RESUMO
While there have been significant advances in the development of peptide oral dosage forms in recent years, highlighted by the clinical and commercial success of approved peptides such as Rybelsus®, there remain several barriers in the way of broad range applicability of this approach to peptide delivery. One such barrier includes the poor physical and chemical stability inherent to their structures, which persists in the solid state although degradation typically occurs at different rates and via different pathways in comparison to the solution state. Using insulin as a model peptide, this work sought to contribute to the development of analytical techniques for investigating common insulin degradation pathways. Chemically denatured, deamidated and aggregated samples were prepared and used to benchmark circular dichroism spectroscopy, reverse phase HPLC and size exclusion chromatography methods for the investigation of unfolding, chemical modifications and covalent aggregation of the insulin molecule respectively. Solid state degraded samples were prepared by heating insulin powder at 60 °C and 75% relative humidity for 1, 3, 5 and 7 d, and the degradation profiles of the samples were evaluated and compared with those observed in solution. While no unfolding was observed to occur, significant deamidation and covalent aggregation were detected. Reductive disulfide bond cleavage using dithiothreitol allowed for separation of the insulin A- and B-chains, offering a facile yet novel means of assessing the mechanisms of deamidation and covalent aggregation occurring in the solid state. Supplementary Information: The online version contains supplementary material available at 10.1007/s41664-024-00302-5.
RESUMO
The absence of established protocols for studying the in vitro performance of dissolvable microarray patches (MAPs) poses a significant challenge within the field. To overcome this challenge, it is essential to optimize testing methods in a way that closely mimics the skin's environment, ensuring biorelevance and enhancing the precision of assessing MAP performance. This study focuses on optimizing in vitro release testing (IVRT) and in vitro permeation testing (IVPT) methods for MAPs containing the antihistamine drugs loratadine (LOR) and chlorpheniramine maleate (CPM). Our primary objective is to investigate the impact of the composition of in vitro release media on the drug release rate, penetration through the skin, and permeation into the release medium. Artificial interstitial fluid is introduced as a biorelevant release medium and compared with commonly used media in IVRT and IVPT studies. Prior to these studies, we evaluated drug solubility in different release media and developed a method for LOR and CPM extraction from the skin using a design of experiment approach. Our findings highlight the effect of the in vitro release medium composition on both LOR and CPM release rate and their penetration through the skin. Furthermore, we identified the importance of considering the interplay between the physicochemical attributes of the drug molecules, the design of the MAP formulation, and the structural properties of the skin when designing IVRT and IVPT protocols.
RESUMO
Sucrose and trehalose pharmaceutical excipients are employed to stabilize protein therapeutics in a dried state. The mechanism of therapeutic protein stabilization is dependent on the sugars being present in an amorphous solid-state. Colyophilization of sugars with high glass transition polymers, polyvinylpyrrolidone (PVP), and poly(vinylpyrrolidone vinyl acetate) (PVPVA), enhances amorphous sugar stability. This study investigates the stability of colyophilized sugar-polymer systems in the frozen solution state, dried state postlyophilization, and upon exposure to elevated humidity. Binary systems of sucrose or trehalose with PVP or PVPVA were lyophilized with sugar/polymer ratios ranging from 2:8 to 8:2. Frozen sugar-PVPVA solutions exhibited a higher glass transition temperature of the maximally freeze-concentrated amorphous phase (Tg') compared to sugar-PVP solutions, despite the glass transition temperature (Tg) of PVPVA being lower than PVP. Tg values of all colyophilized systems were in a similar temperature range irrespective of polymer type. Greater hydrogen bonding between sugars and PVP and the lower hygroscopicity of PVPVA influenced polymer antiplasticization effects and the plasticization effects of residual water. Plasticization due to water sorption was investigated in a dynamic vapor sorption humidity ramping experiment. Lyophilized sucrose systems exhibited increased amorphous stability compared to trehalose upon exposure to the humidity. Recrystallization of trehalose was observed and stabilized by polymer addition. Lower concentrations of PVP inhibited trehalose recrystallization compared to PVPVA. These stabilizing effects were attributed to the increased hydrogen bonding between trehalose and PVP compared to trehalose and PVPVA. Overall, the study demonstrated how differences in polymer hygroscopicity and hydrogen bonding with sugars influence the stability of colyophilized amorphous dispersions. These insights into excipient solid-state stability are relevant to the development of stabilized biopharmaceutical solid-state formulations.
