Study of the influence of carrier bases on the structural and mechanical properties of the rectal dosage form of amiodarone hydrochloride

During last years clopidogrel keeps leading positions among medicines with platelet antiaggregation mechanism. The rectal dosage form with clopidogrel, namely suppository containing 0.075 g of active substance on hydrophilic base with addition of 2 % twin-80 was proposed by the Department of Medicinal Preparations Technology (Zaporizhzhia State Medical University on the base of complex investigations. The aim of present work is the study of structural-mechanical characteristics of rectal dosage form with clopidogrel depending on the temperature of technological process of supposirory manufacturing. The study of structural-mechanical characteristics of suppository mass with clopidogrel was carried out using the rotational viscosimeter “Rheotest2”with cylinder device at the human body temperature (37 oС) and at temperature of manufacturing technological process. Results . Results testify presence of structure in suppository mass system, because limit shear stress increases and effective viscosity decreases with deformation speed rising. Conclusions . Study of consistent characteristics of suppository mass with clopidogrel on polyethylenoxyde base with addition of 2 % twin-80 at the human body temperature was carried out. It was established that it is structural system with expressed thixotropic properties and with the uniform distribution of active substance and excipients both at the moment of manufacturing and during administration or long storage. It was revealed that increasing of temperature of suppository mass to 50 oС doesn't lead to essential modification of its structural-mechanical characteristics and transformation into Newtonian system. Taking obtained results into account it was determined that temperature rate of manufacturing of rectal suppositories with clopidogrel on the hydrofiflic base (processes of mixing, homogenization, pouring into forms) within 50–55 oС creates sufficient fluidity of mass for unhampered technological process and thixotropy of suppository mass providing the uniform distribution of active substance and excipients in this dosage form.

Solubilization of an amphiphilic drug by poly(ethylene oxide)- block-poly(ester) micelles

Aim. The study aims to develop the composition of the oromucosal gel with the IL-1β interleukin antagonist for complex treatment of inflammatory periodontal diseases. Materials and methods. Experimental studies were conducted based on the Department of Medicines Technology of Zaporizhzhia State Medical and Pharmaceutical University and the Training Medical and Laboratory Center of Zaporizhzhia State Medical and Pharmaceutical University of the Ministry of Health of Ukraine. As an active component, in the recipe of oromucosal gel, used antagonist of the interleukin IL-1B. Excipients: D-panthenol (the plasticizer), carboxymethylcellulose sodium salt (the viscosity modifier and mucoadhesive component), Tween-80 (the enhancer absorption), benzalkonium chloride (the preservative), sodium hydrophosphate + citric acid (the phosphate buffer solution), purified water. The experiments used existing and auxiliary ingredients of pharmaceutical purity, which were obtained from Sinbias LLC, Istok-Plus LLC, LLC “Mobile Medical”. For the design of the experiment, the methodology of the response surface (Box-Behnken Design) is used: Na CMC, Tween-80, D-panthenol; and four answers: pH, viscosity test, system type, mucoadhesive properties. Research methods: rheological research (viscosity test, amplitude test, frequency test, mucoadhesive test, thixotropy test) performed in oscillation mode on the modular compact Rheometer Anton Paar MCR 302 (CP50-1 SN71317), which, compared to cylindrical devices, requires a much smaller amount of gel sample and allows the planned tests in the oscillation mode, the temperature in the experiments was provided with a built-in thermostat (Peltier Temperature Control, C-PTD 200). Pharmaco-toxicological studies were conducted on 46 white outbred rats of both sexes, weighing 160–180 grams, which were received from Vivarium by the Institute of Pharmacology and Toxicology. The studies were performed on enough animals, all manipulations were carried out by the provisions on the use of animals in biomedical experiments. The results of the study were calculated using the standard statistical package of the Statistica for Windows 13 (StatSoft Inc., No. JPZ804I382130ARCN10-J), as well as SPSS 16.0, Microsoft Office Excel 2003. Results. According to the design of the experiment, it is established that the components of the system do not change the value of pH in experimental oromucosal gels (6.5500 ± 0.0334). The Anova for Quadratic Model statistical analysis data certify the significant impact of Na CMC, and Tween-80 factors on the viscous characteristics of oromucosal gels (F-value > p-value). Comparison of mucoadhesive characteristics of the studied samples of oromucosal gels was made using dynamic mechanical analysis and the results of statistical analysis of ANOVA for Quadratic Model highlight the significant influence of Na CMC, D-panthenol, Tween-80. Optimized oromucosal gel test data is obtained that its structure is restored after the applied effort, namely the restoration of the structure after 10 seconds occurs by 69.5 %, after 30 s by 76.1 %, after 180 s by 85.4 %, after 180 s which allows to predict the stability of the dosage form, both after manufacture and after use. Conclusions. The composition of the oromucosal gel of anti-inflammatory action with the IL-1β interleukin antagonist for the complex treatment of inflammatory diseases of periodontal is developed. The optimized composition of the oromucosal gel obtained has satisfactory performance of kinetic stability and thixotropic properties. The developed gel for dentistry meets all the requirements for harmlessness and safety for dosage forms of this group toxicity, lack of local irritant and allergic action.

