Amount Of Active Pharmaceutical Ingredient Research Articles

Photostability evaluation of manidipine tablets and structural determination of its photoproducts.

Manidipine (MP) is a dihydropyridine drug, which is treated for the reduction of high blood pressure. The aim of this study is to clarify the photochemical behavior of MP in the case of ultraviolet light (UV) irradiation for MP tablets (Calslot® tablets). The tablets and its altered forms (powders and suspensions) were UV-irradiated using a black light, and residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography (HPLC). Due to the photoproducts of MP were detected in HPLC chromatograms, the elucidation of their chemical structures was carried out utilizing electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). As a result, APIs in Calslot® tablets were almost completely photodegraded in the case that Calslot® tablets were suspended in an aqueous media along with the generation of some MP photoproducts. LC-ESI-MS/MS analysis clarified the chemical structures of three MP photoproducts, indicating that they were a pyridine analogue, benzophenone and a hydrolysate. Benzophenone was a main MP photoproduct. It was possible that MP might be firstly oxidized to form its pyridine analogue, followed by the oxidation of a dimethyl methylene moiety. This moiety seemed to be eliminated as a benzophenone, and the cleavage of an ester bond of the residual moiety resulted in the generation of a hydrolysate. Finally, toxicological potencies of MP and its photoproducts were predicted in silico toxicity evaluation, suggesting some of biological effects of the photoproducts might be altered compared with MP.

Research for the selection of taste corrigents, filter materials and primary packaging for oral solution with magnesium salts

The aim. Theoretically and experimentally, justify the choice of excipients for a combined oral solution with organic magnesium salts. Determine the compatibility of filter materials of three types. Select single-dose primary packaging for the developed oral solution and confirm its suitability during the relevant studies. Materials and methods. Organoleptic, physicochemical, and pharmaco-technological methods were used in the investigation. All methods meet the requirements of the State Pharmacopoeia of Ukraine and the European Pharmacopoeia. Organoleptic methods indicated the taste of the medicinal speciality behind the methods of O.I. Tentsova and I.A. Egorov. Physicochemical methods were used to determine pH, colour, density, and quantitative amount of active pharmaceutical ingredients. Pharmaco-technological methods were used to determine the properties of filter materials and primary packaging. Results. A sweetener and a flavouring agent for an oral solution with magnesium salts were selected based on the research. Saccharin sodium was selected as a sweetener in the amount of 0.15 %. «Cherry» in the amount of 0.4 % and «caramel» in the amount of 0.2 % were selected as flavouring agents. As a result of experiments, the suitability of filter materials made of сapron, nylon and polyethersulfone was proven. This is determined by the constancy of the main quality indicators of the drug 24, 48 and 72 hours after filtration. The suitability of the single-dose primary packaging in the process of storing the oral solution has been studied and proven. In the work, polymer ampoules of the «Moplen EP 2S 12 B» brand and the «Purell HP 371P» brand were used. The conducted research allows us to create a competitive domestic drug that will be technologically simple and convenient in administration and will also be distinguished by relatively low raw material costs and production. Conclusions. Based on theoretical and experimental studies, auxiliary substances, such as sweeteners and flavouring agents, were selected for the combined magnesium-containing drug. The suitability of filter materials for the combined oral solution was investigated and confirmed. The suitability of single-dose primary packaging of two types was selected and experimentally proven

Levofloxacin and Ciprofloxacin Co-Crystals with Flavonoids: Solid-State Investigation for a Multitarget Strategy against Helicobacter pylori.

In this paper, we address the problem of antimicrobial resistance in the case of Helicobacter pylori with a crystal engineering approach. Two antibiotics of the fluoroquinolone class, namely, levofloxacin (LEV) and ciprofloxacin (CIP), have been co-crystallized with the flavonoids quercetin (QUE), myricetin (MYR), and hesperetin (HES), resulting in the formation of four co-crystals, namely, LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE. The co-crystals were obtained from solution, slurry, or mechanochemical mixing of the reactants. LEV∙QUE and LEV∙MYR were initially obtained as the ethanol solvates LEV∙QUE∙xEtOH and LEV∙MYR∙xEtOH, respectively, which upon thermal treatment yielded the unsolvated forms. All co-crystals were characterized by powder X-ray diffraction and thermal gravimetric analysis. The antibacterial performance of the four co-crystals LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE in comparison with that of the physical mixtures of the separate components was tested via evaluation of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). The results obtained indicate that the association with the co-formers, whether co-crystallized or forming a physical mixture with the active pharmaceutical ingredients (API), enhances the antimicrobial activity of the fluoroquinolones, allowing them to significantly reduce the amount of API otherwise required to display the same activity against H. pylori.

