Parenteral Dosage Forms Research Articles

In vitro dissolution testing of parenteral aqueous solutions and oily suspensions of paracetamol and prednisolone

The number of intramuscularly applied dosage forms has been continuously increasing during the last decades. However, up to date no in vitro dissolution test method for parenteral dosage forms has been described in the Ph. Eur. or USP. It was the aim of this study to investigate dissolution test setups based on the compendial flow-through cell and the reciprocating holder for this purpose. Both apparatuses were equipped with dialysis membranes to accommodate the drug formulation. The suitability of the dissolution method was evaluated by comparing release profiles with blood level curves that were obtained previously in an in vivo study in rats by our group. Aqueous solutions and oily suspensions of paracetamol and prednisolone were tested in vitro that were also applied in the in vivo study. In the case of the aqueous solutions in which no formal dissolution occurs, transport from the applied depot across a dialysis membrane was investigated. While the drug transport across the dialysis membrane of both drugs in aqueous solution was similar in all applied test methods, differences in the release behavior of paracetamol and prednisolone as an oily suspension were observed. This was mainly due to sedimentation of the particles within the oily depot.

USP Apparatus 4: a Valuable In Vitro Tool to Enable Formulation Development of Long-Acting Parenteral (LAP) Nanosuspension Formulations of Poorly Water-Soluble Compounds.

Long-acting or extended release parenteral dosage forms have attracted extensive attention due to their ability to maintain therapeutic drug concentrations over long periods of time and reduce administration frequency, thus improving patient compliance. It is essential to have an in vitro release (IVR) testing method that can be used to assure product quality during routine production as well as predict and understand the in vivo performance of a formulation. The purpose of this work was to develop a discriminatory in vitro release method to guide formulation and process development of long-acting parenteral (LAP) nanosuspension formulations composed of poorly water-soluble drugs (BCS class II). Injectable nanosuspension formulations were developed to serve as test articles for method development. Several different IVR methods were evaluated for their application to the formulation screening and process development including (1) USP apparatus 2, (2) dialysis and reverse dialysis sac, and (3) continuous flow-through cell (USP apparatus 4). Preliminary data shows the promising results to support the utilization of USP 4 over more widely accepted USP 2 and dialysis methods. A combination of more representative in vivo hydrodynamics and ease of maintaining sink conditions yields the USP 4 flow-through cell method a more suitable in vitro release method for nanosuspension-based LAP formulations of poorly water-soluble compounds, such as compounds A and B.

TECHNOLOGICAL APPROACHES TO IMPROVING THE PROCESS LYOPHILIZATION OF PROTEIN AND PEPTIDE DRUGS

Lyophilization of protein and peptide anticancer drugs is a promising method to create a stable and effective parenteral dosage forms. This article reviews the main problems encountered during lyophilization of protein and peptide drugs, and describes the best practices for solving these problems. The ways of optimization and improvement of the freeze-drying are given. Temperatures to improve the properties and prevent the destruction of the cake lyophilizatiе are suggested.

Muscle Injury After Intramuscular Administration of Diclofenac: A Case Report Supported by Magnetic Resonance Imaging

Intramuscular injection of diclofenac is still frequently practiced, although there is ample evidence that the risk of local tissue intolerability is highly underestimated. The aim of this study was to evaluate local toxicity in a patient using magnetic resonance imaging. A patient who gave written informed consent received a medically indicated intramuscular administration of diclofenac 75 mg/2 mL. Simultaneously with magnetic resonance imaging of the depot, a clinical–chemical evaluation and quantification of diclofenac in plasma was performed. A manifold enhancement of the T2-weighted magnetic resonance signal was observed in a muscle area of approximately 60 mL volume, with maximum signal intensity 30 min after injection, the time of maximum diclofenac plasma exposure. Plasma creatine kinase activity was elevated approximately sixfold within 8 h and normalized within 1 week, whereas the magnetic resonance enhancement disappeared within 5 weeks. Interestingly, the patient did not complain about any clinical symptoms at the injection site. Asymptomatic tissue injury after intramuscular injection of diclofenac, caused by intramuscular dosing, can be reliably evaluated by magnetic resonance imaging and should be applied early during the development of parenteral dosage forms. Clinical Trials Registration Number: BB130/16 (Ethics Committee of the University Medicine Greifswald).

Antimicrobial utilization in an Iraqi province: a comprehensive evaluation of antibiotic source and cost.

