Injectable Dosage Form Research Articles

ДИНАМІЧНИЙ МАРКЕТИНГОВИЙ АНАЛІЗ ВІТЧИЗНЯНОГО РИНКУ ПРОТИВІРУСНИХ ЛІКАРСЬКИХ ЗАСОБІВ ГРУП J05AB01, J05AХ05, J05AХ10

У статті висвітлені результати маркетингового аналізу груп противірусних препаратів, які рекомендовано для лікування хворих на дитячі вірусні інфекції (вітряну віспу, кір, краснуху). Упродовж 42 місяців - з 01.01.2013 до 01.07.2016 р. - був проведений щомісячний моніторинг їх асортименту, середніх оптово-відпускних цін, коефіцієнтів ліквідності та платоспроможності населення. Встановлено, що противірусні препарати груп ацикловіру У05ДВ01), інозинпранобексу^05ДХ05) та інших противірусних У05ДХ10: амізону, протефлазіду, флавозіду) є достатньо представлені на вітчизняному фармацевтичному ринку, доступність яких зросла наприкінці моніторингу. Найнижчою їх оптово-відпускна ціна була у січні 2013 р., а найвищою - у жовтні - листопаді 2014 та 2015 рр., березні - квітні 2016 р. Не спостерігається прямої залежності між динамікою оптової ціни препаратів і динамікою курсу гривні відносно до долара, оскільки стрибки підйому оптово-відпускних цін випереджували ріст долара на 1-3 місяці для одних ліків, а для інших, навпаки, на тлі загального росту відбулося різке зниження ціни. Тому на даний час цей сегмент оптового фармацевтичного ринку лікарських засобів не можна вважати достатньо прогнозованим.

Stability Indicating RP-HPLC Method Development and Validation for the Estimation of Atezolizumab in Bulk and Its Injectable Dosage Form

Stability Indicating RP-HPLC Method Development and Validation for the Estimation of Atezolizumab in Bulk and Its Injectable Dosage Form

CREATING LABORATORY TECHNOLOGY OF GENERIC EPIRUBICIN PHARMECEUTICAL DOSAGE FORM

Introduction. Governments around the world seek to reduce rapidly rising health care costs. Using the same high quality and often cheaper than the original brands, generics greatly reduces costs while providing an adequate quality of care. Therefore the development of generic medicines is an important task. The purpose of the study - the reproduction of the pharmaceutical dosage form for creation of national drug-generic epirubicin. Materials and methods. The study used a substance epirubicin (Ph. Eur current edition, Teva Pharmaceutical Industries Ltd., Israel); “Farmorubicin”, production “Pfizer Italia Srl” for “Pfizer Inc.”, Italy / US and excipients conforming to with relevant regulatory documents. Mice transplanted tumor: lymphocytic leukemia P388. Methods: technological, pharmaco-analytical, biological and pharmacological. Results. Pharmaceutical analysis of reproduced generic-drug “Epirubicin-RONC®” showed that itfully meets the requirements of manufacturer’s monograph. The results of “acute” toxicity study in rats and observations of the experimental animals within 30 days after a single administration suggest that both drugs have similar toxicological properties and are almost identical. Generic “Epirubicin RONC®” and “Farmorubicin” in lyophilized dosage form for injection 10.0 mg/vial, administered once, shows equal antitumor effect at two administration routes in mice with transplantable tumor: lymphocytic leukemia P-388. Conclusion. N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia has been reproduced generic - “Epirubi-cin-RONC®”, which is fully conform to the imported drug.