Assuntos
Estabilidade de Medicamentos , Excipientes , Liofilização , Polímeros , Povidona , Temperatura de Transição , Trealose , Liofilização/métodos , Povidona/química , Trealose/química , Excipientes/química , Polímeros/química , Sacarose/química , Açúcares/química , Ligação de Hidrogênio , Armazenamento de Medicamentos , Química Farmacêutica/métodos , Varredura Diferencial de Calorimetria , Umidade , Pirrolidinas/química , Compostos de Vinila/químicaRESUMO
The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.
Assuntos
Excipientes , Tecnologia Farmacêutica , Excipientes/química , Tecnologia Farmacêutica/métodos , Preparações Farmacêuticas/química , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Indústria Farmacêutica/métodosRESUMO
In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.
Assuntos
Asma , Aerossóis e Gotículas Respiratórios , Humanos , Citosol , RNA Interferente Pequeno , PulmãoRESUMO
In this paper, a roadmap is provided for the regulatory approval of one of the exciting and dynamic drug delivery fields, microneedles, by using a Quality by Design approach to pharmaceutical product development. In this regard, a quality target product profile (QTPP) and the critical quality attributes (CQA) of microneedles are identified. A case study of the recently patented method of fabricating glass microneedles entirely from a therapeutic agent, thus eliminating the requirement for additional excipients is discussed. The glass microneedle, ArrayPatch, is a propriety wearable device with platform potential consisting of an array of sharp, but painless, dissolvable microneedles manufactured with 100% drug. The microneedles penetrate the skin on application and dissolve to deliver a locally effective dose. The in vitro characterization of the microneedle CQAs under WHO-guided stability conditions will be described to assess the manufacturing readiness of ArrayPatch. A live technical video is also provided, presenting a unique procedure of jugular vein cannulation through the ear vein of a pig animal model to study the in vivo pharmacokinetics of ArrayPatch compared to standard-of-care marketed products.
Assuntos
Agulhas , Pele , Animais , Suínos , Administração Cutânea , Preparações Farmacêuticas , Sistemas de Liberação de Medicamentos/métodos , MicroinjeçõesRESUMO
BACKGROUND: Palatability is a key element of paediatric acceptability for medicines. Many patient and drug factors are considered when choosing an antibiotic for a child. Pharmacists report that they receive questions about the palatability of oral liquid antibiotics for children. This study aimed to explore the experiences of GPs and pharmacists concerning palatability of oral liquid antibiotics for children. METHODS: A questionnaire about the impact of palatability on the choice of antibiotic formulation for children was emailed to all community pharmacists in Ireland and to GPs and trainee GPs in the Cork region and posted on social media. Survey items were not compulsory; therefore, percentage responses were calculated based on the number of responses to that item. GP and pharmacist responses were analysed independently. RESULTS: Responses were received from 244 participants (59 GPs, 185 pharmacists). Clinical guidelines and availability of supply were the most important factors considered when choosing an oral liquid antibiotic formulation for children by GP (79.7%) and pharmacist (66.5%) respondents respectively. Forty GP respondents (76.9%) reported ensuring adherence was the most common palatability-related reason leading to deviation from guidelines. Pharmacist respondents (52%) reported advising a parent/caregiver to manipulate the required antibiotic dose to improve acceptability. The least palatable oral liquid antibiotics reported were flucloxacillin (16% GPs, 18% pharmacists) and clarithromycin (17% of each profession). CONCLUSION: This study identified palatability issues associated with oral liquid antibiotics for children reported by GPs and pharmacists. Pharmaceutical approaches to adapting oral liquid antibiotic formulations must be developed to improve palatability and thus paediatric acceptability.
RESUMO
The conventional quality control techniques for identifying the denaturation of biopharmaceuticals includes sodium dodecyl sulfate-polyacrylamide gel electrophoresis for identifying fragmentation, ion exchange chromatography and isoelectric focusing for identifying deamidation, reverse-phase high-performance liquid chromatography (HPLC) for identifying oxidation, and size-exclusion HPLC for identifying aggregation. These stability assessments require essential processes that are destructive to the product tested. All these techniques are lab based and require sample removal from a sealed storage vial, which can breach the sterility. In this work, we investigate the heat- and surfactant-induced denaturation of an in-vial-stored model protein, bovine serum albumin (BSA), by analyzing its intrinsic fluorescence without removing the sample from the vial. A lab-based bespoke setup which can do the measurement in vial is used to demonstrate the change in fluorescence polarization of the protein to determine the denaturation level. The results obtained are compared to circular dichroism and size-exclusion HPLC measurements. The results prove that in-vial fluorescence measurements can be performed to monitor protein denaturation. A cost-effective portable solution to provide a top-level overview of biopharmaceutical product stability from manufacture to the point of patient administration can be further developed using the same technique.