The aims were to calculate total systemic antibiotic consumption and cost in both public and private sectors in all care settings in Al-Najaf province, Iraq, during 2012, recognize the percentage of each pharmacological class for the dispensed antibiotics and identify oral and parenteral antibiotic percentages dispensed and the portions manufactured nationally and imported. Cross-sectional study was conducted in Al-Najaf to calculate the total cost and quantities of antibiotics consumed during 2012 using World Health Organization Guidelines for Defined Daily Dose (DDD). The results showed more than 21 million DDDs were dispensed in Al-Najaf in one year, and more than half (54.2%) were dispensed by governmental healthcare institutions. A thousand inhabitants in the province consumed 45.26 DDDs per day. Extended-spectrum (34.49%) and combined penicillins (26.08%) were the most frequently consumed while meropenem was the least frequently consumed (0.02%). Ninety-five per cent of the consumed antibiotics were oral dosage forms, and five per cent were parenteral dosage forms. The total cost of antibiotic consumed was more than nine million U.S dollars. The antibiotic consumption ratio in this province was comparable to neighbouring countries, but far higher compared to European countries. Penicillins, cephalosporins and quinolones were the most popular antibiotics. Around half of the antibiotics consumed were made by national pharmaceutical companies that mainly produce oral antibiotics. The public sector consumed a higher portion, but spent a lower amount compared to private sectors. This is the first time report of antibiotic consumption in Iraq. More studies evaluating antibiotic consumption can improve utilization.

An Insight About the Drug Release Mechanisms from Different Dosage Forms

A process in which drug comes out from drug product and exposed to ADME and finally become accessible for pharmacological activity is known as drug release and mechanism involves the study of its rate and factors influencing its rate. Factors influencing the rate of drug release are drug related, polymer related and formulation variables. Drug delivery systems are discriminated on the basis of way drug is delivered, which are immediate release and modified release. Parenteral dosage forms are the most prominent among different dosage forms. The mechanisms involved in drug release are diffusion and dissolution-controlled processes. Nasal disposal basically depends on the particle size, its geometry and rate of airflow. Nasal sprays are commonly used than powders and gels. Buccal and sublingual systems show more effective drug release mechanisms than oral and transdermal systems. Main focus of paper is to elaborate different mechanisms performed by drug delivery systems for drug release.

Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques

As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design.

Microbiological control of parenteral dosage forms

The microbiological control of injectable forms aims to ensure that the product does not contain any microorganisms that may be pathogenic or induce pathological symptoms after administration. Thus, the study of techniques that allow the elimination and prevention of microorganisms is extremely important. In this field, there are classic techniques that are used to evaluate certain drugs, and novel techniques are currently under development. These new approaches have advantages over the previous ones since they have a higher level of efficacy and accuracy. This review presents a simple description of the main techniques available (from the classic to the most recent) for microbiological control of parenteral dosage forms. It can be regarded as a useful practical tool for all professionals already working (or aiming to work) in this area.

The substantiation for introduction of the innovative technological process for industrial production of parenteral dosage forms by the example of torasemіde, solution for injection

The introduction of the innovative technological process for industrial production of parenteral dosage forms by the example of Torasemide, solution for injection has been substantiated in the article. The experimental studies for improving the manufacturing technology of Torasemide, solution for injection, 5 mg/ml, the choice of the filter material, the scientific substantiation of the innovative technological process are presented. In particular, the aseptic conditions of production have been selected using sterile filtration and thermal sterilization (stabilization), the algorithm of monitoring of the critical parameters has been developed using the elements of risk management design of pharmaceutical production.

Hydrophilic interaction liquid chromatography in analysis of granisetron HCl and its related substances. Retention mechanisms and method development