DEVELOPMENT OF THE BASICS OF SPRAY TECHNOLOGY FOR EXTERNAL APPLICATION

The basics of the technology for the preparation of a spray formulation for external use with analgesic and anti-inflammatory effects was developed. The quantitative content of active pharmaceutical ingredients and excipients was proposed. Comparative analysis of some indicators of the obtained spray with analogues on the pharmaceutical market of Ukraine was carried out. Material calculations allowed to estimate the amount of active pharmaceutical ingredients and excipients for the preparation of the spray and its packaging in bottles with a dropper in the laboratory. Based on the material calculations, a basic technological scheme for the production of the finished product was proposed. Economic calculations have been carried out, which demonstrate a high level of economic profitability of the development of such a preparation.

Comparative Analysis of Different Brands of Ibuprofen available on the Georgian Pharmaceutical Market

According to the World Health Organization (WHO), 1 out of 10 medical products in developing countries are substandard or falsified. Since Georgia is a developing country and is listed among the countries where substandard and falsified medical products have been discovered and reported to WHO, it is important to explore the quality of medical products available on the Georgian pharmaceutical market. As an initial study, we have chosen one of the most widely used drugs worldwide – ibuprofen, available in the pharmacy network in Tbilisi – the capital of Georgia. We have studied 10 different brands, imported and locally produced, and 2 brand-name ibuprofens (Motrin and Advil). The content of the Active Pharmaceutical Ingredient (API) was determined by a spectrophotometer, in the ultraviolet region. The obtained results showed that all brand ibuprofens contained labeled amounts of API.

Evaluation of photostability of azelnidipine tablets and structure determination of its photoproducts

Photo-exposure has a crucial effect on the natures of photosensitive pharmaceuticals in addition to their contents in medicines through the photodegradation. Generated photoproducts might be more bioactive and contribute to the expression of adverse side effects. This study aimed to clarify the photochemical behavior of medicines of azelnidipine, which is a member of dihydropyridine antihypertensive drugs, by the evaluation of its photostability and the determination of chemical structures of generated photoproducts. Calblock® tablets and its altered forms (powders and suspensions) were UV-irradiated by a black light. Residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography. The chemical structures of two photoproducts were determined by electrospray ionization tandem mass spectrometry. API of Calblock® tablets was photodegraded with the generation of several photoproducts. Its photodegradability was more significant when Calblock® tablets were crushed or suspended. Structural determination revealed that two photoproducts were benzophenone and a pyridine derivative. It was speculated that these photoproducts were generated by the elimination of diphenyl methylene radical and additional chemical reaction including oxidation and hydrolysis. Azelnidipine was photosensitive and its photodegradation in Calblock® tablets was promoted by the change of the dosage form. This difference might be derived from the light emission efficiency. This study suggests that API contents of Calblock® tablets might decrease when tablets or its altered forms are exposed to sunlight irradiation with the generation of benzophenone, which is a toxicological potent.

From market to environment – consumption-normalised pharmaceutical emissions in the Rhine catchment

Direct and indirect threats by organic micropollutants can only be reliably assessed and prevented if the exposure to these chemicals is known, which in turn requires a confident estimate of their emitted amounts into the environment. APIs (Active Pharmaceutical Ingredients) enter surface waters mostly through the sewer system and wastewater treatment plants (WWTPs). However, their effluent fluxes are highly variable and influenced by several different factors that challenge robust emission estimates. Here, we defined a dimensionless, theoretically consumption-independent ‘escape factor’ (kesc) for estimating the amount of APIs (expected to be) present in WWTP effluents. The factor is determined as the proportion of marketed and actually emitted amounts of APIs. A large collection of German and Swiss monitoring datasets were analyzed to calculate stochastic kesc values for 31 APIs, reflecting both the magnitude and uncertainty of consumption-normalised emissions. Escape factors provide an easy-to-use tool for the estimation of average API emissions and expected variability from numerous WWTPs given that consumption data are provided, thereby supporting simulation modeling of the fate of APIs in stream networks or exposure assessments.

