Background: In animal studies, some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been shown to be reproductive and developmental toxicants. Human studies show widespread population exposure to background levels of phthalates. Limited evidence suggests that particularly high exposure levels may result from orally ingested medicinal products containing phthalates as excipients (inactive ingredients).
Objective: In this study we aimed to identify and describe the scope of prescription (RX) and nonprescription (over-the-counter; OTC) medicinal products and dietary supplements marketed in the United States and Canada since 1995 that include phthalates as excipients.
Methods: We used lists of modified-release drug products to identify potential drug products. Inclusion of phthalates was verified using available electronic databases, print references, published package inserts, product packages, and direct communication from manufacturers. Additional products were identified using Internet searches utilizing keywords for phthalates.
Results: Based on labeling information, 6 RX drug products included DBP as an excipient, and 45 specified the use of diethyl phthalate (DEP). Phthalate polymers with no known toxicity—hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP)—were included in 75 RX products. Three OTC drug and dietary supplement products listed DBP, 64 listed DEP, and > 90 indicated inclusion of polymers.
Conclusions: Numerous RX and OTC drug products and supplements from a wide range of therapeutic categories may use DBP or DEP as excipients in oral dosage forms. The potential effects of human exposure to these phthalates through medications are unknown and warrant further investigation.
coating; dietary supplements; excipients; medications; phthalates
Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients) used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models.
Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo"), or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility.
The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML) formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8). For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol.
As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.
Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.
excipients; impurities; interaction; mitigation; variability
Objective: To examine and compare the long term outcome after polio in an east European and a west European country with different access to rehabilitation and with different medical and social conditions.
Design and Setting: The patients who were acutely hospitalised for polio 1950–54 in the University Hospital in Bergen, Norway and 1958 in the University Hospital in Tartu, Estonia received the mailed questionnaire in the period between January 1998 and December 1998.
Patients: Patient files concerning 334 patients hospitalised in Tartu and 243 patients hospitalised in Bergen were obtained; of these 128 Estonian and 148 Norwegian patients were re-examined.
Main results: Despite more pronounced disability in the acute stage, significantly more Norwegian patients were working full time and part time in 1998 (p<0.0001) and also through the period 1958–1998. In both countries, 30% of patients had manual work and 18% changed profession during their career. Low income (below 50% of national average) was reported by 73% of Estonian and 35% of Norwegian patients (p<0.0001). Except for the odds ratio for muscular pain of 1.89 (95%CI =1.14 to 3.14) for Norwegian patients, new symptoms indicating late progression did not differ. Norwegian patients were more independent with significantly less need for assistance in housekeeping (p=0.02), whereas the use of orthopaedic devices did not differ.
Conclusions: The long term outcome after polio is different in eastern and western Europe. Access to continuous rehabilitation seems to maintain physical independence in polio patients, improves their ability to earn their own income, and lessens the need for disability pensions.
The use of natural excipients to deliver the bioactive agents has been hampered by the synthetic materials. However advantages offered by these natural excipients are their being non-toxic, less expensive and freely available. The performance of the excipients partly determines the quality of the medicines. The traditional concept of the excipients as any component other than the active substance has undergone a substantial evolution from an inert and cheap vehicle to an essential constituent of the formulation. Excipients are any component other than the active substance(s) intentionally added to formulation of a dosage form. This article gives an overview of herbal excipients which are used in conventional dosage forms as well as novel drug delivery systems.
Polysaccharides; volatile oils; controlled delivery
The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations.
The aim of this study was to develop a derivative of chitosan as pharmaceutical excipient used in sustained-release matrix tablets of poorly soluble drugs. A water-soluble quaternary ammonium carboxymethylchitosan was synthesized by a two-step reaction with carboxymethylchitosan (CMCTS), decylalkyl dimethyl ammonium and epichlorohydrin. The elemental analysis showed that the target product with 10.27% of the maximum grafting degree was obtained. To assess the preliminary safety of this biopolymer, cell toxicity assay was employed. In order to further investigate quaternary ammonium carboxymethylchitosan application as pharmaceutical excipient, aspirin was chosen as model drug. The effect of quaternary ammonium CMCTS on aspirin release rate from sustained-release matrix tablets was examined by in-vitro dissolution experiments. The results showed that this biopolymer had a great potential in increasing the dissolution of poorly soluble drug. With the addition of CMCTS-CEDA, the final cumulative release rate of drug rose up to 90%. After 12 h, at the grade of 10, 20 and 50 cps, the drug release rate increased from 58.1 to 90.7%, from 64.1 to 93.9%, from 69.3 to 96.1%, respectively. At the same time, aspirin release rate from sustainedrelease model was found to be related to the amount of quaternary ammonium CMCTS employed. With the increase of CMCTS-CEDA content, the accumulated release rate increased from 69.1% to 86.7%. The mechanism of aspirin release from sustained-release matrix tablets was also preliminary studied to be Fick diffusion. These data demonstrated that the chitosan derivative has positive effect on drug release from sustained-release matrix tablets.