In this paper separation of granisetron and its two related substances in HILIC mode is presented. Separation was done on silica column derivatized with sulfoalkylbetaine groups (ZIC-HILIC). Firstly, retention mechanisms were assessed whereby retention factors of substances were followed in wide range of acetonitrile content (80–97%), at constant concentration of aqueous buffer (10mM) as well as at constant pH value of 3.0. Further, in order to developed optimal HILIC method, Design of Experiments (DoE) methodology was applied. For optimization full factorial design 32 was employed. Influence of acetonitrile content and ammonium acetate concentration were investigated while pH of the water phase was kept at 3.3. Adequacy of obtained mathematical models was confirmed by ANOVA. Optimization goals (α>1.15 and minimal run time) were accomplished with 94.7% of acetonitrile in mobile phase and 70mM of ammonium acetate in water phase. Optimal point was in the middle of defined Design Space. In the next phase, robustness was experimetally tested by Rechtschaffen design. The investigated factors and their levels were: acetonitrile content (±1%), ammonium acetate molarity in water phase (±2mM), pH value of water phase (±0.2) and column temperature (±4°C). The validation scope included selectivity, linearity, accuracy and precision as well as determination of limit of detection (LOD) and limit of quantification (LOQ) for the related substances. Additionally, the validation acceptance criteria were met in all cases. Finally, the proposed method could be successfully utilized for estimation of granisetron HCl and its related substances in tablets and parenteral dosage forms, as well as for monitoring degradation under various stress conditions.

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.

Drug-Excipient Interactions: Case Studies and Overview of Drug Degradation Pathways

The objective of the current research article is to provide a comprehensive review of excipients impact on the stability of the drug product and their implications during the product development. Recent developments in the understanding of the degradation pathways further impact methodologies used in the pharmaceutical industry for potential stability assessment. The formation of drug excipient adducts was very common based on the sensitive chemical moieties in the drugs and the excipients. The formation of the impurities was not limited to drug related impurities but there were several possibilities of the drug-excipient adduct formations as well as excipient impurities reaction with Active Pharmaceutical Ingredients. Identification of drug degradation in presence of excipients/excipient impurities requires extensive knowledge and adequate analytical characterization data. Systematic literature review and understanding about the drug formulation process, give you a smooth platform in establishing the finished product in the drug market. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes in solid, semisolid and parenteral dosage forms.

Pharmacist Cognitive Service and Pharmaceutical Care: Today and Tomorrow Outlook

The aim of this work was to ask more use of clinical pharmacists in medical team .The application of pharmaceutical care principle in practice settings can improve clinical outcomes, reducing therapy errors and containment cost. An opportunity to use pharmacist’s expertise in assisting physician’s drug and medical devices specialists. Isn’t time for the medical community to get aid of the clinical pharmacists to work side by side and assist the physicians, in order to give a better care, protect and safeguard patients. The rationale of this focus article was to invite pharmacists to take a much more active role and to help physicians using their expertise in order to complete the therapeutic work in a more rational way. Pharmacists need to get out of their private stores, sharing their expertise and knowledge, by making active presence in the very infrastructure of clinical centers, such as hospitals and ambulatory.Physicians alone cannot cover every aspect of the pharmacological treatment, for example in the field of drug therapy monitoring, interactions, adverse drug reaction (ADR), toxicology, novel delivery systems, immunoglobuline-based therapeutics and other innovative drugs and medical devices systems, which have their pharmaceutical specific worlds.
 For over 80 years the only role's pharmacists played were compounding and consulting for over the counter drugs. By the year 2025, the innovative polymer and nano drug delivery systems, genomes, immunoglobuline-based therapeutics and stem cells and other innovation will add or substitute to the ordinary local, enteral, or parenteral dosage forms. That era is now rapidly changing, and the all nations pharmacists need to come out of their convenient type of stores to the aid of the physicians in their actual duties, taking role in that missing rescuing the patients which in many occasions, their health and even lives can be at risk (Drug allergy undetected ).
 Observing some actual university courses of clinical pharmacy in different countries and some old and new studies involving clinical pharmacists taking part of wards’ medical teams, we have noticed that the pharmaceutical care service given by a pharmacist has an undeniable positive impact on, and improves the clinical outcome in the pharmacological therapies (Pharmaceutical treatments, on therapeutic levels).

HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR THE QUANTITATIVE ANALYSIS OF CEFUROXIME IN PHARMACEUTICAL PREPARATIONS

ABSTRACT New Analytical method has been developed for the determination of Cefuroxime in pharmaceutical formulations. The method involves the application of high performance Liquid chromatography (HPLC) for the quantitative analysis of cefuroxime. HPLC method has a shorter analysis time of 10 min. The developed method obeyed the Beer’s law in the range of 5- 300 µg mL -1 . Limit of detection (LOD) and limit of quantitation (LOQ) of the developed method was found to be 0.538 and 1.63, µg mL -1 respectively. Keywords: Cefuroxime, High Performance liquid chromatography, Method validation, Pharmaceutical preparations INTRODUCTION Cefuroxime sodium is chemically known as [6R - [6α,7β(Z)]] - 3 - [[(2 - Aminocarbonyl)oxy]methyl] - 7 - [2 - furanyl(methoxyimino)acetyl]amino] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid monosodium salt. It is a broad spectrum, semi synthetic cephalosporin antibiotics which is administered for treating variety of bacterial infections such as case of pharyngitis, chronic bronchitis and infection of urinary tract as well as uncomplicated gonorrhea, bone and joint infections, meningitis and septicaemia [1,2]. It is a second generation cephalosporin and can be administered orally as well as in the parenteral dosage form [3]. The mode of action of cefuroxime against the bacteria is upon inhibiting the bacterial wall synthesis by binding to one or many penicillin binding proteins. Due to such type of binding, development of osmotically unstable defective cell wall occurs which shows bactericidal properties [3, 4]. Assay of the pharmaceuticals is one of the important aspects of the pharmaceutical industry, as it determines the drug product having same quantity as label claim; however, advanced analytical instruments are also capable of detecting the impurities. Some of the analytical methods are reported for the assay of cefuroxime in marketed form includes spectrophotometry [5-8], High performance liquid chromatography (HPLC) [9-11], Capillary electrophoresis [12-14], HPTLC [15] and LC-MS/MS [16]. The current communication proposes simple analytical procedure to quantify cefuroxime in pure and marketed products using HPLC. The proposed HPLC analytical procedure is based on the separation of cefuroxime using ion pair reagent, octane-1-sulfonic acid sodium salt.

Selected Genotoxic Impurities Profiling During WFI Qualification to Control Carcinogenesis in Large Volume Parenterals

Water For Injections (WFI) which is the main vehicle of Large Volume Parenterals (LVPs) should be free from trace amount of genotoxic impurities. This review gives emphasis on quantification of genotoxic trace metals during qualification of WFI in LVPs manufacturing unit. According to ICH guidelines, impurities related to drug substances are classified into three main categories: Organic impurities, inorganic (elemental) impurities and residual solvents. Within these categories, genotoxic impurities form a special case that poses a significant safety risk, even at low concentrations, because they may be mutagenic and are therefore potentially damaging to DNA. As a result they can lead to mutations or cause cancer. Chemical carcinogens most often directly or after xenobiotic metabolism, act as genotoxic causes to induce DNA damage. The roles of trace metals (some of which are either genotoxic or non-genotoxic) in cancer development and inhibition have a complex character and have raised many questions because of their essential and toxic effects on people's health. Trace metals such as cadmium, nickel, arsenic, beryllium and chromium (VI) have been recognized as human or animal carcinogens by International Agency for Research on Cancer (IARC). There are several genotoxic chemicals like residual solvent, impurities and trace metals present in Pharmaceuticals to form carcinogens. Regulatory body like FDA and EMEA has fixed up specific limits for these elemental impurities. The toxicity of an elemental impurity is related to its extent of exposure (bioavailability). In that sense, parenteral dosage forms has its most possibility to be bioavailable than the other dosage forms, the limit of genotoxic impurities are 10 times lower than that of oral dosage forms by United States Pharmacopoeia (USP). The present article is for the importance of identification and quantification of the trace amount of the metal genotoxic impurities in Water For Injection (WFI) during qualification (IQ, OQ, PQ) as a preventive measure to control the production and distribution of WFI for Large Volume Parenteral (LVP) production.

Hplc estimation of coenzyme Q(10) redox status in plasma after intravenous coenzyme Q(10) administration

The pharmacokinetics of the total pool of coenzyme Q(10) (Co(10)), its oxidized (ubiquinone) and reduced (ubiquinol, CoQ(10)H₂) forms have been investigated in rats plasma during 48 h after a single intravenous injection of a solution of solubilized CoQ(10) (10 mg/kg) to rats. Plasma levels of CoQ(10) were determined by HPLC with spectrophotometric and coulometric detection. In plasma samples taken during the first minutes after the CoQ(10) intravenous injection, the total pool of coenzyme Q(10) and proportion of CoQ(10)H₂ remained unchanged during two weeks of storage at -20°C. The kinetic curve of the total pool of coenzyme Q(10) corresponds to a one-part model (R² = 0.9932), while the corresponding curve of its oxidized form fits to the two-part model. During the first minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in the total plasma coenzyme Q(10) content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ(10) by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ(10) into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ(10) for the use in the treatment of acute pathological conditions.