Pharmacokinetics study of ginsenoside Rg1 liposome by pulmonary administration

Recently, a novel dosage form topical vaginal delivery has been developed utilizing drug-fibers fabricated by electrospinning. Biocompatible and biodegradable nanofiber meshes suitable for drug delivery systems were electrospun based on poly (ethylene oxide) (PEO) with high molecular weight (HMW) and low molecular weight (LMW) to design innovative vaginal delivery systems. It is desirable to encapsulate a drug inside the fibers to enhance the drug antiviral activity in addition to controlling the fiber diameter. The surface morphology and average diameter of the nanofibers were determined by field emission scanning electron microscopy (FE-SEM). Based on SEM results it was revealed that the HMW PEO has more uniform nanofibers with good average diameters than LMW PEO. We formulated acyclovir (ACV) at 20 wt% into electrospun solid dispersions construct from PEO nanofibers and examined distribution in characterizing drug release rates into aqueous media. We assumed that ACV-loaded PEO nanofiber scaffolds were prepared using electrospinning when applied to vaginal environment, should remain undamaged as long as the environment is acidic.

Пироктон оламин (октопирокс) вместе с выраженным антимикотическим действием обладает широким спектром антибактериальной активности в отношении грам-положительных и грам-отрицательных патогенных микроорганизмов. Октопирокс характеризуется хорошей переносимостью и безвредностью при наружном применении, а также наличием дезодорирующего эффекта. Также перспективным представляется сочетание в рецептуре мази для наружного применения пироктон оламина с нафталаном обессмоленным. Нафталан обессмоленный – натуральное вещество минерального происхождения, обладает десенсибилизирующими, противовоспалительными, обезболивающими, рассасывающими, противозудными, согревающими и антибактериальными свойствами. Сотрудники кафедры технологии лекарств Запорожского государственного медицинского университета на основании комплексных исследований предложили композиционный состав мази с пироктон оламином и нафталаном обессмоленным для топической терапии больных себорейным дерматитом с поражением волосистой части головы. Прогнозируется, что применение разработанного фармакотерапевтического средства будет способствовать нормализации липидной мантии, кератинизации, десквамации, устранению зуда и воспаления пораженных кожных покровов. Цель работы – изучение последствий термообработки комбинационной трихологической мази на гидрофильной основе в интервале температур, сопровождающих технологический процесс производства этой лекарственной формы. Материалы и методы. В качестве объектов дериватографических исследований использовали экспериментальную мазь для местного применения, а также действующие (пироктон оламин, нафталан обессмоленный) и вспомогательные (натрий карбоксиметилцеллюлоза, глицерин, твин 80, пропиленгликоль) вещества этой лекарственной формы. Термогравиметрический анализ проводили с использованием дериватографа «Shimadzu DTG-60» (Япония), снабженного платиново-платинородиевой термопарой. Результаты. Полученные данные термического анализа убедительно свидетельствуют о термической стойкости активных фармацевтических ингредиентов и вспомогательных веществ исследуемой лекарственной формы. На дериватограмах мази с пироктон оламином и ее гидрофильного носителя-плацебо наблюдают совпадение тепловых эффектов с таковыми активно действующего компонента и вспомогательных веществ. Это указывает на отсутствие химического взаимодействия между ними. Выводы. Установлено, что ингредиенты разработанной мягкой лекарственной формы для топической терапии себорейного дерматита с пироктон оламином на гидрофильной основе не взаимодействуют, и потому эта композиция является механической смесью действующих и вспомогательных веществ. Учитывая результаты анализа тепловых эффектов ингредиентов разработанной мази для внешнего применения, целесообразно проведение технологического процесса ее изготовления при температурах, не превышающих 90°С.