Impact of material properties and process parameters on tablet quality in a continuous direct compression line

The current paper shows how excipient properties impact the process parameters and the final tablet properties in a fully integrated continuous direct compression line. Blend properties of low-dose (1% w/w) and high-dose (40% w/w) paracetamol formulations were evaluated and linked to the blending and tableting performance via multivariate models (Partial Least Squares analysis, PLS). Feeding behavior was analyzed separately, as the amount of active pharmaceutical ingredient (API) that ended into tablets was driven by random fluctuations in the API feeding behavior. The developed PLS models elucidated that formulation behavior was mainly driven by the concentration of the active pharmaceutical ingredient (API), explained by the distinct API properties. Excipient properties also had a substantial impact on formulation behavior. Generally, formulations with microcrystalline cellulose as a filler showed better compactability, lower hold-up mass, lower flowability and higher cohesion than formulations with different lactose grades. The relative performance of a formulation with different fillers differed for 1% w/w and 40% w/w drug loading. Granular and spray dried lactose grades increased in compactability ranking compared to anhydrous lactose when evaluating higher drug loading, due to the difference in morphology. It was shown that besides understanding the impact of excipients on the formulation performance, processability of ingredients is crucial for formulation design.

Reducing Medication Errors: Rethinking Prescribing Drugs in Standardized Units over Quantities of Ingredients

The prescribers need to memorize the dose and strength of thousands of drugs often with similar sounding names but differing actions, by their weight (strengths), which could lead to significant errors in medication. When prescribing, instead of using amounts in milligrams, a “standard unit” - a universal standard adult dose unit- concept can be employed to minimize such instances of erroneous recollection of dosages. Prescribers would not essentially need to know the composition and actual amount of active pharmaceutical ingredients in prescribed drugs if such a standardized unit prescribing system could be adopted. They could simply resort to prescribing the required number of units of medication instead. The standard adult dose of any drug could be referred to as one adult unit regardless of the amounts by weight. Only drug manufacturers and research scientists would need to know the actual strengths of the medications in milligrams of what would be referred to as a standard adult unit. Implementation of the unit system, along with the incorporation of electronic prescribing, could allow for simple data entry, and easier corrections for lean body weight/BMI, renal function, age, pregnancy, etc., leading to improvements in patient safety and optimal dosage achieved, eliminating difficult calculations. Moreover, a parallel paediatric unit could also be developed. The conceptual study to arouse an interest cannot address all issues and details relating to actual implementations.

Embedding of Poorly Water-Soluble Drugs in Orodispersible Films-Comparison of Five Formulation Strategies.

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation.

UV–visible absorption spectroscopy for in-line API concentration measurement in nanoparticle production process using controlled expansion of supercritical solutions (CESS®)

Most new small drug molecules in pharmaceutical development require improvement of solubility. The controlled expansion of supercritical solutions (CESS®) process is a nanoparticle production technology, dedicated to enhancing the dissolution rate of active pharmaceutical ingredients (APIs) suffering from poor solubility and enabling novel drug delivery opportunities. In this process, the API is dissolved in supercritical carbon dioxide (scCO2) and nanoparticles are formed through controlled pressure reduction. To improve process visibility and control, ultraviolet-visible (UV-Vis) spectroscopy was incorporated into CESS® process as a process analytical technology (PAT) tool. The tool quantifies the amount of API dissolved in scCO2 during the solubilization phase of the process. Sample interfacing of the UV-Vis spectrometer was done with a custom-made pressure and temperature rated transmission flow-through cell. In-process calibration was developed to correlate the UV-Vis absorption spectra to the API concentration. Due to the density-dependent molar absorption coefficient of API in scCO2, the calibration was done for each combination of temperature and pressure. The developed PAT tool provides insight into the process enabling real-time API quantity estimation. It also facilitates process development through Quality by Design (QbD) and offers a system for enhanced process control and troubleshooting. For instance, the in-line API concentration data allows one to study the solubilization behavior of the API in the process and to optimize the process parameters in order to maximize throughput.