Chitosan derivatives; Drug release rate; Aspirin; Sustained-release matrix tablet
To characterise the prescription of non-formulary drugs to children and neonates at a Brazilian teaching hospital and identify adverse drug reactions (ADRs), drug interactions, and prescription of potentially hazardous medicines.
A prospective exploratory study was carried out between January and May 2011 at the general paediatric wards and paediatric oncology, paediatric intensive care, and neonatal care units of the study hospital. Non-formulary drugs were categorised as approved, off-label, or not approved for use in children according to Brazilian compendia. Electronic health records were actively searched for ADRs and the possibility of moderate to severe interactions between non-formulary drugs and other medicines was determined with the Micromedex® database.
Overall, 109 children or neonates received non-formulary drugs. Of these drugs, 54% were approved for use in children, 12.2% were used off-label, and 33.8% were not approved for use in children. Non-formulary drugs accounted for 13.4% of total prescriptions; 5.3% of drugs had a potential for interactions and five were possibly associated with ADRs.
Prescription of non-formulary drugs not approved for use in children was common at the study hospital. Studies such as this provide information on the use of medicines for special indications and permit assessment of the relevance of hospital formularies for the paediatric population.
Drug Utilization Review; Off-Label Use; Inpatients; Child; Brazil
Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline α-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1∶1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.
nitrofurantoin; near-infrared spectroscopy; sorption; X-ray powder diffraction
The incidence, aetiology and pathophysiology of pneumomediastinum (PM), an uncommon and potentially serious disease in neonates and children, were evaluated. A retrospective chart review of all patients diagnosed with PM who were hospitalised in the intensive care unit of the University Children’s Hospital Zürich, Switzerland, from 2000 to 2006, was preformed. We analysed the incidence, severity and causes of PM and investigated the possible differences between neonatal and non-neonatal cases. Seven children and nine neonates were identified with PM. All patients had a good outcome. Six cases of PM in the group of children older than 4 weeks were deemed to be caused by trauma, infection and sports, whereas one case was idiopathic. All nine neonatal cases presented with symptoms of respiratory distress. We were able to attribute four cases of neonatal PM to pulmonary infection, immature lungs and ventilatory support. Five neonatal cases remained unexplained after careful review of the hospital records. In conclusion, PM in children and neonates has a good prognosis. Mostly, it is associated with extrapulmonary air at other sites. It is diagnosed by chest X-ray alone. We identified mechanical events leading to the airway rupture in most children >4 weeks of life, whereas we were unable to identify a cause in half of the neonates studied (idiopathic PM).
Pneumomediastinum; Pneumopericardium; Subcutaneous emphysema; Air leak; Respiratory distress syndrome
The present study explores the hepatoprotective activity of various extracts of Ferula asafoetida, Momordica charantia Linn and Nardostachys jatamansi against experimental hepatotoxicity. Polyherbal suspensions were formulated using extracts showing significant activity and evaluated for both physicochemical and hepatoprotective activity in comparison with LIV-52 as standard. Petroleum ether (60-80°), chloroform, benzene, ethanol and aqueous extracts of Ferula asafetida, Momordica charantia Linn and Nardostachys jatamansi were evaluated for hepatoprotective activity against carbon tetrachloride-induced liver toxicity in Wistar rats. Polyherbal suspensions were prepared by the trituration method using a suspending agent and other excipients. Formulation F3 has shown significant hepatoprotective effect by reducing the elevated serum enzyme levels such as glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase. These biochemical observations were supplemented by histopathological examination of liver sections. Various parameters evaluated for all formulations were within the official specifications. Experimental data suggested that treatment with formulation F3 enhances the recovery from carbon tetra chloride-induced hepatotoxicity. From these results it may be concluded that the F3 formulation (containing chloroform, petroleum ether and aqueous extracts of Ferula asafetida, petroleum ether and ethanol extracts of Momordica charantia Linn. and petroleum ether and ethanol extracts of Nardostachys jatamansi) demonstrated significant hepatoprotective activity, that might be due to combined effect of all these extracts.