RESEARCH OF SUBCHRONIC TOXICITY IN RATS OF GLYCOSIDE DERIVATIVE OF INDOLOCARBAZOLE LCS-1208

Background. In N.N. Blokhin Russian Cancer Research Center has been developed injectable dosage form based on the substance of indolocarbazole derivative LCS-1208, studied its antitumor activity and mechanism of antitumor effect, which was the basis for the pre-clinical study of the drug toxicity. Objective. The study of subchronic toxicity of formulation of glycoside derivative of indolocarbazole - LCS-1208 after intraperitoneal application to rats. Materials and methods. Dosage form of study drug: lyophilisate for preparation of solution for injection of 9,0 mg in vial. The study was conducted on 40 healthy non inbred male rats, which were obtained from the breeding of the N.N. Blokhin Russian Cancer Research Center. It was studied the action of the drug on the peripheral blood, the functional state of the liver, kidney and gastrointestinal tract of animals. Results. The drug LCS-1208 by daily intraperitoneal administration to rats for 15 days in the 3 studied doses (total dose 200 mg/kg, 100 mg/kg and 50 mg/kg) did not cause death of animals, had no effect on the general condition of the animals, did not cause external manifestations of toxicity, did not change behavioral responses of animals and had no effect on the functioning of the studied organs. Conclusion. The results obtained by the study of the subchronic toxicity in rats were the basis for further preclinical toxicology study of the drug LCS-1208.

An Accelerated Release Study to Evaluate Long-Acting Contraceptive Levonorgestrel-Containing in Situ Forming Depot Systems.

Biodegradable polymer-based injectable in situ forming depot (ISD) systems that solidify in the body to form a solid or semisolid reservoir are becoming increasingly attractive as an injectable dosage form for sustained (months to years) parenteral drug delivery. Evaluation of long-term drug release from the ISD systems during the formulation development is laborious and costly. An accelerated release method that can effectively correlate the months to years of long-term release in a short time such as days or weeks is economically needed. However, no such accelerated ISD system release method has been reported in the literature to date. The objective of the current study was to develop a short-term accelerated in vitro release method for contraceptive levonorgestrel (LNG)-containing ISD systems to screen formulations for more than 3-month contraception after a single subcutaneous injection. The LNG-containing ISD formulations were prepared by using biodegradable poly(lactide-co-glycolide) and polylactic acid polymer and solvent mixtures containing N-methyl-2-pyrrolidone and benzyl benzoate or triethyl citrate. Drug release studies were performed under real-time (long-term) conditions (PBS, pH 7.4, 37 °C) and four accelerated (short-term) conditions: (A) PBS, pH 7.4, 50 °C; (B) 25% ethanol in PBS, pH 7.4, 50 °C; (C) 25% ethanol in PBS, 2% Tween 20, pH 7.4, 50 °C; and (D) 25% ethanol in PBS, 2% Tween 20, pH 9, 50 °C. The LNG release profile, including the release mechanism under the accelerated condition D within two weeks, correlated (r2 ≥ 0.98) well with that under real-time conditions at four months.

Development of the fast, simple and fully validated high performance liquid chromatographic method with diode array detector for quantification of testosterone esters in an oil-based injectable dosage form

Counterfeit steroids are available on the black market, ultimately to consumers who believe they are buying a legitimate pharmaceutical item from the labeled company. In many cases, counterfeit steroids can contain lower doses or some products can be overdosed. This can unwittingly expose users to a significant health risks. The mixture of testosterone propionate, phenylpropionate, isocaproate and decanoate in an oil-based injectable dosage form belongs to the one of the most misused illicit drugs by a variety of athletes.This study developed a new, fast, simple and reliable HPLC method combined with a simple sample preparation step to determine testosterone propionate, phenylpropionate, isocaproate and decanoate in an oil-based injectable dosage form without the use of sophisticated and expensive instrumentation. The developed analytical procedure provides high throughput of samples where LC analysis takes only 6min and sample preparation of oil matrix in one step takes approximately 10min with precision ranging from 1.03 to 3.38% (RSD), and accuracy (relative error %) within ±2.01%. This method was found to be precise, linear, accurate, sensitive, selective and robust for routine application in screening of commercial pharmaceutical products based on content of mentioned testosterone esters in their oil-based injectable dosage form for counterfeit drugs.This method was successfully applied to the analysis of nine samples of commercial testosterone mixtures purchased from various sources and will be further used as an effective screening method for determination of previously mentioned testosterone esters in samples confiscated by Institute of Forensic Science (Slovakia) during the illegal trade.

