Stability of Ertapenem 100 mg/mL in Manufacturer’s Glass Vials or Syringes at 4°C and 23°C

Background:

Prophylactic administration of ertapenem as a single 1-g IV dose has been shown to reduce sepsis after prostate biopsy.

Objective:

To evaluate the stability of ertapenem after reconstitution with 0.9% sodium chloride to a final concentration of 100 mg/mL and storage in the manufacturer’s original glass vials or polypropylene syringes.

Methods:

On study day 0, 100 mg/mL solutions of ertapenem were retained in the manufacturer’s glass vials or packaged in polypropylene syringes and stored at 4°C or 23°C without protection from fluorescent room light. Samples were assayed periodically over 18 days using a validated, stability-indicating liquid chromatographic method with ultra-violet detection. A beyond-use date was determined as the time for the concentration to decline to 90% of the initial (day 0) concentration, based on the fastest degradation rate, with 95% confidence.

Results:

Reconstituted solutions stored in the manufacturer’s glass vials or polypropylene syringes exhibited a first-order degradation rate, such that 10% of the initial concentration was lost in the first 2.5 days when stored at 4°C or within the first 6.75 h when stored at room temperature (23°C). Analysis of variance showed differences in the percentage remaining due to temperature (p < 0.001) and study day (p < 0.001) but not type of container (p = 0.98). When a 95% CI for the degradation rate was calculated and used to determine a beyond-use date, it was established that more than 90% of the initial concentration would remain for 2.35 days at 4°C and for 0.23 day (about 5 h, 30 min) at room temperature.

Conclusions:

A 100 mg/mL ertapenem solution stored in the manufacturer’s glass vial or a polypropylene syringe will retain more than 90.5% of the initial concentration when stored for 48 h at 4°C and for an additional 1 h at 23°C.     

Impact of Ethylene Oxide Sterilization of Polymer-Based Prefilled Syringes on Chemical Degradation of a Model Therapeutic Protein During Storage

Materials from prefilled syringe systems—such as silicone oil, tungsten, glass, and rubber—may enhance therapeutic protein aggregation and particle formation. Also, the sterilization method used for syringes may impact aggregation and chemical degradation of biologics during storage. Syringes are generally sterilized by radiation, ethylene oxide gas (EO), or steam. Among the sterilization methods, EO has the potential to cause chemical degradation by the formation of adducts with susceptible amino acid residues in the protein. In this study, EO- and steam-sterilized syringes were compared to determine the influence of residual EO on human serum albumin (HSA) degradation. Although the amount of residual EO in the EO-sterilized syringes was less than 220 μg/syringe, well below the International Organization for Standardization limit, EO adduction to cysteine (Cys) and methionine (Met) in HSA was observed by liquid chromatography and mass spectrometry analysis. The EO adduct ratio of HSA stored for 2 weeks in EO-sterilized syringes was about 45%. In contrast, no chemical degradation was observed in HSA formulation stored in steam-sterilized syringes. Because of the propensity of EO to readily form adducts with proteins, an alternative to EO sterilization should be used for prefilled syringes that will be used for therapeutic protein products.     

Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions

The effect of silicone oil on the stability of therapeutic protein formulations is of concern in the biopharmaceutical industry as more proteins are stored and delivered in prefilled syringes. Prefilled syringes provide convenience for medical professionals and patients, but prolonged exposure of proteins to silicone oil within prefilled syringes may be problematic. In this study, we characterize systems of silicone oil‐in‐aqueous buffer emulsions and model proteins in formulations containing surfactant, sodium chloride, or sucrose. For each of the formulations studied, silicone oil‐induced loss of soluble protein, likely through protein adsorption onto the silicone oil droplet surface. Excipient addition affected both protein adsorption and emulsion stability. Addition of surfactant stabilized emulsions but decreased protein adsorption to silicone oil microdroplets. In contrast, addition of sodium chloride increased protein adsorption and decreased emulsion stability. Silicone oil droplets with adsorbed lysozyme rapidly agglomerated and creamed out of suspension. This decrease in the kinetic stability of the emulsion is ascribed to surface charge neutralization and a bridging flocculation phenomenon and illustrates the need to investigate not only the effects of silicone oil on protein stability, but also the effects of protein formulation variables on emulsion stability. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1721–1733, 2010     

Buffered lidocaine hydrochloride solution with and without epinephrine: stability in polypropylene syringes

Background:

Pain associated with infiltrating the skin with lidocaine can be reduced by buffering the solution with sodium bicarbonate.