Hepatoprotective; polyherbal; M. charantia; N. jatamansi; F. asafoetida
Just after midnight on the 28th of September 1994, the Estonian-flagged ro-ro passenger ferry MV Estonia was shipwrecked on its route between Tallinn and Stockholm. Out of about 1000 persons on board only 137 survived. This paper describes the work that the Psychiatric Clinic at Ersta Hospital performed with the relatives of the MV Estonia victims after the disaster, in addition, we present data from seven consecutive Swedish nationwide surveys based on a questionnaire, which started as a correspondence between the hospital and the relatives of the Estonia victims. Findings concerning the care relatives received and issues regarding their collaboration with the decisionmaking authorities are presented. The importance of inviting the relatives to participate in discussions concerning the Estonia victims is stressed.
disaster at sea; grief response; coping; relative; survivor; posttraumatic stress disorder
Objective: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in medical products made with polyvinyl chloride (PVC) plastic and may be toxic to humans. DEHP is lipophilic and binds non-covalently to PVC, allowing it to leach from these products. Medical devices containing DEHP are used extensively in neonatal intensive care units (NICUs). Among neonates in NICUs, we studied exposure to DEHP-containing medical devices in relation to urinary levels of mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP.
Design: We used a cross-sectional design for this study.
Participants: We studied 54 neonates admitted to either of two level III hospital NICUs for at least 3 days between 1 March and 30 April 2003.
Measurements: A priori, we classified the infants’ exposures to DEHP based on medical products used: The low-DEHP exposure group included infants receiving primarily bottle and/or gavage feedings; the medium exposure group included infants receiving enteral feedings, intravenous hyperalimentation, and/or nasal continuous positive airway pressure; and the high exposure group included infants receiving umbilical vessel catheterization, endotracheal intubation, intravenous hyperalimentation, and indwelling gavage tube. We measured MEHP in the infants’ urine using automated solid-phase extraction/isotope dilution/high-performance liquid chromatography/ tandem mass spectrometry.
Results: Urinary MEHP levels increased monotonically with DEHP exposure. For the low-, medium-, and high-DEHP exposure groups, median (interquartile range) MEHP levels were 4 (18), 28 (58), and 86 ng/mL (150), respectively (p = 0.004). After adjustment for institution and sex, urinary MEHP levels among infants in the high exposure group were 5.1 times those among infants in the low exposure group (p = 0.03).
Conclusion: Intensive use of DEHP-containing medical devices in NICU infants results in higher exposure to DEHP as reflected by elevated urinary levels of MEHP.
di(2-ethylhexyl) phthalate; hospital equipment and supplies; mono(2-ethylhexyl) phthalate; neonatal intensive care units; newborn infants
Aggregation of insulin into insoluble fibrils (fibrillation) may lead to complications for diabetes patients such as reduced insulin potency, occlusion of insulin delivery devices, or potentially increased immunological potential.
Even after extensive investigation of fibril formation in regular human insulin, there are little published data about the intrinsic fibrillation of fast-acting analogs. This article investigates and compares the intrinsic fibrillation of three fast-acting insulin analogs—lispro, aspart, and glulisine—as a function of their primary protein structure and exclusive of the stabilizing excipients that are added to their respective commercial formulations.
The insulin analogs underwent a buffer exchange into phosphate-buffered saline to remove formulation excipients and then were heated and agitated to characterize intrinsic fibrillation potentials devoid of excipient stabilizing effects. Different analytical methods were used to determine the amount of intrinsic fibrillation for the analogs. After initial lag times, intrinsic fibrillation was detected by an amyloid-specific stain. Precipitation of insulin was confirmed by ultraviolet analysis of soluble insulin and gravimetric measurement of insoluble insulin. Electron microscopy showed dense fibrous material, with individual fibrils that are shorter than typical insulin fibrils. Higher resolution kinetic analyses were carried out in 96-well plates to provide more accurate measures of lag times and fibril growth rates.