Predictive Drug Release Modeling Across Dissolution Apparatuses I and II using Computational Fluid Dynamics

A modeling process is developed and validated with which active pharmaceutical ingredient (API) release is predicted across the United States Pharmacopeia (USP) dissolution apparatuses I and II based on limited experimental dissolution data (at minimum two dissolution profiles at different apparatus settings). The process accounts for formulation-specific drug release behavior and hydrodynamics in the apparatuses over the range of typical agitation rates and medium volumes. This modeling process involves measurement of experimental mass transfer coefficients via a conventional mass balance and the relationship of said mass transfer coefficients to hydrodynamics and apparatus setting via computational fluid dynamics (CFD). A novel 1-D model is hence established, which provided calibration data for a particular formulation, can model mass transfer coefficients and their corresponding drug release at apparatus configurations of interest. Based on validation against experimental data produced from five erosion-based formulations over a range of apparatus configurations, accuracy within 8 %LA (labelled amount of API) and an average root mean square deviation of 3 %LA is achieved. With this predictive capability, minimizing the number of dissolution experiments and the amount of chemical materials needed during method development appears feasible.

Digital twin of a continuous direct compression line for drug product and process design using a hybrid flowsheet modelling approach

The pharmaceutical industry is continuously overcoming ways to reduce its development times to market and bring new medicines to patients with the highest quality standards faster. This can be achieved with continuous manufacturing and digital design by minimising the amount of active pharmaceutical ingredient (API) needed in drug product design, early project de-risking, and reducing the use of clinical manufacturing equipment, rework, and quality investigations. This paper presents the digital twin of a continuous direct compression line combining first-principles models, residence time distribution (RTD) models obtained from discrete element method (DEM) simulations, science of scale tools and data-driven models from process data in a hybrid flowsheet approach. The flowsheet predicts critical process parameters in the feeders, blender, and tablet press, and critical quality attributes, like tablet composition, weight, thickness, and hardness. It allows the study of the steady state operation in the design space, the impact of operating conditions, material and process parameters, and the dynamic response to disturbances. This is used to de-risk and optimise drug product and process development while reducing the number of experiments. The digital twin also has the potential to guide manufacturing runs and respond to new drug product market approval queries using flowsheet modelling.

Occurrence and toxicity impact of pharmaceuticals in hospital effluents: Simulation based on a case of study

In the University Hospital of Albacete (Spain), the distribution of Active Pharmaceutical Ingredients (APIs) was studied to estimate the occurrence of the most prevalent analgesics and anti-inflammatories and antibiotics in patients’ urines. This estimation was based on the consumption amounts of APIs and their pharmacokinetic data. Results showed that metamizole would be the most prevalent drug among analgesics and anti-inflammatories with estimated concentrations ranging 100 – 1000 mg dm−3 in patients’ urines hospitalized in the surgical ICU, followed by around 10 mg dm−3 of acetylcysteine in surgical ICU and paracetamol in geriatrics. Likewise, estimated concentrations of 1–10 mg dm−3 were calculated for the 20 most representative antibiotics. Two β-lactam antibiotics (imipenem, meropenem) and one fluoroquinolone antibiotic (levofloxacin) would be present in patients’ urine from more than 3 surgical and medical areas. Additionally, the simulation of the toxicity impacts of active pharmaceutical ingredients (APIs) in hospital effluents was developed using the SimaPro 9.3.0.3 software and Ecoinvent 3.3 database since few studies were reported based on the real occurrence of drugs in urines. Ibuprofen was observed to have 2.4 times more ecotoxicity in freshwaters than paracetamol, although they did not show human toxicity related to carcinogenic effects. Amoxicillin presented a high potential ecological risk with a 3 kg equivalence of 1.4-DB per gram of drug. Overall, results demonstrate the importance to develop an adequate management and treatment of hospital effluents, including hospital urines, to reduce environmental and sanitary impacts.