Objectives:

To determine the physical compatibility and chemical stability of lidocaine hydrochloride solution buffered with 8.4% sodium bicarbonate, with and without epinephrine, packaged in polypropylene syringes and stored at 5°C with protection from light.

Methods:

Lidocaine solutions (1% and 2%), with and without epinephrine 1:100 000, were diluted 10:1 with 8.4% sodium bicarbonate, packaged in 3-mL polypropylene syringes, and stored at 5°C (range 3°C to 8°C). On each of days 0, 3, 7, 10, 14, 17, 21, 24, and 28, the contents of 3 syringes for each solution of lidocaine combined with epinephrine were collected separately in glass vials and frozen at −70°C for subsequent analysis. In addition, on days 0, 7, 14, 21, and 28, the contents of 3 syringes for each lidocaine solution without epinephrine were collected separately in glass vials and frozen at −70°C for subsequent analysis. Chemical stability was determined with a validated, stability-indicating high-performance liquid chromatography method. Changes in colour, clarity, and pH were used to determine physical compatibility of the solutions.

Results:

All buffered lidocaine solutions containing epinephrine (1:100 000) retained at least 93.3% of the original concentration of epinephrine and 97.5% of the lidocaine concentration for 7 days when stored at 5°C with protection from light. In contrast, the epinephrine-free solutions retained at least 94.7% of the initial concentration of lidocaine for the duration of the study (28 days). All samples remained clear, colourless, and free of precipitate throughout the study, and there were no significant changes in pH.

Conclusion:

Extemporaneously prepared buffered lidocaine (1% and 2%) packaged in polypropylene syringes remained stable for up to 28 days when properly refrigerated with protection from light. A 7-day expiry date was established for buffered lidocaine solutions containing epinephrine, packaged in polypropylene syringes, and stored with refrigeration and protection from light.     

Sweeping of Adsorbed Therapeutic Protein on Prefillable Syringes Promotes Micron Aggregate Generation

This study evaluated how differences in the surface properties of prefillable syringe barrels and in-solution sampling methods affect micron aggregates and protein adsorption levels. Three syringe types (glass barrel with silicone oil coating [GLS/SO+], glass barrel without silicone oil coating [GLS/SO?], and cyclo-olefin polymer [COP] barrel syringes) were tested with 3 therapeutic proteins (adalimumab, etanercept, and infliximab) using 2 sampling methods (aspiration or ejection). After quiescent incubation, solutions sampled by aspiration exhibited no significant change in micron aggregate concentration in any syringes, whereas those sampled by ejection exhibited increased micron aggregates in both GLS syringe types. Micron aggregate concentration in ejected solutions generally increased with increasing density of adsorbed proteins. Notably, COP syringes contained the lowest micron aggregate concentrations, which were independent of the sampling method. Correspondingly, the adsorbed protein density on COP syringes was the lowest at 1-2 mg/m², which was much less compared with that on GLS syringes and was calculated to be equivalent to only 1–2 protein layers, as visually confirmed by high-speed atomic force microscopy. These data indicate that low-adsorption prefillable syringes should be used for therapeutic proteins because protein aggregate concentration in the ejected solution is elevated by increased protein adsorption to the syringe surface.     

Stability of pantoprazole sodium in glass vials, polyvinyl chloride minibags, and polypropylene syringes

Background:

Pantoprazole sodium, a proton-pump inhibitor, is approved for the short-term treatment of several types of ulcer, Zollinger–Ellison syndrome, and gastroesophageal reflux disease.

