dados de absorção obtidos pela técnica de deconvolução e dos dados de dissolução foi estabelecida a correlação. Os resultados demonstraram que o aumento da concentração de HPMC produziu a redução da velocidade de dissolução e, dependendo da condição de estudo, estas diferenças foram mais ou menos significativas. Os comprimidos com concentração intermediária de HPMC (15 a 20%) foram mais sensíveis às alterações de formulação e das condições do ensaio de dissolução. As formulações contendo 30% de HPMC praticamente não modificaram o perfil de dissolução, mesmo com alterações na formulação e condições de estudo. No...

The term in vitro-in vivo correlation (IVIVC) refers to the establishment of a rational relationship between the biological properties, or a parameter derived from a biological property produced by a dosage form, and a physicochemical characteristic or property of the same dosage form. The establishment of IVIVC enables the substitution of in vivo studies for in vitro studies to evaluate bioequivalence, e.g. in case of post-approval changes. Matrix tablets employ mainly hydrophilic polymers to control drug release. Hydroxypropylmethylcellulose (HPMC) is an excipient of choice for preparation of hydrophilic matrices, due to its gel formation and controlled drug release capacities. Sodium diclofenac (SD) is a non-steroidal anti-inflammatory drug with analgesic and antipyretic effects. Considering its physicochemical and pharmacological characteristics, the objective of this work is to establish an IVIVC for HPMC matrix tablets containing SD. HPMC matrix tablets with SD were formulated and submitted to dissolution testing using apparatus 1, 2, 3 and 4 in accordance with pharmacopoeial specifications. The bioavailability study was carried out under ethical guidelines, using the selected formulations. The correlation was obtained by plotting absorption data, obtained from diclofenac plasmatic curves through a deconvolution technique, against dissolution data. The results showed that the increase of HPMC concentration produces a decrease of the drug dissolution rate and these differences were more or less significant, depending on the study conditions. Tablets with intermediate HPMC concentrations (15 to 20%) were more sensitive to changes in dissolution conditions. Formulations containing 30% HPMC do not present changes in dissolution profiles, even when the formulation or the study conditions change. Formulations F1, F2A, F3 and Voltaren® 50 mg as reference product were used in the bioavailability study to establish IVIVC. The linear correlation between...