DEVELOPMENT OF A TECHNOLOGY FOR PRODUCING A STABLE INJECTABLE DOSAGE FORM OF A HYDROPHOBIC INDOLOCARBAZOLE DERIVATIVE

Objective: Development of a technology for the production of a stable injectable dosage form (IDF) of indolocarbazole derivative LHS-1269. Methods: LHS-1269 is an active pharmaceutical ingredient that was synthesized in the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation. The IDF includes dimethyl sulfoxide (DMSO), 95% ethanol, Kollidon® 17PF and water for injection. Magnetic stirrer and overhead stirrer with a propeller stirring element were used to prepare the model solution of the IDF of LHS-1269. Sterilizing filtration of the solution was performed with 0.2−0.22 um polycarbonate, cellulose, polyvinylidene fluoride, polyethersulfone and nylon membrane filters. The aqueous solution of LHS-1269 was lyophilized in Edwards Minifast DO.2 freeze dryer. Assay of LHS-1269 was performed by spectrophotometry at 320±3 nm. Potentiometry was used to measure pH, a viscosimetry method was used to measure the viscosity of the solutions. The average weight was estimated by weighing a sample of 10 vials with the concentrate. Results: 0.5% aqueous solution of LHS-1269 was produced by mixing the solution of the active substance in DMSO and ethanol with an aqueous solution of polyvinylpyrrolidone gradually at the ratio of LHS-1269/DMSO/ethanol/Kollidon® of 1/11/32/40 by weight. The aqueous solution of the study substance cannot be lyophilized, so a sequence of technological operations was presented to produce an anhydrous concentrate “LHS-1269, concentrate for solution for injection and infusion 25 mg”. Conclusion: A technology was developed to produce a stable IDF of a hydrophobic indolocarbazole derivative LHS-1269, a high-potential antitumor drug.

Development and Validation of a Stability-Indicating UPLC Method for the Determination of Hexoprenaline in Injectable Dosage Form Using AQbD Principles

A novel and efficient stability-indicating, reverse phase ultra-performance liquid chromatographic (UPLC®) analytical method was developed and validated for the determination of hexoprenaline in an injectable dosage form. The development of the method was performed using analytical quality by design (AQbD) principles, which are aligned with the future requirements from the regulatory agencies using AQbD principles. The method was developed by assessing the impact of ion pairing, the chromatographic column, pH and gradient elution. The development was achieved with a Waters Acquity HSS T3 (50 × 2.1 mm i.d., 1.8 µm) column at ambient temperature, using sodium dihydrogen phosphate 5 mM + octane-1-sulphonic acid sodium salt 10 mM buffer pH 3.0 (Solution A) and acetonitrile (Solution B) as mobile phases in gradient elution (t = 0 min, 5% B; t = 1 min, 5% B; t = 5 min, 50% B; t = 7 min, 5% B; t = 10 min, 5% B) at a flow rate of 0.5 mL/min and UV detection of 280 nm. The linearity was proven for hexoprenaline over a concentration range of 3.50–6.50 µg/mL (R2 = 0.9998). Forced degradation studies were performed by subjecting the samples to hydrolytic (acid and base), oxidative, and thermal stress conditions. Standard solution stability was also performed. The proposed validated method was successfully used for the quantitative analysis of bulk, stability and injectable dosage form samples of the desired drug product. Using the AQbD principles, it is possible to generate methodologies with enhanced knowledge, which can eventually lead to a reduced regulatory risk, high quality data and lower operational costs.