Objective:

To determine the physical compatibility and chemical stability of ethylenediaminetetra-acetic acid (EDTA)–free pantoprazole in glass vials, polypropylene syringes, and polyvinylchloride (PVC) minibags, after storage at 2°C to 8°C with protection from light or at 20°C to 25°C with exposure to light.

Methods:

Solutions of pantoprazole 4 mg/mL reconstituted in 0.9% sodium chloride (normal saline [NS]) were stored in glass vials at 20°C to 25°C. Similar solutions were transferred to polypropylene syringes and stored at 2°C to 8°C. Stock solution was further diluted, in 5% dextrose in water (D5W) or NS, to 0.4 or 0.8 mg/mL, and samples were then packaged in PVC minibags for storage at 2°C to 8°C or at 20°C to 25°C. Samples collected on days 0, 2, 3, 7, 14, 21, and 28 were analyzed in duplicate with a stability-indicating high-performance liquid chromatography assay.

Results:

Pantoprazole 4 mg/mL was stable (i.e., retained at least 90% of initial concentration) for 3 days when stored in glass vials at 20°C to 25°C or for 28 days when stored in polypropylene syringes at 2°C to 8°C. Pantoprazole 0.4 mg/mL diluted in D5W and stored in PVC minibags was stable for 2 days at 20°C to 25°C or for 14 days at 2°C to 8°C. At 0.8 mg/mL, pantoprazole in D5W was stable for 3 days at 20°C to 25°C or 28 days at 2°C to 8°C. Pantoprazole diluted to either 0.4 or 0.8 mg/mL in NS and stored in PVC minibags was stable for 3 days at 20°C to 25°C or 28 days at 2°C to 8°C.

Conclusions:

The present study confirmed or extended previously reported expiry dates for pantoprazole sodium packaged in glass vials, polypropylene syringes, and PVC minibags.     

Plasma Polymerized HMDSO Coatings For Syringes To Minimize Protein Adsorption

Current parenteral containers used for the storage and delivery of protein-based drugs, contain silicone oil which may seep into the protein solution and can result in adsorption, aggregation and denaturation of the protein. Tightly adherent surface coatings prepared by radio frequency glow-discharge (RFGD) plasma polymerization are described in this paper. Using this robust technique, methacrylic acid (MA) (hydrophilic), hexamethyldisiloxane (HMDSO) (hydrophobic), tetraglyme (TG) (hydrophilic) were plasma polymerized onto glass. In addition, HMDSO and MA were copolymerized to create a plasma polymerized HMDSO-MA (hydrophobic) surface. Untreated glass and glass dip-coated in PDMS were used as controls. TG and MA plasma coatings adsorbed the least amount of protein in all pH conditions. Interestingly HMDSO-MA retained significantly lesser protein compared to HMDSO and dip-coated PDMS samples. In the presence of Polysorbate 80 (PS80) all plasma polymerized coatings adsorbed and retained negligible amounts of protein, compared to controls. Furthermore, the peak glide force of plasma coated syringes did not significantly increase compared to syringes without plasma coating. Due to the versatility of RFGD plasma, this process is scalable and could potentially be used for the treatment of hypodermic syringes used for the storage and delivery of protein-based therapeutics.     

Stability of cefazolin sodium in polypropylene syringes and polyvinylchloride minibags

Background:

Cefazolin is a semisynthetic penicillin derivative with a narrow spectrum of activity covering some gram-positive organisms and a few gram-negative aerobic bacteria.

Objective:

To determine the physical and chemical stability of cefazolin sodium reconstituted with sterile water for injection and stored in polypropylene syringes or diluted with either 5% dextrose in water (D5W) or 0.9% sodium chloride (normal saline [NS]) and stored in polyvinylchloride (PVC) minibags.