This review article presents the pharmacology of combined Amiodarone Hydrochloride and Ranolazine therapy specialy in Atrial Fibrillation. Amiodarone Hydrochloride is Anti Arrhythmic agent. Ranolazine is a Anti Anginal agent. The Antianginal agent was used in Ischaemia. Amiodarone Hydrochloride is Antiarrhythmic agent and use in Arrhythmia and Atrial fibrillation. If Amiodarone Hydrochloride is administered in large quantities, the condition of patient become worse by occurrence of adverse effect of Thyroid toxicity due to presence of Iodine moiety in Amiodarone. The use of Ranolazine in combination with Amiodarone Hydrochloride has been proved to provide beneficial effect in Atrial Fibrillation. The combination therapy has fewer adverse effect. The mechanism of Amiodarone Hydrochloride and Ranolazine is quite different. Amiodarone Hydrochloride inhibit potassium channel and inactivated-state blocker of cardiac sodium channel while Ranolazine inhibit late inward sodium current(INa) in cardiac cell and activated-state blocker of cardiac sodium channel. The combination of both have decrease dose dependent side effect of Amiodarone Hydrochloride. Both the drugs were approved by US government and has been used in Atrial Fibrillation in US. The main objective of this review article is to provide pharmacological information of combined therapy of Amiodarone Hydrochloride and Ranolazine to researcher in development of combined dosage form of this.

Abuse and misuse of prescription medicine is a major public health concern resulting in an increasing number of deaths every year. Abuse-deterrent formulations (ADFs) have been introduced to deter the abuse of prescription opioids by making the extraction and recovery of the active pharmaceutical ingredient difficult. Among various formulation approaches used to develop ADFs, sintered polyethylene oxide (PEO) matrices are widely used due to their simplicity in manufacturing. Although sintered polyethylene oxide is commonly used, the understanding of the impact of sintering on the formulation components and the dosage forms abuse-deterrent properties and performance is limited. Various active pharmaceutical ingredients were evaluated for their suitability in sintered PEO matrices; tablets prepared using dextromethorphan HBr monohydrate and ketoprofen led to changes in tablet dimensions and tablet microstructure following sintering at temperatures above the melting point of polyethylene oxide (80 °C). In contrast, the inclusion of promethazine HCl or theophylline did not impact tablet properties. Thermal characterization showed that dextromethorphan HBr monohydrate and ketoprofen were solubilized in the polyethylene oxide matrix, leading to tablet expansion and the creation of a more porous matrix after cooling. Additionally, sintering above PEO’s melting point led to decreased PEO crystallinity. These changes resulted in changes to the tablet’s dimensions, microstructure, and PEO crystallinity which contributed to the matrix's erosion, leading to faster API release from the dosage form. The results indicate that care must be taken while incorporating APIs able to dissolve in PEO to mitigate performance alterations. The impact of various PEO grades and the sintering process on the ADFs' abuse-deterrent properties were studied. A sintering temperature above the melting point (80 °C) of PEO was necessary to impart adequate tablet hardness to resist manipulation. Lower molecular weight PEO resulted in less viscous gels able to be drawn into and pushed out of syringes with less effort. Sintering at 80 °C for longer durations (≥ 2 h) led to polymer degradation impacting the resistance to intravenous abuse (syringability and injectability). In addition to sintering duration and temperature, the weight fraction of PEO affected the abuse-deterrent properties of the dosage forms with tablets containing lower fractions (≤ 25% w/w) of PEO, resulting in a greater fraction of smaller granules (≤ 500 µm) which have increased potential for abuse.Finally, in-vitro release testing studies were conducted to evaluate the retention of the manipulated ADF's abuse-deterrent properties. Non-homogenous drug distribution among the granule fractions obtained from crushed matrices manufactured using direct compression were observed with higher amounts of the drug in the smaller size granules compared with the larger granules. Release testing performed on various granule fractions using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus indicated high variability in release results using the USP type I and type II apparatus; sticking of the hydrated granules to the baskets and paddles; and ongoing PEO hydration with subsequent gel formation further altered particle sizes and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules. Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500 μm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500 μm) provided rapid drug release that was un-hindered by the hydrated granule matrix. Since < 500-μm size particles are preferred for nasal abuse, direct-compression ADF formulations should minimize and be carefully evaluated for the formation of these smaller-sized particles following tampering to maintain the product’s abuse-deterrent features.