Quality assessment of different brands of atorvastatin tablets available in Riyadh, Saudi Arabia

BackgroundHypolipidemic agents have been shown to be helpful in the primary and secondary prevention of cardiovascular disease. Most often, statins are prescribed to treat hyperlipidemia. There are a number of statins available in the market today, but atorvastatin is the most widely prescribed. It is essential that the drugs should have the appropriate amount of active pharmaceutical ingredient and meet the necessary physical properties. The main purpose of the study was to evaluate the quality of different marketed brands of atorvastatin calcium tablets available in Saudi Arabia.MethodsIn this study, innovator product coded as (AS-1) and five generics brands (coded as AS-2 to AS-6) of atorvastatin tablets 20 mg available in Saudi Arabia were evaluated for in vitro dissolution test, weight variations, friability and hardness tests. The analysis of drug was carried out by “high-performance liquid chromatography” (HPLC) method using C18 column (4.6 × 150 mm, 5 μm). The mobile phase was consisted of acetonitrile and HPLC water (pH 2.1, adjusted with orthophosphoric acid) in ratio of 52:48 v/v, the flow rate was 1.0 ml/min. Atorvastatin was detected at a wavelength of 254 nm.ResultsAccording to the results of the dissolution study, the investigated products released more than 90% of atorvastatin in 15 min. Within 60 min, the brands AS-1, AS-3, AS-5, and AS-6 depicted nearly 100% atorvastatin release, while the brand AS-2 displayed 91.69% drug release. According to our findings, the investigated atorvastatin innovator (AS-1) and generic brands such as AS-2 to AS-6 were of good pharmaceutical quality.ConclusionsAll generic brands of atorvastatin tablets available in the Saudi Arabian market met the pharmacopoeia's consistency checks such as weight variation, friability, hardness and in vitro dissolution. Hence, focusing on their in vitro release properties, it was determined that these brands could be used interchangeably.

The Effect of Cellulose Nanofibers on the Manufacturing of Mini-Tablets by Direct Powder Compression.

Mini-tablets (MTs) contain a small amount of active pharmaceutical ingredients in one small tablet. MTs are advantageous because they can be fine-tuned according to the age and weight of pediatric patients and they are easy for children and the elderly to swallow. However, there are manufacturing concerns such as the difficulty in achieving both hardness and disintegration of a small tablet and it is difficult to keep the tablet weight and drug content consistent in MTs because the mold used for its production is special. In this study, we aimed to determine if an additive such as cellulose nanofibers (CNF), which has been studied in various fields in recent years, could be used to manufacture MTs without difficulties. In this study, an MT was manufactured using a rotary tableting press with a compression force of 2, 5, and 8 kN, and the weight variation, drug content variation, tensile strength, friability, disintegration time, and drug dissolution were evaluated. Of note, the tensile strength of MTs produced with a compression force of ≥5 kN was ≥1.3 MPa, which was comparable to that of an ordinary tablet with an 8 mm diameter and a hardness of ≥30 N. The disintegration time of the MT which was 20-30% CNF was ≤30 s at any compression force. MTs with CNF showed similar disintegration to MTs with other common disintegrants. Therefore, we found that CNF is a functional additive capable of manufacturing MTs by direct powder compression which has both strength and disintegration.

The impact of the size of acetylated cyclodextrin on the stability of amorphous metronidazole

Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-β-CD) with various molecular weights (Mw) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-β-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-β-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (Ecr) in ASDs with the oligosaccharide having a greater Mw (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs’ core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-β-CD. Therefore, this modified saccharide is a better stabilizer of the examined API.

In-line Fluorescence Spectroscopy for Quantification of Low Amount of Active Pharmaceutical Ingredient

The pharmaceutical industry is currently implementing new manufacturing principles and modernizing the related processing solutions. A key element in this development is implementation of process analytical technologies (PAT) for measuring product quality in a real-time mode, ideally for a continuously operating processing line. Near-infrared (NIR) spectroscopy is widely used for this purpose, but has limited use for low concentration formulations, due to its inherent detection limit. Light-induced fluorescence (LIF) spectroscopy is a PAT tool that can be used to quantify low concentrations of active pharmaceutical ingredient, and recent development of instrumentation has made it available for in-line applications. In this study, the content of tryptophan in a dynamic powder flow could be measured as low as 0.10 w/w % with LIF spectroscopy with good accuracy of RMSEP = 0.008 w/w %. Both partial least squares regression and support vector machines (SVM) were investigated, but we found SVM to be the better option due to non-linearities between the calibration test and the in-line measurements. With the use of SVM, LIF spectroscopy is a promising candidate for low concentration applications where NIR is not suitable.