Methods:

Reconstituted solutions of cefazolin (100 or 200 mg/mL) were packaged in polypropylene syringes. More dilute solutions (20 or 40 mg/mL) were prepared in D5W or NS and packaged in PVC minibags. For each concentration–diluent–container combination, 3 containers were designated for each day of analysis (days 7, 14, 21, and 30). Containers were stored under refrigeration (5°C) with protection from light until the designated day of analysis, at which time one 5-mL sample was collected from each the designated container. The designated containers were then stored at room temperature (21°C to 25°C) with exposure to light for an additional 72 h, and additional samples were drawn. The samples were assayed using a validated, stability-indicating high-performance liquid chromatography method. The colour and clarity of the solutions, as well as their pH, were also monitored on each sampling day.

Results:

All samples remained clear for the duration of the study; they had a slight yellow colour that darkened over time, and there was an increase in pH. Solutions diluted with sterile water for injection and stored in polypropylene syringes retained at least 94.5% of the initial concentration after 30 days of refrigerated storage and at least 92.1% after an additional 72 h at room temperature with exposure to light. Samples diluted in D5W or NS and stored in PVC minibags retained at least 95.8% of the initial concentration after 30 days of refrigerated storage and at least 91.8% after an additional 72 h at room temperature with exposure to light.

Conclusions:

Cefazolin at various concentrations stored in polypropylene syringes or PVC minibags was stable for up to 30 days with storage at 5°C with protection from light, followed by an additional 72 h at 21°C to 25°C with exposure to light.     

Influence of Protein Adsorption on Aggregation in Prefilled Syringes

Protein aggregate formation in prefilled syringes (PFSs) can be influenced by protein adsorption and desorption at the solid–liquid interface. Although inhibition of protein adsorption on the PFS surface can lead to a decrease in the amount of aggregation, the mechanism underlying protein adsorption-mediated aggregation in PFSs is unclear. This study investigated protein aggregation caused by protein adsorption on silicone oil-free PFS surfaces [borosilicate glass (GLS) and cycloolefin polymer (COP)] and the factors affecting the protein adsorption on the PFS surfaces. The adsorbed proteins formed multilayered structures that consisted of two distinct types of layers: proteins adsorbed on the surface of the material and proteins adsorbed on top of the proteins on the surface. A pH-dependent electrostatic interaction was the dominant force for protein adsorption on the GLS surface, while hydrophobic effects were dominant for protein adsorption on the COP surface. When the repulsion force between proteins was weak, protein adsorption on the adsorbed protein layer was increased for both materials and as a result, protein aggregation increased. Therefore, a formulation with high colloidal stability can minimize protein adsorption on the COP surface, leading to reduced protein aggregation.     

The Impact of Syringe Age Prior to Filling on Migration of Subvisible Silicone-Oil Particles into Drug Product

Silicone oil is often applied to the inner surface of glass syringes and cartridges to reduce friction between the glass surface and elastomeric plunger stopper. This oil can appear as intrinsic and non-proteinaceous particles in the ejected fluid or drug product. Limited data is available to understand the impact of age (time between syringe manufacture and filling) on silicone oil migration into the drug product. This study compares subvisible particle count and extrusion force of siliconized syringes from two different manufacturers stored at ambient condition for 2-3 (fresh syringes) and 13-14 (aged syringes) months then filled and placed at 40°C for an additional three months. The fresh syringes exhibit a 2.5-fold increase in subvisible particle count compared to those aged ones. Moreover, the fresh syringes exhibit up to a 2-fold increase in extrusion force. These findings suggest the degree and amount of silicone oil migration is influenced by the time in storage of the glass syringe prior to filling. This rapid communication highlights syringe storage time prior to filling as a factor to be considered during development.     