A 505(b)(2) application is a type of US new drug application (NDA) that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. Most 505(b)(2) applications consist of changes to a previously approved drug product (ie, a new dosage form, new routes of administration, etc). Sponsors often face challenges determining the studies to be conducted to support approval via 505(b)(2) pathway. This 5-year (2012-2016) retrospective analysis reviewed approved 505(b)(2) NDAs available on the FDA website, to determine the nature of studies (preclinical, clinical pharmacology, and efficacy/safety) conducted for various types of submissions and to better understand the trends in terms of regulatory requirements. The database consisted of 226 NDAs. One hundred twelve of those 226 had complete FDA review information, with the following FDA submission classes being more prevalent: type 3, new dosage form; type 4, new combination; and type 5, new formulation or new manufacturer. Therefore, only these 112 NDAs were further examined as they could show trends in terms of the studies conducted for various types of applications. Based on the investigation of NDA review documents, coupled with guidance documents, decision trees for studies to be conducted have been developed, which may serve as a guide of recommendations for a successful 505(b)(2) development program and NDA submission.

Prior to Pediatric Research Equity Act’s enactment, Food and Drug Administration had approved several suitability petitions to permit abbreviated new drug applications to be submitted for drugs that had a different active ingredient, dosage form, or route of administration than their reference-listed drugs. Pediatric Research Equity Act does not impose pediatric assessment requirements on abbreviated new drug applications for generic drugs. However, abbreviated new drug applications submitted under an approved suitability petition under section 505(j)(2)(C) of the Act and the said difference from the reference-listed drugs are subject to the pediatric assessment requirements that Pediatric Research Equity Act imposes. In the federal notice dated 23 February 2007, Food and Drug Administration explained that the approval of 128 suitability petitions was being withdrawn because abbreviated new drug applications were never submitted and Pediatric Research Equity Act requires that all applications submitted on or after 1 April 1999, for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration containing an assessment of the safety and effectiveness of the drug for the claimed indications in relevant pediatric subpopulations unless the requirement is waived or deferred. Underlining information in this article helps in understating the Pediatric Research Equity Act, pediatric assessment for suitability petitions, pediatric review committee and its role, types of pediatric waivers, and its importance in suitability petitions. Also there are several examples provided for the Pediatric Research Equity Act assessment in recently filed suitability petitions by the various firms.

A comprehensive review on celastrol, triptolide and triptonide: Insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes

A 505(b)(2) application is a type of US new drug application (NDA) that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. Most 505(b)(2) applications consist of changes to a previously approved drug product (ie, a new dosage form, new routes of administration, etc). Sponsors often face challenges determining the studies to be conducted to support approval via 505(b)(2) pathway. This 5-year (2012-2016) retrospective analysis reviewed approved 505(b)(2) NDAs available on the FDA website, to determine the nature of studies (preclinical, clinical pharmacology, and efficacy/safety) conducted for various types of submissions and to better understand the trends in terms of regulatory requirements. The database consisted of 226 NDAs. One hundred twelve of those 226 had complete FDA review information, with the following FDA submission classes being more prevalent: type 3, new dosage form; type 4, new combination; and type 5, new formulation or new manufacturer. Therefore, only these 112 NDAs were further examined as they could show trends in terms of the studies conducted for various types of applications. Based on the investigation of NDA review documents, coupled with guidance documents, decision trees for studies to be conducted have been developed, which may serve as a guide of recommendations for a successful 505(b)(2) development program and NDA submission.