Exploration of Mixed Hydrotropy Strategy in Formulation and Development of Etodolac Injection

Etodolac is a non-steroidal anti-inflammatory drug used in the treatment of mild to moderate pain, osteoarthritis or rheumatoid arthritis and it is basically available in the market only as tablet dosage form for human use. The present study was investigated with an intention to develop a stable and effective parenteral formulation, containing Etodolac for acute pain management. Etodolac is a Biopharmaceutical Classification System (BCS) class II drug and it is insoluble in water hence solubility and dissolution rate enhancement was carried out by using various hydrotropic blends.. Etodolac was blended in different proportion with various hydrotropic agents like sodium acetate, sodium benzoate, sodium citrate etc and other co-solvents. The drug was formulated in injectable dosage form using a optimized hydrotropic blend as solvent. The optimized batches of Etodolac injection formulation were subjected to various evaluation tests and accelerated stability study. Amongst all trial batches, formulation containing 15% sodium benzoate and 25% solvent system S (Blend C) and 10% sodium acetate, 5% sodium citrate and 25% solvent system S (Blend O) were found to be more stable and passed all tests satisfactorily.

Designing Solvent Exchange-Induced In Situ Forming Gel from Aqueous Insoluble Polymers as Matrix Base for Periodontitis Treatment.

An in situ forming gel is a dosage form which is promised for site-specific therapy such as periodontal pocket of periodontitis treatment. Ethylcellulose, bleached shellac, and Eudragit RS were applied in this study as a polymeric matrix for in situ forming gel employing N-methyl pyrrolidone (NMP) as solvent. Solutions comprising ethylcellulose, bleached shellac, and Eudragit RS in NMP were evaluated for viscosity, rheology, and rate of water penetration. Ease of administration by injection was determined as the force required to expel polymeric solutions through a needle using texture analyzer. In vitro gel formation and in vitro gel degradation were conducted after injection into phosphate buffer solution pH 6.8. Ethylcellulose, bleached shellac, and Eudragit RS could form the in situ gel, in vitro. Gel viscosity and pH value depended on percentage amount of the polymer, whereas the water diffusion at early period likely relied on types of polymer. Furthermore, the solutions containing higher polymer concentration exhibited the lower degree of degradation. All the preparations were acceptable as injectable dosage forms because the applied force was lower than 50N. All of them inhibited Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyrommonas gingivalis growth owing to antimicrobial activity of NMP which exhibited a potential use for periodontitis treatment. Moreover, the developed systems presented as the solvent exchange induced in situ forming gel and showed capability to be incorporated with the suitable antimicrobial active compounds for periodontitis treatment which should be further studied.

RP-HPLC Method Development and Validation for Simultaneous Determination of Esomeprazole and Diclofenac Sodium in Pharmaceutical Dosage Forms

A new RP-HPLC method was developed and validated for simultaneous determination of esomeprazole (ESO) and diclofenac sodium (DIC) in pharmaceutical dosage forms. BDS Hypersil C18 column (250 × 4.6 mm, 5 μm) and mobile phase consisting of methanol and 50 mM phosphate buffer (35:65) were used in this analysis. The flow rate was adjusted at 1.0 mL/min and detection was performed at 213 nm wavelength for both esomeprazole and diclofenac sodium. Etoposide (ETO) was used as internal standard giving a retention time of 4.13 min. The method was linear in a range of 25 – 1000 ng/mL and 15.5 – 500 ng/mL for ESO and DIC, respectively. The method has good linearity (r 2 = 0.999) with the intra-day and inter-day variability less than 3% for both drugs. The limits of detection were 15 and 10.5 ng/mL, while the limits of quantification were 25 and 15.5 ng/mL for ESO and DIC, respectively. The proposed method demonstrates good robustness, resisting to small deliberate changes in pH and flow rate of mobile phase. The developed method was successfully applied for determining drug concentrations in spiked human plasma, injection, capsule and tablet dosage forms, where it exhibited good performance and reproducibility.