Effect of Various Silicone Oil And Tungsten Levels on the Stability of a Monoclonal Antibody in Nine Commercially Available Prefilled Syringes

Prefilled syringes are widely used as a primary container for therapeutic proteins because they are more convenient than glass vials. The stability of biologic molecules can be affected by different syringe materials and techniques, such as silicone oil levels and coating method, amount of tungsten remaining in the glass barrel after using a tungsten pin to create the needle hole, and end of the syringe, which can be Luer locked or pre-staked with a needle. We investigated the impact of these parameters by using a monoclonal antibody to collect the antibody's stability profile and the prefilled syringes’ functionality data. Silicone oil levels had no impact on aggregation levels, and particle counts were lowest for silicone oil–free syringes. Functionality performance was similar and did not change throughout all stability time points for all syringe configurations. The break-loose force for Ompi syringes was initially lower and increased over time to align with those of the other configurations, all of which remained well below 25 N. Tungsten contaminants and agitation stress from shipping studies did not impact quality attributes. This work can help guide the development of similar products in prefilled syringes to ensure selection of the primary container that provides adequate stability for the protein, as well as maintain the desired functionality features over the shelf life of the drug product.     

Evaluation of the effect of syringe surfaces on protein formulations

Packaging of drugs in prefillable syringes offers considerable advantages over conventional vials. Almost all major biotech molecules are available on the market today in prefilled syringes, and are safe and efficacious. Newer high-concentration liquid formulations, especially fusion proteins, however, can suffer from instability in prefilled syringes due to syringe components like silicone oil. To assess the effect of siliconized and modified syringe surfaces on protein formulations, the stability of the recombinant protective antigen (rPA) for anthrax, abatacept, a fusion protein formulation with known silicone oil sensitivity, and an antistaphylococcal enterotoxin B (anti-SEB) monoclonal antibody (mAb) was assessed in siliconized, uncoated, and BD-42-coated (a proprietary coating developed by BD Technologies) prefilled syringes under different conditions. Both the soluble protein content and the number of subvisible particles were followed over time. When filled in siliconized syringes, all three protein solutions showed increased number of subvisible particles relative to uncoated or BD-42-coated syringes; the abatacept formulation with known silicone sensitivity also developed visible particles. Although rPA and anti-SEB mAb formulations mainly showed individual droplets, presumably of silicone, the abatacept formulation also showed droplets entangled in a fibrous structure. Uncoated glass and BD-42-coated syringes considerably reduced the formation of both visible and subvisible particles after immediate contact and after agitation. The anti-SEB mAb also adhered as a thin layer to the siliconized surface after agitation, irrespective of storage temperature. The development of visible particles could not be correlated with the loss of soluble protein fraction at protein concentrations above 4 mg/mL. It appears that protein formulations interact differently with different surfaces. The BD-42 coating appears to be a promising solution for packaging silicone-sensitive proteins in prefillable syringes and needs to be investigated further. It is demonstrated that BD-42 provides an inert surface with adequate lubrication while limiting the formation of visible and subvisible particles. It is hypothesized that these particles are formed due to the release of silicone droplets in the solution and result in the formation of silicone-induced visible aggregates.     

Particle Characterization for a Protein Drug Product Stored in Pre-Filled Syringes Using Micro-Flow Imaging,Archimedes, and Quartz Crystal Microbalance with Dissipation

Micro-flow imaging (MFI) has been used for formulation development for analyzing sub-visible particles. Archimedes, a novel technique for analyzing sub-micron particles, has been considered as an orthogonal method to currently existing techniques. This study utilized these two techniques to investigate the effectiveness of polysorbate (PS-80) in mitigating the particle formation of a therapeutic protein formulation stored in silicone oil-coated pre-filled syringes. The results indicated that PS-80 prevented the formation of both protein and silicone oil particles. In the case of protein particles, PS-80 might involve in the interactions with the hydrophobic patches of protein, air bubbles, and the stressed surfaces of silicone oil-coated pre-filled syringes. Such interactions played a role in mitigating the formation of protein particles. Subsequently, quartz crystal microbalance with dissipation (QCM-D) was utilized to characterize the interactions associated with silicone oil, protein, and PS-80 in the solutions. Based on QCM-D results, we proposed that PS-80 likely formed a layer on the interior surfaces of syringes. As a result, the adsorbed PS-80 might block the leakage of silicone oil from the surfaces to solution so that the silicone oil particles were mitigated at the presence of PS-80. Overall, this study demonstrated the necessary of utilizing these three techniques cooperatively in order to better understand the interfacial role of PS-80 in mitigating the formation of protein and silicone oil particles.     