Assuntos
Temperatura Alta , Soroalbumina Bovina , Humanos , Desnaturação Proteica , Polarização de FluorescênciaRESUMO
The increasing awareness of acceptability and usability of pharmaceutical drug products by the patient as a key quality requirement continues to drive need for integrating patient centric drug product design into the pharmaceutical development process. The complex matrix of multiple drug product related decisions during the early drug development process often limits patient-centric drug product (PCDP) design options in the final commercial drug product development phase. To integrate the specific needs and perspectives of patients into drug development and product design process, a rational approach integrated into the complex development matrix is required from the start and weighs product development decision options accordingly. The aim of this work was to develop a roadmap for PCDP design in a multidisciplinary approach that leads to better usability, adherence and acceptance of the drug by patients via early integration into the development matrix. The proposed rational approach is based upon regulatory requirements and lessons learned from pediatric and geriatric drug development.
Assuntos
Desenho de Fármacos , Desenvolvimento de Medicamentos , Idoso , Criança , Humanos , Assistência Centrada no PacienteRESUMO
The ability to predict formulation behaviour at production scale during formulation design can reduce the time to market and decrease product development costs. However, it is challenging to extrapolate compaction settings for direct compression formulations between tablet press models during scale-up and transfer from R&D to commercial production. The aim of this study was to develop statistical process models to predict tablet tensile strength, porosity and disintegration time from compaction parameters (pre-compression and main compression force, and press speed), for three formulations, with differing deformation characteristics (plastic, brittle and elastic), on three tablet press models (one pilot-scale tablet press (KG RoTab) and two production-scale presses (Fette 1200i and GEA Modul P)). The deformation characteristics of yield pressure and elastic recovery were determined for the model placebo formulations investigated. To facilitate comparison of dwell time settings between tablet press models, the design of experiments (DoE) approach was 9 individual 16-run response surface DoEs (3 formulation × 3 press models), whose results were combined to create a polynomial regression model for each tablet property. These models predicted tablet tensile strength, porosity and disintegration time and enabled the construction of design spaces to produce tablets with specified target properties, for each formulation on each press. The models were successfully validated. This modelling approach provides an understanding of the compaction behaviour of formulations with varying deformation behaviour on development and commercial tablet press models. This understanding can be applied to inform achievable production rates at a commercial scale, during the formulation development.
RESUMO
Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm-1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10570-021-04093-1.
RESUMO
Optimizing processing conditions to achieve a critical quality attribute (CQA) is an integral part of pharmaceutical quality by design (QbD). It identifies combinations of material and processing parameters ensuring that processing conditions achieve a targeted CQA. Optimum processing conditions are formulation and equipment-dependent. Therefore, it is challenging to translate a process design between formulations, pilot-scale and production-scale equipment. In this study, an empirical model was developed to determine optimum processing conditions for direct compression formulations with varying flow properties, across pilot- and production-scale tablet presses. The CQA of interest was tablet weight variability, expressed as percentage relative standard deviation. An experimental design was executed for three model placebo blends with varying flow properties. These blends were compacted on one pilot-scale and two production-scale presses. The process model developed enabled the optimization of processing parameters for each formulation, on each press, with respect to a target tablet weight variability of <1%RSD. The model developed was successfully validated using data for additional placebo and active formulations. Validation formulations were benchmarked to formulations used for model development, employing permeability index values to indicate blend flow.
RESUMO
Stability testing is essential in the pharmaceutical industry to determine product shelf- life and the conditions under which drug products should be stored. Stability testing involves a complex set of procedures, considerable cost, time, and scientific expertise to build quality, efficacy and safety in a drug formulation. This paper highlights a new complementary approach to stability testing called Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS measurements are based on reproducible changes in the compressibility of a solvent during dissolution. It is monitored acoustically via associated changes in the frequency of induced acoustic resonances. This study presents a novel approach to track the change of various drug formulations to determine the formulation's stability. Pellets, tablet and multiple-unit pellet system (MUPS) formulations were investigated to examine the effect of polymer coating and formulation core degradation over time. In combination with minimal usage of Ultra Violet - Visible Spectroscopy, BARDS can effectively track these changes. The technique offers a rapid approach to characterizing pharmaceutical formulations. BARDS can enable rapid development of solid drug formulation dissolution and disintegration testing as an In-Process Control test and drug stability analysis. The data show that a solid oral dose formulation has an intrinsic acoustic signature specific to the method of manufacture, excipient composition and elapsed time since the production of a product. BARDS data are also indicative of which aspect of a formulation may be unstable, whether a coating, sub-coating or core. It is potentially a time-efficient, cost-effective and greener approach to testing coating stability, disintegration and overall formulation stability.