All three analogs exhibited longer lag times and slower intrinsic fibrillation rates than human insulin, with glulisine and lispro rates slower than aspart. This is the first study comparing the intrinsic fibrillation of fast-acting insulin analogs without the stabilizing excipients found in their commercial formulations.
Data show different intrinsic fibrillation potentials based on primary molecular structures when the formulation excipients that are critical for stability are absent. Understanding intrinsic fibrillation potential is critical for evaluating insulin analog stability and device compatibility.
amyloid; circular dichroism; excipients; fibrils; insulin; insulin stability; intrinsic fibrillation; protein aggregation; protein precipitation; thioflavine T
A pharmaceutical formulation typically contains one or more excipients in addition to the active pharmaceutical ingredient(s). Though excipients have been considered inert components of a formulation, variability in their properties has been shown to affect the performance of drug dosage forms and delivery systems. This study investigates the inter- and intra-manufacturer variability among different NF grades and lots of xanthan gum made by two manufacturers. As many formulators rely on compendial standards to monitor and control the variability of excipients, this study focuses on the adequacy of the NF specifications, in particular the viscosity specification, to discern the variability in solution properties of different pharmaceutical grades and lots of xanthan gum. All the grades and lots in this study were NF grade materials. Xanthan gum solutions were prepared in accordance with NF test methodology and were rheologically evaluated using a rotational rheometer. Both steady shear measurements and small amplitude oscillatory measurements were carried out on 1% w/w xanthan gum solutions. Results showed significant inter- and intra-manufacturer variability among the NF grades and lots of xanthan gum that was not reflected in the NF viscosity test specifications.
excipient variability; rheology; xanthan gum
The aim of the current survey was to investigate the complementary self-treatment of the common cold and flu with medicinal plants among pharmacy customers in Estonia. A multiple-choice questionnaire listing 10 plants and posing questions on the perceived characteristics of cold and flu, the effectiveness of plants, help-seeking behaviour, self-treatment and sources of information, was distributed to a sample of participants in two medium size pharmacies. The participants were pharmacy customers: 150 in Tallinn (mostly Russian speaking) and 150 in Kuressaare (mostly Estonian speaking). The mean number of plants used by participants was 4.1. Of the respondents, 69% self-treated the common cold and flu and 28% consulted with a general practitioner. In general, medicinal plants were considered effective in the treatment of the above-mentioned illnesses and 56% of the respondents had used exclusively medicinal plants or their combination with OTC medicines and other means of folk medicine for treatment. The use of medicinal plants increased with age and was more frequent among female than male respondents. Among Estonian-speaking customers lime flowers, blackcurrant and camomile were more frequently used, and among Russian speaking customers raspberry and lemon fruits. Regardless of some statistically significant differences in preferred species among different age, education, sex and nationality groups, the general attitude towards medicinal plants for self-treatment of the common cold and flu in Estonia was very favourable.
The objective of the study was to produce rapidly dissolving formulations of the poorly water-soluble drug repaglinide using an innovative new technology, ultra-rapid freezing (URF), and to investigate the influence of excipient type on repaglinide stability. Repaglinide compositions containing different types and levels of excipients and different drug potencies (50%–86%) were produced by the URF technology. Repaglinide/excipient solutions were frozen on a cryogenic substrate, collected, and lyophilized to form a dry powder. Surfactants, including sodium dodecyl sulfate, and alkalizing agents such as diethanolamine (DEA) and tromethamine (TRIS) were incorporated into the compositions. Forced degradation of repaglinide was conducted under stressed conditions (eg, elevated temperature, exposure to peroxide) to determine the stability of the drug in such environments. The solubility of repaglinide increased as a function of increasing pH; therefore, incorporation of an alkalizing agent into the URF formulations increased the drug's solubility. Drug instability resulted when the drug was exposed to pH values above 9.0. URF formulations containing alkalizing agents showed no degradation or spontaneous recrystallization in the formulation, indicating that increased stability was afforded by processing. URF processing created nanostructured drug/excipient particles with higher dissolution rates than were achieved for unprocessed drug. Alkalizing agents such as TRIS and DEA, present at levels of 25% to 33% wt/wt in the formulations, did not cause degradation of the drug when processed using URF. URF processing, therefore, yielded fast-dissolving formulations that were physically and chemically stable, resistant to alkali degradation or spontaneous recrystallization in the formulation.