Demonstrating the stability of albinterferon alfa-2b in the presence of silicone oil

Silicone oil is often used to decrease glide forces in prefilled syringes and cartridges, common primary container closures for biopharmaceutical products. Silicone oil has been linked to inducing protein aggregation (Diabet Med 1989;6:278; Diabet Care 1987;10:786-790), leading to patient safety and immunogenicity concerns. Because of the silicone oil application process (Biotech Adv 2007;25:318-324), silicone oil levels tend to vary between individual container closures. Various silicone oil levels were applied to a container closure prior to filling and lyophilization of an albumin and interferon alfa-2b fusion protein (albinterferon alfa-2b). Data demonstrated that high silicone oil levels in combination with intended and stress storage conditions had no impact on protein purity, higher order structure, stability trajectory, or biological activity. Subvisible particulate analysis (1-10 μm range) from active and placebo samples from siliconized glass barrels showed similar particle counts. Increases in solution turbidity readings for both active and placebo samples correlated well with increases in silicone oil levels, suggesting that the particles in solution are related to the presence of silicone oil and not large protein aggregates. Results from this study demonstrate that silicone oil is not always detrimental to proteins; nevertheless, assessing the impact of silicone oil on a product case-by-case basis is still recommended.     

Stability of nifedipine in an extemporaneously compounded oral solution.

The stability of nifedipine in an extemporaneously compounded oral solution is described. A solution of nifedipine 10 mg/mL was prepared from commercially available nifedipine powder with polyethylene glycol 400, glycerin, and peppermint oil. Four samples were stored in amber glass bottles at room temperature under fluorescent lighting and analyzed in duplicate. Samples were analyzed immediately and at 7, 14, 23, and 35 days. Eight samples were stored in amber oral syringes and eight in amber oral syringes wrapped in aluminum foil; all were stored at room temperature under fluorescent lighting. Samples from foil-wrapped syringes were analyzed at 7 and 14 days; samples not wrapped in foil were analyzed after 7 days. Nifedipine concentrations were measured with a modified stability-indicating high-performance liquid chromatographic method. Excessive degradation was defined as a greater than 10% loss of initial drug concentration. There were no detectable changes in color or odor and no visible solids or microbial growth was observed in any sample. Samples in amber glass bottles and amber oral syringes wrapped in aluminum foil retained more than 90% of the initial nifedipine for 35 and 14 days, respectively. Samples packaged in amber oral syringes not wrapped in foil lost over 20% of the initial nifedipine concentration within 7 days. Nifedipine 10 mg/mL was stable in an oral solution prepared from commercially available powder in a peppermint-flavored vehicle for at least 35 days when stored at 22-25 degrees C in amber glass bottles and for at least 14 days when stored in amber oral syringes wrapped in aluminum foil.     

An Assessment of the Ability of Submicron- and Micron-Size Silicone Oil Droplets in Dropped Prefillable Syringes to Invoke Early- and Late-Stage Immune Responses

A number of biopharmaceuticals are available as lyophilized formulations along with a prefilled syringe (PFS) containing water for injection (WFI). Submicron- and micron-size droplets of lubricating silicone oil (SO) applied to the inner surface of the PFS barrel might migrate into the WFI, to which protein pharmaceuticals can adsorb, potentially inducing an immune response. In the present study, we subjected siliconized cyclo-olefin polymer PFSs filled with WFI to dropping stress to simulate actual shipping conditions as well as evaluated the risk associated with the released SO droplets. The results confirmed the undesirable effects of SO on therapeutic proteins, including adsorption to SO droplets and increased secretion of several innate cytokines from human peripheral blood mononuclear cells of a small donor panel. Assessment of immunogenicity in vivo using BALB/c mice revealed a slight increase in the plasma concentrations of antidrug antibodies over 21 days in response to SO-containing antibody samples compared to the absence of SO. These results indicate that SO droplets form complexes with pharmaceutical proteins that can potentially invoke early- and late-stage immune responses. Therefore, the use of SO-free cyclo-olefin polymer PFSs as primary containers for WFI could contribute to the enhanced safety of reconstituted biopharmaceuticals.     