Objectives Amiodarone hydrochloride is a class III antiarrhythmic drug indicated for the treatment of ventricular and supraventricular tachycardias. Oral amiodarone is only available in a tablet dosage form, which is not suitable for pediatric use. The stability of amiodarone hydrochloride suspension at 5 mg/mL was assessed in SyrSpend® SF PH4 (liquid) but oral amiodarone is typically given as a loading dose of 10–15 mg/kg/day for 4–10 days and then reduced to a maintenance dose of 5 mg/kg/day, making the 20 mg/mL concentration a better option. A hospital preparation of 20 mg/mL amiodarone hydrochloride oral suspension was developed. The purpose of this study was to determine the physicochemical stability of a 20 mg/mL amiodarone hydrochloride oral multidose suspension in a commercial compounding excipient, SyrSpend® SF PH4 (liquid) at ambient temperature and under dark conditions. Methods Three batches of oral suspension were prepared using amiodarone hydrochloride powder and SyrSpend SF PH4 (liquid). The suspensions were stored at room temperature and protected from light (amber glass vials). A sample was withdrawn from each bottle immediately after preparation and at 1, 2, 5, 10, 15, 30, 60, and 90 days. After additional dilution to an expected concentration of 100 μg/mL with methanol, the samples were assayed in triplicate using a stability-indicating high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The physicochemical properties (pH, osmolality, amiodarone concentration, macroscopic changes) were assessed over 90 days at each day of analysis. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point and defined as retention of at least 95% of the initial concentration of amiodarone hydrochloride. Results After 90 days, the study showed that amiodarone hydrochloride concentrations did not go below 95% of the initial drug concentration. Neither degradation products nor changes of physicochemical properties were detected. Conclusions Compounded oral suspensions of 20 mg/mL amiodarone hydrochloride in SyrSpend® SF PH4 (liquid) were stable for at least 90 days when stored in amber glass bottles at room temperature.

After the dosage form of tamsulosin hydrochloride was changed from a capsule to on orally disintegrating tablet (ODT, Harnal D), we often received patient complaints and noted an increase in noncompliance with medication regimens. The change in dosage form appeared to cause poor compliance by patients who had become accustomed to the light pink/white capsule over many years. Therefore, we carried out a questionnaire survey of patients taking the ODT form to determine the effects of changing the dosage form and the usefulness of the ODT. Most (92%) of respondents took the ODT with water. In addition, 16% missed taking the medicine after the change in dosage form. ODT is a dosage form that is easy to take for patient with dysphagia, or those on restricted water intake. However, it appears that elderly men and patients with visual disorders cannot distinguish the ODT from other medicines and this affects patient compliance. In conclusion, all pharmaceutical companies should consider the design of medications in terms of coloration, indications, or shape in anticipation of the aging society in future, so that patients can distinguish them. Furthermore, sufficient pharmaceutical care is needed to improve both compliance and safety management for the elderly.

The article deals with the application of the system approach for constructing informationalgorithmic support for the pharmaceutical development of solid dosage forms. Information modeling of the life cycle of pharmaceutical drug development has been carried out starting from the stage of studying the active pharmaceutical substance and ending with the utilization of the drug. These models are built in the IDEF0 nomination. A generalized block diagram is presented that reflects, in its most general form, the iterative process of developing a ready-made dosage form as applied to the further transfer of technology. The basis of the system approach is QbD - "Quality planned in the development". To implement the QbD principle on the basis of the system approach, systemic set-theoretic models of information support of pharmaceutical development in the nomenclature of Melentiev have been constructed. A model for controlling the pressing process is also provided, which takes into account all the technological stages in the development of a solid dosage form. Functional models in the IDEF0 nomenclature of the technological process are constructed from the preparation of premises, personnel and components of the dosage form to the stage of packing and packaging of the finished dosage form. The construction of an informational intellectual control system for pharmaceutical development has been considered in detail with particular attention paid to the construction of a database of medicinal and auxiliary substances using the example of solid dosage forms. In Melentiev's bracket notation, the database of auxiliary substances necessary for the design of a solid dosage form is filled. The "Entity-relationship" model and the relational model for the database of medicinal and auxiliary substances have been constructe