Parenteral dosage form development and testing of dimethyl trisulfide, as an antidote candidate to combat cyanide intoxication

This study focused on the solubility enhancement and the in vivo antidotal efficacy testing of a new potential cyanide (CN) countermeasure, dimethyl trisulfide (DMTS). Various FDA approved cyclodextrins (HPβCD, RMβCD, HPγCD), cosolvents (ethanol, polyethylene glycols, propylene glycol), surfactants (cremophor EL, cremophor RH 40, sodium cholate, sodium deoxycholate, polysorbate 80) and their combinations were applied. Based on the solubility enhancing potential of the tested systems, polysorbate 80 was chosen for further in vivo efficacy studies. A composition comprising 15% polysorbate 80 and 50 mg/ml DMTS with the applied DMTS dose of 100 mg/kg provided a therapeutic antidotal protection of 3.4 × LD50. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 × LD50 protection, and at the dose of 200 mg/kg, the LD50 was enhanced by 1.3 times. No difference in the therapeutic protection by DMTS was detected when the concentration of polysorbate 80 was increased to 20% (3.2 × LD50 protection). These data demonstrate the potential importance of DMTS as a CN countermeasure, and the formulation comprising polysorbate 80 provides the base of an injectable intramuscular dosage form that can later serve as a CN antidotal kit suitable for mass scenario.

Quantification of Newer Anti-Cancer Drug Clofarabine in their Bulk and Pharmaceutical Dosage Form

Quantitative determination of Clofarabine in their Pharmaceutical Dosage form was carried out by Liquid chromatographic method. The aim of the present work was to develop a RP-HPLC method for Clofarabine (CFB). The column used was Luna C-18 column (250 mm × 4.6 mm id, 5 m particle size) using Water: Methanol (60:40 v/v) as a mobile phase at a flow rate of 1.0 ml/min. Quantification was achieved with UV detection at 266 nm over the concentration range 0.05-20 μg/ml and % recovery was found to be in the range of 99.58-100.95 for CFB by the RPHPLC method. The proposed method was validated with respect to linearity, accuracy, precision, selective, sensitive and robustness. The method was fruitfully applied for the estimation of clofarabine in injection dosage forms.

Tolerability and Pharmacokinetic Comparison of Oral, Intramuscular, and Intravenous Administration of Levosulpiride After Single and Multiple Dosing in Healthy Chinese Volunteers

PurposeThe aim of this study was to characterize the pharmacokinetic (PK) properties and assess the safety profiles of different formulations of levosulpiride in healthy Chinese volunteers. MethodsLevosulpiride was administered to 42 healthy male and female (1:1) subjects in tablet (PO) and injectable (IM and IV) dosage forms. Blood samples were collected at regular intervals after single and multiple drug administration. The concentration of levosulpiride in plasma was determined by a validated liquid chromatography tandem mass spectrometry method. Noncompartmental analysis was performed to estimate PK parameters. One-way ANOVA was used to test for linearity and assess the effect of sex on the PK properties of the drug. Adverse effects were monitored using investigators’ questionnaires and subjects’ spontaneous reports, vital sign measurements, hematology, clinical chemistry, and electrocardiography. FindingsLevosulpiride exhibited linear pharmacokinetic properties over the dose range of 25 to 100 mg by PO route and 25 to 75 mg by IM route. The corresponding mean AUC0−t increased from 449 to 1443 ng/h/mL and from 2874 to 7559 ng/h/mL, respectively. After repeated PO and IM administration, steady state was reached on day 4 of multiple dosing with accumulation index of 1.8 and on day 2 of multiple dosing with accumulation index of 1.3, respectively. The bioavailability of levosulpiride via IM and PO routes was 96.8% and 23.4%, respectively. No significant differences were observed on PK properties between male and female subjects. More than half (23 of 42 [54.8%]) of healthy volunteers experienced one or more adverse events in total, including constipation, diarrhea, drowsiness, skin rash, and extrapyramidal reactions. ImplicationsThe regimen of 50-mg levosulpiride tablets 3 times daily and 50-mg levosulpiride injection (IM) twice daily provided similar accumulation coefficient, and the former reached steady state much more slowly. The bioavailability of levosulpiride after oral administration was poor and the absorption rate was slower compared with IM administration, which imply delayed clinical efficacy for patients with dyspepsia or neuropsychiatric disorders. On multiple dosing, levosulpiride exhibited poor tolerability with high incidence of adverse reactions. There was no need to adjust administration regimen based on sex. ClinicalTrials.gov Identifier: NCT02481583.