Assuntos
Acústica , Excipientes , Solubilidade , Análise Espectral , ComprimidosRESUMO
Poor integration of orthopaedic devices with the host tissue owing to aseptic loosening and device-associated infections are two of the leading causes of implant failure, which represents a significant problem for both patients and the healthcare system. Novel strategies have focused on silver to combat antimicrobial infections as an alternative to drug therapeutics. In this study, we investigated the impact of increasing the % substitution (12% wt) of silver and strontium in hydroxyapatite (HA) coatings to enhance antimicrobial properties and stimulate osteoblasts, respectively. Additionally, we prepared a binary substituted coating containing both silver and strontium (AgSrA) at 12% wt as a comparison. All coatings were deposited using a novel blasting process, CoBlast, onto biomedical grade titanium (V). Surface physicochemical properties, cytocompatibility and antimicrobial functionality were determined. The anticolonising properties of the coatings were screened using Staphylococcus aureus ATCC 1448, and thereafter, the AgA coating was evaluated using clinically relevant strains. Strontium-doped surfaces demonstrated enhanced osteoblast viability; however, a lower inhibition of biofilm formation was observed compared with the other surfaces. A co-substituted AgSrA surface did not show enhanced osteoblast or anticolonising properties compared with the SrA and AgA surfaces, respectively. Due to its superior anticolonising performance in preliminary studies, AgA was chosen for further studies. The AgA coated surfaces demonstrated good antibacterial activity (eluted and immobilised ion) against methicillin-resistant S. aureus followed by methicillin-sensitive Staphylococcus aureus clinical isolates; however, the AgA surface displayed poor impact against Staphylococcus epidermidis. In conclusion, herein, we demonstrate that HA can be substituted with a range of ions to augment the properties of HA coatings on orthopaedic devices, which offer promising potential to combat orthopaedic device-associated infections and enhance device performance.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Ortopedia , Antibacterianos/farmacologia , Biofilmes , Materiais Revestidos Biocompatíveis , Durapatita , Humanos , Prata/farmacologia , Estrôncio , Propriedades de Superfície , TitânioRESUMO
Lyophilisation is a prominent technique used to create stabilised, dried forms of biopharmaceutical formulations. Reconstitution of lyophilised parenteral formulations is a key step prior to patient administration. The accurate determination of reconstitution time is a necessity to aid formulation development and support product quality control. Traditional methods for quantifying reconstitution time involve the visual identification of the endpoint, which has led to variable values reported across studies. In this work, the use of ultra-violet (UV) excited fluorescence spectroscopy as an alternative to the visual quantification of the reconstitution time was investigated. Spectrographic information was collected via a bespoke setup that allowed the measurement of the reconstitution time in a standard sealed lyophilisation vial. The spectra were analysed via principal component analysis (PCA) to obtain a time-based representation of the changes in a reconstituting formulation. The analysis was followed by the identification of an endpoint using three techniques ranging from fully automated to manual with regards to the required level of user input. At high protein concentration, the variability of the reconstitution time measurements was reduced from 80.4% relative standard deviation obtained via the traditional method to 8.2% for the instrumental method presented in.
Assuntos
Espectrometria de Fluorescência , Liofilização , HumanosRESUMO
Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.
Assuntos
Cristalização/métodos , Preparações Farmacêuticas/química , Espectrofotometria Infravermelho/métodos , Varredura Diferencial de Calorimetria , Química Farmacêutica/métodos , Simulação por Computador , Hidroclorotiazida/química , Análise Multivariada , Niacinamida/química , Solventes/química , Termodinâmica , Difração de Raios XRESUMO
The study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0-30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC.