Redox status and pharmacokinetics of coenzyme Q10 in rat plasma after its single intravenous administration

Q10 corresponds to a onecompartment model ( R 2 = 0.9932), while the corresponding curve of its oxidized form fits to the twocompartment model. During the fi rst minutes after the injection a significant portion of plasma ubiquinone undergoes reduction, and after 7 h the concentration of ubiquinol predominates. The decrease in total plasma coenzyme Q10 content was accompanied by the gradual increase in plasma ubiquinol, which represented about 90% of total plasma CoQ10 by the end of the first day. The results of this study demonstrate the ability of the organism to transform high concentrations of the oxidized form of CoQ10 into the effective antioxidant (reduced) form and justify prospects of the development of parenteral dosage forms of CoQ10 for the use in the treatment of acute pathological conditions.

PP-009 Implementing appropriate compounded paediatric chloral hydrate rectal dosage form

BackgroundAlthough no commercial products containing chloral hydrate are available in our country paediatricians are increasingly requesting oral and parenteral dosage forms. Facing that problem we set about compounding a rectal...

Sesquiterpene lactone in nanostructured parenteral dosage form is efficacious in experimental Chagas disease.

The drugs available for Chagas disease treatment are toxic and ineffective. We studied the in vivo activity of a new drug, lychnopholide (LYC). LYC was loaded in nanocapsules (NC), and its effects were compared to free LYC and benznidazole against Trypanosoma cruzi. Infected mice were treated in the acute phase at 2.0 mg/kg/day with free LYC, LYC-poly-ε-caprolactone NC (LYC-PCL), and LYC-poly(lactic acid)-co-polyethylene glycol NC (LYC-PLA-PEG) or at 50 mg/kg/day with benznidazole solution by the intravenous route. Animals infected with the CL strain, treated 24 h after infection for 10 days, evaluated by hemoculture, PCR, and enzyme-linked immunosorbent assay exhibited a 50% parasitological cure when treated with LYC-PCL NC and 100% cure when treated with benznidazole, but 100% of the animals treated during the prepatent period for 20 days with these formulations or LYC-PLA-PEG NC were cured. In animals with the Y strain treated 24 h after infection for 10 days, only mice treated by LYC-PCL NC were cured, but animals treated in the prepatent period for 20 days exhibited 100, 75, and 62.5% cure when treated with LYC-PLA-PEG NC, benznidazole, and LYC-PCL NC, respectively. Free LYC reduced the parasitemia and improved mice survival, but no mice were cured. LYC-loaded NC showed higher cure rates, reduced parasitemia, and increased survival when used in doses 2five times lower than those used for benznidazole. This study confirms that LYC is a potential new treatment for Chagas disease. Furthermore, the long-circulating property of PLA-PEG NC and its ability to improve LYC efficacy showed that this formulation is more effective in reaching the parasite in vivo.

Uptake of Etoposide in CT-26 Cells of Colorectal Cancer Using Folate Targeted Dextran Stearate Polymeric Micelles

Targeted drug delivery using folate receptors is one of the most interesting chemotherapeutic research areas over the past few years. A novel folate targeted copolymer was synthesized using dextran stearate coupled to folic acid. FT-IR and NMR spectroscopy were used to confirm successful conjugation. Micelles prepared using this copolymer were characterized for their particle size, zeta potential, critical micelle concentration (CMC), drug loading capacity, and release efficiency. Cytotoxicity and cellular uptake of the micelles were estimated using CT-26 colorectal carcinoma cell line. FT-IR and NMR spectroscopy confirmed production of folate grafted dextran stearate copolymer. Low CMC value indicates that the copolymers are suitable for preparation of stable micelles useful in parenteral dosage forms. Particle size and zeta potential of the targeted nanoparticles were 105.5 ± 2.0 nm and −21.2 mV, respectively. IC50 of etoposide loaded in folate grafted dextran stearate enhanced about 20-fold compared to the pure drug (0.49 ± 0.11 μg/mL versus 9.41 ± 0.52 μg/mL). It seems that etoposide loaded in micelles of folate grafted dextran stearate copolymer is promising in reducing drug resistance of colorectal cancer by boosting etoposide cellular uptake.