INDICADORES DE PRESCRICÃO MÉDICA: UMA REVISÃO SISTEMÁTICA

O farmacêutico, por meio da atenção farmacêutica, pode acompanhar a farmacoterapia, orientando e intervindo quando necessário, buscando melhoria na educação em saúde e na qualidade de vida do paciente. O objetivo deste trabalho foi realizar uma revisão bibliográfica sobre a importância da atenção farmacêutica na identificação e resolução das interações fármaco-nutriente, evidenciando as implicações dessas interações no efeito terapêutico do fármaco ou no estado nutricional. Foram realizadas pesquisas em livros e artigos científicos em bases de dados como Science Direct, Pubmed e Scielo, no período de 2000 a 2014. Os resultados mostraram que existem inúmeras possibilidades de interações fármaco-nutriente, as quais podem causar prejuízos ao efeito do fármaco e/ou ao estado nutricional do paciente, e essas muitas vezes não são identificadas, por falta de conhecimento dos profissionais da saúde ou devido aos testes de biodisponibilidade dos medicamentos serem realizados em jejum, por exigência dos órgãos sanitários. Desse modo, vê-se a necessidade da atuação do farmacêutico, que por meio do seu amplo conhecimento, pode colaborar com a diminuição dos riscos dessas interações fármaco-nutriente e nutriente-fármaco, resgatando assim a confiança do paciente e a essência da profissão.

Development and validation of a stability indicating RP-HPLC method for determination of flucytosine and its process related impurities in injectable pharmaceuticals

A simple, sensitive, reproducible and cost effective reversed-phase liquid chromatography (RPHPLC) method coupled with a photodiode array detector was developed and validated for determination of Flucytosine and its related substances in pharmaceutical dosage forms, especially for injectable solution. The separation was achieved from octadecylsilyl silica gel, C18 (4.6 mm x 250 mm, 5µ) column with a mobile phase consisting of HPLC grade Water and Methanol (95:5) at a flow rate of 1ml/min with UV detection at 260 nm at 30 ° C column temperature. Total run time was 10 min within which main compound and other known (Fluorouracil) and unknown impurities were separated. Stability indicating capability was established by force degradation experiments and separation of known degradation products. This chromatographic method was optimized using the samples generated from forced degradation studies and the impurity spiked solution. Good resolution between the peaks corresponds to process-related impurities and degradation products from the analyte were achieved. The method was validated for Accuracy, Repeatability, Reproducibility and Robustness, Linearity, LOQ, LOD were established for Flucytosine and its impurities in a single RPHPLC method. Therefore, this method can be used as a more convenient and efficient option for the analysis of Flucytosine assay and it’s related substances in injectable pharmaceutical dosage form to establish the quality of the drug product during routine analysis with consistent and reproducible results.

Development and Validation of RP-HPLC Method for the Simultaneous Determination of Trimethoprim, Sulfadimidine Sodium and Tylosin Tartrate in injectable solution formulation

Formation and Characterization of Sulfamethoxazole-Trimethoprim Cocrystal by Milling ProcessErizal Zaini, Yeyet C. Sumirtapura, Auzal Halim, Lili Fitriani, Sundani N. Soewandhi

Stability-indicating HPLC determination of gemcitabine in pharmaceutical formulations.

A simple, sensitive, inexpensive, and rapid stability indicating high performance liquid chromatographic method has been developed for determination of gemcitabine in injectable dosage forms using theophylline as internal standard. Chromatographic separation was achieved on a Phenomenex Luna C-18 column (250 mm × 4.6 mm; 5μ) with a mobile phase consisting of 90% water and 10% acetonitrile (pH 7.00 ± 0.05). The signals of gemcitabine and theophylline were recorded at 275 nm. Calibration curves were linear in the concentration range of 0.5–50 μg/mL. The correlation coefficient was 0.999 or higher. The limit of detection and limit of quantitation were 0.1498 and 0.4541 μg/mL, respectively. The inter- and intraday precision were less than 2%. Accuracy of the method ranged from 100.2% to 100.4%. Stability studies indicate that the drug was stable to sunlight and UV light. The drug gives 6 different hydrolytic products under alkaline stress and 3 in acidic condition. Aqueous and oxidative stress conditions also degrade the drug. Degradation was higher in the alkaline condition compared to other stress conditions. The robustness of the methods was evaluated using design of experiments. Validation reveals that the proposed method is specific, accurate, precise, reliable, robust, reproducible, and suitable for the quantitative analysis.