Assuntos
Excipientes , Ibuprofeno , Celulose , Solubilidade , ComprimidosRESUMO
Incomplete drug release from mesoporous silica systems has been observed in several studies. This work aims to increase the understanding of this phenomenon by investigating the mechanism of drug-silica interactions and adsorption behavior from supersaturated aqueous solutions of two similar drug molecules with different hydrogen bonding capabilities. Drug-silica interactions between indomethacin or its methyl ester and SBA-15 were investigated using spectroscopic techniques (infrared, fluorescence and X-ray photoelectron) and adsorption experiments. The results demonstrate that the predominant mechanism of interaction of both drugs with silica is hydrogen bonding between drug acceptor carbonyl groups with donor groups on the silica surface. The presence of a drug hydrogen bond donor group did not enhance drug adsorption. No evidence was obtained for drug adsorption through nonspecific hydrophobic interactions. Drug adsorption onto the silica surface was investigated under supersaturating conditions through the generation of adsorption isotherms. Similar adsorption isotherms were observed for each compound when the concentration scale was normalized to the drug amorphous solubility. In other words, the equilibrium between the drug adsorbed on the silica surface and free drug in solution was related to the drug activity in solution. The high tendency of the drug to adsorb when the solution is supersaturated was, in turn, found to limit the extent of drug release during dissolution under nonsink conditions. Thus, adsorption provides an explanation for incomplete drug release.
Assuntos
Adsorção/fisiologia , Liberação Controlada de Fármacos/fisiologia , Ésteres/metabolismo , Indometacina/metabolismo , Dióxido de Silício/metabolismo , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Porosidade , Solubilidade/efeitos dos fármacos , Água/metabolismoRESUMO
Long-term stability is one of the main challenges for translation of therapeutic proteins into commercially viable biopharmaceutical products. During processing and storage, proteins are susceptible to denaturation. The aim of this work was to evaluate the stability of amphiphilic cyclodextrin-based nanoparticles (NPs) containing insulin glulisine. The stability of the NP dispersion was systematically evaluated following storage at three different temperatures (4 °C, room temperature (RT) and 40 °C). While the colloidal parameters of the NPs in terms of size and zeta potential were maintained (109 ± 9 nm, polydispersity index 0.272, negative zeta potential -25 ± 3 mV), insulin degraded over 60 days during storage. To enhance the shelf life of the product and to circumvent the need for cold-chain maintenance, a lyophilized formulation containing insulin glulisine NPs (1.75 mg/mL of NPs) and 25 mg/mL trehalose was produced. The freeze-dried powder extended the stability of the product for up to 30 days at ambient temperature and 90 days at 4 °C (with 95% and >80% insulin recovery, respectively). Following intra-intestinal administration of the freeze-dried formulation, while no lowering of blood glucose was seen, insulin glulisine was detected in both portal and systemic blood indicating that potential exists for further development of the formulation to simultaneously achieve prolonged stability and therapeutic efficacy.
Assuntos
Ciclodextrinas , Insulina/análogos & derivados , Nanopartículas , Estabilidade de Medicamentos , Liofilização , Insulina/químicaRESUMO
BACKGROUND: Oral medicines are commonly modified (e.g. tablets split/crushed) to meet the dosing and swallowing requirements of older adults. However, there is limited research investigating the opinions of community-dwelling patients and carers about medicine modification. OBJECTIVES: The aim of this study was to investigate the views of community-dwelling older adults and their carers about oral medicine modification. METHODS: Semi-structured, face-to-face interviews were conducted with community-dwelling older adults and carers of older adults who experienced difficulty swallowing medicines, or who required medicines to be modified. Participants were recruited from purposively selected community pharmacies using a combination of purposive, convenience and snowball sampling. Interviews were audio-recorded, transcribed verbatim and analysed thematically. The Francis method governed when data saturation had been reached. RESULTS: Twenty-six interviews (13 patients, 13 carers) were conducted (76.9% female, median length 11â¯min (IQR 8-16â¯min)). Four themes emerged from the data: variation in medical needs and preferences; balancing acceptance and resignation; healthcare professional engagement and; opportunities for optimising formulation suitability. The heterogeneity of medical conditions experienced by community-dwelling older adults resulted in a variety of modifications being required. Patients and carers are accepting of their medications and formulations. However, when challenges arise, they tend to feel resigned to coping within the constraints of the current medication regimen, resulting in a lack of focused communication with healthcare professionals. Thus, healthcare professionals were unaware of their difficulties and unable to offer advice or solutions. CONCLUSION: Healthcare professionals must engage proactively with this group. Whilst a holistic approach to medication management is ideal, the disadvantage is that no single healthcare professional may identify this as their responsibility. Whilst the input and expertise of all healthcare professionals will be required, as medication experts, the pharmacy profession should take ownership and become the champion of, and for, the patient.