Ultra-rapid freezing; dissolution enhancement; stability enhancement; repaglinide; alkalizing agents
Biodegradable controlled-release microsphere
systems made with the biocompatible
biodegradable polyester excipient poly [DL
lactide-co-glycolide] constitute an exciting new
technology for drug delivery to the central nervous
system (CNS). The present study describes
functional observations indicating that implantation
of dopamine (DA) microspheres encapsulated
within two different polymer excipients
into denervated- striatal tissue assures a
prolonged release of the transmitter in vivo.
Moreover, in this regard, the results show that
there were clear cut temporal differences in the
effect of the two DA microsphere formulations
compared in this study, probably reflecting variations
in the actual composition (i.e., lactide to
glycolide ratio) of the two copolymer excipients
examined. This technology has considerable potential
for basic research with possible clinical
Aims of the study were to compare the paediatric outpatient antibiotic use in two countries with low overall antibiotic consumption and antibacterial resistance levels - Sweden and Estonia - and to describe the adherence to Estonian treatment guideline.
All prescriptions for systemic antibiotics for children less than 18 years during 2007 from the Swedish Prescribed Drug Register and Estonian Health Insurance Fund database were identified to conduct a descriptive drug utilisation study.
The total paediatric antibiotic use was 616 and 353 per 1000 in Estonia and Sweden, respectively. The greatest between country differences occurred in the age group 2 to 6 years –Estonian children received 1184 and Swedish children 528 prescriptions per 1000. Extended spectrum penicillin amoxicillin (189 per 1000) or its combination with beta-lactamase inhibitor (81 per 1000) and a newer macrolide clarithromycin (127 per 1000) were prescribed most often in Estonia whereas narrow spectrum penicillin phenoxymethylpenicillin (169 per 1000) and older generation macrolide erythromycin (21 per 1000) predominated in Sweden. For acute bronchitis, 17 different antibiotics (most commonly clarithromycin) were prescribed in Estonia despite the guideline recommendation not to use antibiotics.
The higher rate of antibiotic use especially of extended spectrum antibiotics in Estonia compared to Sweden emphasizes the need for national activities to promote appropriate use of antibiotics while treating children, even when the overall antibiotic consumption is low.
Polacrilin potassium is an ion exchange resin used in oral pharmaceutical formulations as a tablet disintegrant. It is a weakly acidic cation exchange resin. Chemically, it is a partial potassium salt of a copolymer of methacrylic acid with divinyl benzene. It ionizes to an anionic polymer chain and potassium cations. It was hypothesized that polacrilin potassium may be able to improve the permeability of anionic drugs according to the Donnan membrane phenomenon. The effect of polacrilin potassium on the permeability of diclofenac potassium, used as a model anionic drug, was tested in vitro using diffusion cells and in vivo by monitoring serum levels in rats. The amount of drug permeated across a dialysis membrane in vitro was significantly more in the presence of polacrilin potassium. Significant improvement was found in the extent of drug absorption in vivo. It could be concluded that polacrilin potassium may be used as a high-functionality excipient for improving the bioavailability of anionic drugs having poor gastrointestinal permeability.
bioavailability improvement; disintegrants; permeability enhancement; polacrilin potassium
Stability Indicating Method (SIM) is a quantitative analytical procedure used to detect a decrease in the amount of the active pharmaceutical ingredient (API) present due to degradation. According to Food and Drug Administration (FDA) guidelines, an SIM is defined as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from potential interferences, such as degradation products, process impurities, excipients, or other potential impurities, and the FDA recommends that all assay procedures for stability studies be stability indicating. Here in this study we developed simple precise and accurate stability indicating reverse-phase high-performance liquid chromatographic (RP-HPLC) assay to analyze capsaicin (CAP) at concentrations from 70 to 130 μg/mL.
Materials and Methods:
HPLC equipped with Photo diode Array (PDA) detector, Pump model 600E of Waters and Empower software. Column used for the separation is ODS (250 × 4.6 mm) with particle size 5 μm and all the reagents and water were of HPLC grade.
The chromatographic separation was carried out using mobile phase Acetonitrile (ACN):water:buffer::75:10:15 with a flow rate of 1 mL/min on a C18 column. The concentration of the eluting compounds was monitored by a UV detector at 280 nm. No interferences were observed when stress conditions were applied and analyzed. Linearity was established using visual method, residuals plot, Dixon, and lack of fitness test. Limit of detection and limit of quantification was found to be 52.9 and 160 ng/mL, respectively. Recovery studies prove this method as useful in recovering the analytes. Relative Standard Deviation (RSD) of inter- and intraday precision within the acceptable limit of 2% proves that this method is precise. No degradation was found with alkaline conditions, thermal and photodegradation.