Pharmacokinetic and analgesic properties of the injectable dosage form of a new imidazobenzimidazole derivative RU-1205 with kappa agonist activity

Pharmacokinetic properties of imidazobenzimidazole derivative compound RU-1205 were investigated after subcutaneous administration to rabbits as a substance and a dosage form (lyophilisates for injection) at a dose of 25 mg/kg. The lyophilisate was characterized by high values of the relative bioavailability. In tests, the "hot plate" and "vinegar cramps" the dosage form and the substance exhibited the same analgesic effect.

Quantification and stress degradation studies of cefepime/tazobactam in dry injection form by an RP-HPLC method

A simple, specific, precise, accurate, linear, rapid, economic and validated stability indicating an RP-HPLC method for the simultaneous quantification of cefepime and tazobactam in a dry injection dosage form has been developed. Separation was performed on a 5 µm ACE C18column with phosphate buffer, pH adjusted to 4.5 with phosphoric acid: methanol (70:30) at a flow rate of 1 mL/min and at a temperature of 25 °C. Regression analysis showed linearity at a detector wavelength of 290 nm in the range of 200-600 μg/mL for cefepime and 25-75 μg/mL for tazobactam. All of the analytes were adequately resolved with acceptable tailing. The percentage content found for cefepime was 99.98% and of tazobactam was 99.49% in the parenteral formulation. The method was validated in terms of linearity, precision, accuracy, specificity, robustness and system suitability according to ICH guidelines. Stress degradation studies were performed on the placebo and drug products, drugs of interest were well resolved from the degradation products. The developed method was effectively applied for the simultaneous quantification of cefepime and tazobactam in a dry injection formulation.

Microstructural analysis of the fast gelling freeze-dried sodium hyaluronate

Although sodium hyaluronate is a very unstable and heat sensitive molecule, it can remain relatively stable during the freeze-drying process. Aqueous sodium hyaluronate (NaHA) gels were prepared and the obtained samples were freeze-dried. The freeze-dried NaHA samples showed fast gelling ability meanwhile preserved their initial viscoelasticity even after reconstitution. The microstructure of gels obtained from raw substance and freeze-dried NaHA samples was characterized with positron annihilation lifetime spectroscopy and X-ray diffraction patterns while their functionality-related macrostructural properties were tested based on their rheological behavior. The presence of phosphate salts improved the formation of ordered supramolecular structure retaining water in the free volume holes of the polymer chains characterized with decreased ortho-positronium lifetime values. This property may be advantageous in the development of a freeze-dried NaHA injection dosage form.

Measurement uncertainty of a UPLC stability indicating method for determination of linezolid in dosage forms

Many decisions of compliance or non-compliance are based in analytical results. There are in literature several methods described for linezolid determination, however only a few takes into account the measurement uncertainty. The aim of this work was to validate, identify the main sources of uncertainty, quantify the standard deviation of each source of uncertainty, and calculated combined and expended uncertainties for the determination of linezolid in injectable dosage forms. The UPLC method was validated by assessing specificity, linearity/linear range, precision (repeatability and intermediate precision), accuracy and robustness. Eurachem procedure was used in measurement estimation and then evaluated using Monte Carlo simulations. Linezolid was degraded after exposed to light and oxidation. The UPLC method was linear (range from 8.0 to 12.0μg/mL, with r2=0.9985), showed good precision (repeatability of 0.89% and intermediate precision of 0.66%), accurate (recovery from 98.07% to 99.03%) and robust. The contributions of accuracy, precision, linearity and weight of linezolid reference standard are the most significant, contributing with about 72% of the overall uncertainty. The other sources of uncertainties have lower influence on the overall uncertainty. The uncertainty estimated by Eurachem procedure (95.13±2.51%) was found to be similar to the Monte Carlo simulation (95.14±2.46%). Measurement uncertainty was found to be appropriated for its applications.