FEATURES OF THE DEVELOPMENT OF A LYOPHILIZED INJECTABLE DOSAGE FORM OF THE ORIGINAL ANTICANCER DRUG LCS-1208

Objective: Development of a lyophilized injectable dosage form LCS-1208, an original antitumor drug based on an indolocarbazole derivative. Methods: The prepared solution of the injectable dosage form LCS-1208 is transferred to sterilizing filtration, which is carried out under vacuum on a «Stericup» filter unit with a filter pore size of 0.22 μm. The sterile solution of the injectable dosage form LCS-1208 is poured into sterile vials using a dispenser and lyophilized in a freeze-drying chamber. At the end of drying, the preparation is corked in the chamber of a sublimation unit using a hydraulic device and transferred to crimping with aluminum caps using a seaming machine. Quantitative determination of the drug content was determined by spectrophotometry using a standard sample at λ = 320±2 nm. The pH was determined by potentiometry. Results: A freeze-drying regimen for the injectable dosage form LCS-1208 has been developed. The required solution freezing temperature was established taking into account the presence of 2 eutectic zones: a solution of LCS-1208 in DMSO (-35 ÷-32) °С, an aqueous solution of Kollidon 17PF (-10 ÷-8) °С. As a result of a series of experiments, the optimal lyophilization regime was chosen that does not require preliminary freezing in a low-temperature chamber, with freezing on the shelves of freeze-drying at a temperature of-47 °C without their preliminary cooling. The most acceptable vial filling volume was determined, amounting to 3 ml, and the rate of temperature rise during secondary drying of the preparation was justified. When using the developed regime of lyophilization of the LCS-1208 solution, it was shown that it can be sublimated while preserving the initial qualitative and quantitative characteristics. Conclusion: In this article, using the example of creating a lyophilized injectable dosage form LCS-1208 (the original antitumor drug from the indolocarbazole group), the main problems that arose during the lyophilization of the selected composition of the model solution, as well as ways to improve the process.

The pharmacokinetics of the injectable dosage form of GK-2 in rabbits

The pharmacokinetics of the nerve growth factor mimetic GK-2 (dimeric dipeptide mimetic of the 4-th loop NGF, a derivative of fluoro-substituted 5-[2-(5-fluoropyrid-3-yl) -ethyl)]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole) in rabbits after a single intravenous injection of an injectable dosage form at dose 24 mg (7,8-8,7 mg/kg). GK-2 concentrations in the blood plasma were determined by high-performance liquid chromatography with massspectrometric detection. GK-2 can be attributed to "short-lived" drugs, since the half-life from the rabbits blood plasma was 0.9±0.1 h.

Drug-induced dystonia

Drug-induced dystonia (DID) is a rarely diagnosed adverse reaction to a sufficiently large number of drugs. Acute DID (ADID) occurs soon after starting to take a drug or raising its dose, and switching from one antipsychotic medication to another, especially to its injectable dosage form. Tardive DID (TDID) develops a few months or years after starting drug intake or 3 months after stopping therapy. The diagnosis of TDID is based on the persistence of dystonic hyperkinesis for more than 1 month, the use of a dopamine receptor blocking agent, and the absence of other causes of its development. The risk factors for DID are male sex; young age (less than 30 years of age); a history of dystonic reactions; hypocalcemia, alcohol use while taking the drug. DID is most commonly related to therapy with antipsychotics, metoclopramide, antidepressants, and antiepileptic drugs. The short-term use of anticholinergic drugs (benzotropin, diphenhydramine) is effective in treating ADID. Anticholinergic drugs and atypical antipsychotics (clozapine, quetiapine), benzodiazepines, muscle relaxants (baclofen), and dopamine reuptake inhibitors (tetrabenazine) are used to treat TDID. To prevent DID, it is very important that a physician should be aware of that this unwanted adverse reaction may occur and that a drug with the lowest risk for DID should be chosen.

Simultaneous Analysis of Phenylephrine HCl and Ketorolac Tromethamine in Bulk and Injectable Formulations by RP-HPLC-PDA Method

Rapid, isocratic and economical RP-HPLC-PDA method was developed for the simultaneous estimation of Phenylephrine HCl (PEH) and Ketorolac Tromethamine (KTR) in bulk and injectable dosage forms. Chromatographic separation was achieved with the Agilent Eclipse C18 column (150×4.6mm;5µ) and the mobile phase composed of methanol and 2mM Ammonium acetate in the ratio 43:57v/v at a flow rate of 1mL/min. The injection volume was 5µL and eluents were monitored at 220nm. Response was a linear function of concentration in the range 30–105 μg/mL for Phenylephrine HCl (PEH) and 10–35 μg/mL Ketorolac Tromethamine (KTR); the correlation coefficients were 0.999 and 0.999, respectively. The method was validated and is suitable for the simultaneous estimation of PEH and KTR in bulk and injectable dosage forms. Keywords: Ketorolac tromethamine, Phenylephrine HCl, Reverse phase HPLC, PDA detector.