This study can be used for successful separation of CAP and its potential degradants in bulk and formulations. UV spectra of one of the degradants are also presented here and can be the basis to generate chemistry of potential degradants when CAP is kept under environmental conditions.
Capsaicin; stability indicating method; stress conditions; method validation
The purpose of this study is to determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.
To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of 1) the binding of excipient to GLP-1, 2) the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, 3) the in vitro bio-activity of excipient-formulated GLP-1, 4) the in vivo pharmacokinetics of excipient-formulated GLP-1, and 5) the efficacy of the excipient-formulated GLP-1 in diabetic rats.
We showed reproducible synthesis of PGC excipient, showed high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and showed that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.
PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.
Glucagon like peptide; peptide excipient; Protected Graft Copolymer; Diabetes
Background. Conjunctivitis is one of the most frequently occurring hospital-acquired infections among neonates, although it is less studied than potentially life-threatening infections, such as sepsis and pneumonia.
Objectives. The aims of our work were to identify epidemiologic characteristics, pathogens, and susceptibility patterns of bacterial hospital-acquired conjunctivitis (HAC) in a level III neonatal unit. Materials and Methods. Data were collected retrospectively from patient charts and laboratory databases. Hospital-acquired conjunctivitis was defined in accordance with the Centers for Disease Control/National Healthcare Safety Network (CDC/NHSN) diagnostic criteria.
Results. One or more episodes of HAC were diagnosed in 4,0% (n = 60) of 1492 neonates admitted during the study period. Most of the episodes involved premature (75,4%) and low birth weight (75,4%) neonates. Infection rates were higher among patients undergoing noninvasive mechanical ventilation (46,7%), parenteral nutrition (13,6%), and phototherapy (6,8%). Predominant pathogens included Serratia marcescens (27,9%), Escherichia coli (23%), and Pseudomonas aeruginosa (18%). Susceptibility patterns revealed bacterial resistances to several antibiotic classes. Gentamicin remains the adequate choice for empirical treatment of HAC in our NICU. Conclusion. It is important to know the local patterns of the disease in order to adjust prevention strategies. Our work contributes to the epidemiological characterization of a sometimes overlooked disease.
The purpose of this study was to evaluate the mechanisms of aggregate formation and excipient stabilization in freeze-dried formulations of a recombinant humanized monoclonal antibody. Protein degradation was measured using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and native size exclusion chromatography, and protein structure was studied using Fourier transform-infrared spectrometry and circular dichroism. The results showed that protein aggregates present following reconstitution were composed of native antibody structure and a reduced amount of free thiol when compared to protein monomer, which implied that intermolecular disulfides were involved in the aggregation mechanism. An excipient-free formulation resulted in reversible solid-state protein structural alteration and increased aggregation during storage. This correlated with dehydration to an extent that the amount of water was less than the estimated number of surface-accessible hydrogen-bonding sites on the protein. Improved native-like solid-state protein structure and reduced aggregation were obtained by formulation with enough carbohydrate to fulfill the hydrogen-bonding sites on the surface of the protein. Carbohydrate in excess of this concentration has less of an influence on protein aggregation. Reduced aggregation during storage was obtained by the addition of sufficient excipient to both stabilized solid-state protein structure and provide an environment that consisted of an amorphous glassy state matrix.
protein formulation; protein stability; recombinant humanized monoclonal antibody; aggregation; FT-IR spectrometry
► Hydrophobic polymers are extensively used as matrix former in controlled drug delivery. ► We have synthesized a new hydrophobic polymer using acetylation of native moth bean starch. ► The hydrophobic polymer was evaluated as controlled release excipient for pharmaceutical formulation development. ► The results revealed that the acetylated moth bean starch can be used as controlled release polymer.
The present investigation concerns with the development of controlled release tablets of lamivudine using acetylated moth bean starch. The acetylated starch was synthesized with acetic anhydride in pyridine medium. The acetylated moth bean starch was tested for acute toxicity and drug–excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi kinetic model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir®, which proved controlled release potential of acetylated moth bean starch.
Lamivudine; Controlled release tablet; Acetylation; Moth bean starch