Characterizing Medicine Quality by Active Pharmaceutical Ingredient Levels: A Systematic Review and Meta-Analysis across Low- and Middle-Income Countries.

ABSTRACT.Substandard and falsified medicines are often reported jointly, making it difficult to recognize variations in medicine quality. This study characterized medicine quality based on active pharmaceutical ingredient (API) amounts reported among substandard and falsified essential medicines in low- and middle-income countries (LMICs). A systematic review and meta-analysis was conducted using PubMed, supplemented by results from a previous systematic review, and the Medicine Quality Scientific Literature Surveyor. Study quality was assessed using the Medicine Quality Assessment Reporting Guidelines (MEDQUARG). Random-effects models were used to estimate the prevalence of medicines with < 50% API. Among 95,520 medicine samples from 130 studies, 12.4% (95% confidence interval [CI]: 10.2–14.6%) of essential medicines tested in LMICs were considered substandard or falsified, having failed at least one type of quality analysis. We identified 99 studies that reported API content, where 1.8% (95% CI: 0.8–2.8%) of samples reported containing < 50% of stated API. Among all failed samples (N = 9,724), 25.9% (95% CI: 19.3–32.6%) reported having < 80% API. Nearly one in seven (13.8%, 95% CI: 9.0–18.6%) failed samples were likely to be falsified based on reported API amounts of < 50%, whereas the remaining six of seven samples were likely to be substandard. Furthermore, 12.5% (95% CI: 7.7–17.3%) of failed samples reported finding 0% API. Many studies did not present a breakdown of actual API amount of each tested sample. We offer suggested improved guidelines for reporting poor-quality medicines. Consistent data on substandard and falsified medicines and medicine-specific tailored interventions are needed to ensure medicine quality throughout the supply chain.

Surface Functionalization of Silica Nanoparticles: Strategies to Optimize the Immune-Activating Profile of Carrier Platforms.

Silica nanoparticles (SiNPs) are generally regarded as safe and may represent an attractive carrier platform for nanomedical applications when loaded with biopharmaceuticals. Surface functionalization by different chemistries may help to optimize protein loading and may further impact uptake into the targeted tissues or cells, however, it may also alter the immunologic profile of the carrier system. In order to circumvent side effects, novel carrier candidates need to be tested thoroughly, early in their development stage within the pharmaceutical innovation pipeline, for their potential to activate or modify the immune response. Previous studies have identified surface functionalization by different chemistries as providing a plethora of modifications for optimizing efficacy of biopharmaceutical (nano)carrier platforms while maintaining an acceptable safety profile. In this study, we synthesized SiNPs and chemically functionalized them to obtain different surface characteristics to allow their application as a carrier system for allergen-specific immunotherapy. In the present study, crude natural allergen extracts are used in combination with alum instead of well-defined active pharmaceutical ingredients (APIs), such as recombinant allergen, loaded onto (nano)carrier systems with immunologically inert and stable properties in suspension. This study was motivated by the hypothesis that comparing different charge states could allow tailoring of the binding capacity of the particulate carrier system, and hence the optimization of biopharmaceutical uptake while maintaining an acceptable safety profile, which was investigated by determining the maturation of human antigen-presenting cells (APCs). The functionalized nanoparticles were characterized for primary and hydrodynamic size, polydispersity index, zeta potential, endotoxin contamination. As potential candidates for allergen-specific immunotherapy, the differently functionalized SiNPs were non-covalently coupled with a highly purified, endotoxin-free recombinant preparation of the major birch pollen allergen Bet v 1 that functioned for further immunological testing. Binding efficiencies of allergen to SiNPs was controlled to determine uptake of API. For efficacy and safety assessment, we employed human monocyte-derived dendritic cells as model for APCs to detect possible differences in the particles’ APC maturation potential. Functionalization of SiNP did not affect the viability of APCs, however, the amount of API physisorbed onto the nanocarrier system, which induced enhanced uptake, mainly by macropinocytosis. We found slight differences in the maturation state of APCs for the differently functionalized SiNP–API conjugates qualifying surface functionalization as an effective instrument for optimizing the immune response towards SiNPs. This study further suggests that surface-functionalized SiNPs could be a suitable, immunologically inert vehicle for the efficient delivery of biopharmaceutical products, as evidenced here for allergen-specific immunotherapy.