Protein Aggregation and Particle Formation in Prefilled Glass Syringes

The stability of therapeutic proteins formulated in prefilled syringes (PFS) may be negatively impacted by the exposure of protein molecules to silicone oil–water interfaces and air–water interfaces. In addition, agitation, such as that experienced during transportation, may increase the detrimental effects (i.e., protein aggregation and particle formation) of protein interactions with interfaces. In this study, surfactant-free formulations containing either a monoclonal antibody or lysozyme were incubated in PFS, where they were exposed to silicone oil–water interfaces (siliconized syringe walls), air–water interfaces (air bubbles), and agitation stress (occurring during end-over-end rotation). Using flow microscopy, particles (≥2 μm diameter) were detected under all conditions. The highest particle concentrations were found in agitated, siliconized syringes containing an air bubble. The particles formed in this condition consisted of silicone oil droplets and aggregated protein, as well as agglomerates of protein aggregates and silicone oil. We propose an interfacial mechanism of particle generation in PFS in which capillary forces at the three-phase (silicone oil–water–air) contact line remove silicone oil and gelled protein aggregates from the interface and transport them into the bulk. This mechanism explains the synergistic effects of silicone oil–water interfaces, air–water interfaces, and agitation in the generation of particles in protein formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1601–1612, 2014     

Silicone oil induced aggregation of proteins

Prior to delivery to the patient, protein pharmaceuticals often come in contact with a variety of surfaces (e.g., syringes and stoppers), which are treated to facilitate processing or to inhibit protein binding. One such coating, silicone oil, has previously been implicated in the induction of protein aggregation. We have investigated the propensity of model proteins to aggregate when silicone oil is present in solution and find significant induction of aggregation in four proteins of various molecular weights and isoelectric points in the presence of 0.5% oil. The ability of silicone oil to induce conformational changes that might be responsible for this aggregation was also examined by a combination of circular dichroism (CD) and derivative UV spectroscopy. Neither method produces evidence of large conformational changes or alterations in thermal stability although in a limited number of cases some small changes suggest the possibility of minor structural alterations. The most probable explanation for silicone oil induced aggregation is that the oil has direct effects on intermolecular interactions responsible for protein association through interaction with protein surfaces or indirectly through effects on the solvent.     

Stability of valproate sodium syrup in various unit dose containers

The stability of valproate sodium syrup repackaged in three types of unit dose containers was studied. Two-millimeter samples of commercial valproate sodium syrup 250 mg/5 ml (of valproic acid) were packaged in polypropylene oral syringes, glass oral syringes, and glass vials (126 of each type). These were stored at 4, 25, or 60 degrees C and assayed for valproic acid concentration using gas chromatography at 0, 5, 10, 20, 30, 90, and 180 days. Polypropylene syringes that were stored for 180 days at 4 and 25 degrees C were rinsed and put in chloroform 50 ml; valproic acid concentration was determined daily for 12 days. Valproate sodium syrup repackaged in glass oral syringes and glass vials retained 95% of valproic acid label claim after storage at 4 and 25 degrees C for 180 days, while valproate sodium syrup repackaged in polypropylene oral syringes did not retain 90% of label claim after storage for 20 days at 4 or 25 degrees C. All samples stored at 60 degrees C had greater loss than those stored at lower temperatures. An average of 86% of the drug lost from the polypropylene syringes was recovered in 12 days during the desorption experiment (range 80-92%). Repackaging valproate sodium syrup in unit dose glass vials or glass syringes resulted in retention of 95% of valproic acid label claim after storage for 180 days at 4 and 25 degrees C. Repackaging of this drug product in polypropylene oral syringes is not recommended.