Tuning the Shape of Spray-Dried Pullulan Particles Through Feed Rheological Behavior

Pullulan is a natural polysaccharide used in many health products, including dry powders for oral and pulmonary administration. In these cases, the control of the shape and dimensions of particles is crucial for obtaining the desired functionality. Different from other polysaccharides, pullulan cannot be easily shaped without chemical modifications or adjuvants’ addition. This work aims to systematically investigate the impact of the solvent composition and polymer concentration on the possibility of tuning the pullulan particle shape by spray drying. The results revealed that the microparticle-to-fiber transition can be induced using a hydro-alcoholic solution since ethanol increased the relaxation time and reduced the evaporation rate. Furthermore, a high Péclet number during drying favors the formation of wrinkled surfaces at all feed compositions. Overall, these data evidenced the possibility of tuning the spray-dried product morphology without any processing aids, paving the way for new applications of pullulan, especially in the pharmaceutical field

Olanzapine orodispersible films: how preparation methods can impact on the biopharmaceutic performances

INTRODUCTION The design of drug products to be administered to pediatric patients should consider the presentation of the treatment to the end-user (i.e., patient, caregiver, healthcare provider) which includes the dosage form, formulation, dose, dosing frequency and packaging. Patient-centric drug products would also avoid the practice of manipulating tablets or capsules which may compromise the dose accuracy, patient safety and treatment efficacy. In this context, orodispersible films (ODF) have been reported to improve administration, compliance and medication adherence in patients having difficulties with swallowing [1]. The main ODF production processes can be referred to solvent-based or heating-based technologies. Alternatively, in the attempt to produce small batches or to compound personalized therapies, printing technologies have been proposed [2]. However, these processes can cause unintended drug phase transformations, which directly affect its dissolution rate and, therefore, biopharmaceutical performances. This work aimed to assess the relevance of the preparation process, namely solvent casting and hot-melt ram printing, on the biopharmaceutical performances of olanzapine orodispersible films (ODF) made of maltodextrins. Beside the clinical rationale, olanzapine (OLZ) was selected since it is subjected to polymorphism which impacts on its bioavailability [2]. OLZ was selected as model drug since it is also used off-label for treating pediatric diseases [3]. METHODS An amount of 10 mg OLZ was loaded into 23 cm ODF prepared by solvent-casting and hot-melt ram-extrusion printing using maltodextrin DE 6 and glycerol as film forming material and plasticizer, respectively. X-ray diffraction and thermal analysis (i.e., DSC and TGA) were carried out to study the drug solid state. ODF were characterized in terms of thickness, stickiness, loss on drying. Moreover, disintegration time and the in vitro dissolution profiles were also evaluated in buffers mimicking pH values of different GI districts. RESULTS The adopted experimental conditions permitted to obtain ODF without visual defects, easy to handle with a thickness around 140 μm and 278 μm for cast and printing, respectively. Residual water content in ODF was in the 6-8% w/w range. All ODF disintegrated within 80 s, complying the Pharmacopeia specifications. Dissolution testing in 3 mL of artificial saliva at pH = 6.8 evidenced that cast and printed ODF released after 5 min about 2% and 100%, respectively. At higher volume, a yellow precipitate was formed after disintegration of the cast ODF. At pH = 1.2, the t85% for cast ODF was reached after about 20 min and only the 90% OLZ was dissolved increasing the pH value to 6.8. These differences were explained by DSC, TGA and X-ray diffraction data which demonstrated that the casting method, including the preparation of an aqueous slurry, favors the conversion from Form I to a hydrated one, which could be responsible of this anomalous behavior. Extruded ODF resulted physically stable after 30 months CONCLUSIONS The understanding of possible relations between formulation and process variables (e.g., solvents, moisture, and temperature) with solid-state characteristics needs to be addressed also to make the compounding of personalized therapy for pediatric patients a reality. Regarding the loading of OLZ in ODF, the main criticism is the possible conversion from the anhydrous towards hydrated forms with concomitant decrease in solubility. Based on these data hot-melt ram extrusion printing seems to be promising since it limits the exposure of OLZ to stress-factors (i.e., water and temperature) which can trigger solid-state modifications. REFERENCES 1. Cilurzo F., et al. (2018) Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements. Drug Discov. Today, 23, 251-259. 2. Selmin F., et al. (2021) Relevance of production method on the physical stability and in vitro biopharmaceutical performances of olanzapine orodispersible film. Int. J. Pharm., doi: 10.1016/j.ijpharm.2021.120697. 3. Giurin M.S., et al. (2022) Safety of off-label pharmacological treatment in pediatric neuropsychiatric disorders: a global perspective from an observational study at an Italian third level children’s hospital. Front. Pharmacol., doi: 10.3389/fphar.2022.837692

Biorelevant release testing of biodegradable microspheres intended for intra-articular administration

Characterization of controlled release formulations used for intra-articular (IA) drug administration is challenging. Bio-relevant synovial fluids (BSF), containing physiologically relevant amounts of hyaluronic acid, phospholipids and proteins, were recently proposed to simulate healthy and osteoarthritic conditions. This work aims to evaluate the performance of different controlled release formulations of methylprednisolone (MP) for IA administration, under healthy and disease states simulated conditions. Microspheres differed in grade of poly(lactide-co-glycolide) and in the theoretical drug content (i.e. 23 or 30% w/w). Their performance was compared with the commercially available suspension of MP acetate (MPA). Under osteoarthritic state simulated condition, proteins increased the MPA release and reduced the MPA hydrolysis rate, over 48\u202fh. Regarding microspheres, the release patterns over 40 days were significantly influenced by the composition of BSF. The pattern of the release mechanism and the amount released was affected by the presence of proteins. Protein concentration affected the release and the concentration used is critical, particularly given the relevance of the concentrations to target patient populations, i.e. patients with osteoarthritis

Applications of Alginates in the Design and Preparation of Orodispersible Dosage Forms

Orodispersible dosage forms are attractive and innovative drug delivery systems that can fulfill individual patient needs, especially in children, elderly and among dysphagic patients. Indeed, they rapidly disperse in the mouth upon contact with the saliva without the need for water or munching. Examples of such dosage forms include orodispersible tablets (ODT), and orodispersible films (ODF). The ability to obtain ODF with different dimensions (sizes and thicknesses) makes them a suitable for personalized dosing of single or a fixed-dose combination of drugs in special patient populations. Several biopolymers are currently being exploited in the development of orodispersible dosage forms including alginates due to their versatility, availability, naturally occurring, and biosafety profile. This chapter provides an appraisal on the various applications of alginates in the preparations and their role on the properties of orodispersible dosage forms and highlights future perspectives of this very versatile biopolymer for these innovative drug delivery systems

Stability of high concentrated triple intrathecal therapy for pediatrics and mitigation strategies

Stringent formulation requirements are defined to intrathecally administer drug substances, avoiding neurological complications. In case of pediatric patients, these are further complicated due to the limited volumes of the celebrospinal fluid and, therefore, high concentrated solutions of methotrexate (MTX), cytarabine and corticosteroids (i.e., methylprednisolone or hydrocortisone) are prepared based on the patient's age. This work aims to assess the chemical and physical stability of triple intrathecal mixtures differing in volume and compositions by a bracketing approach and to identify possible stress causes and mitigation strategies. Low solubility of MTX was the main factor limiting the physical stability of triple mixtures. Regarding solutions containing methylprednisolone, the amount of MTX remaining was about 95% in the solution at highest concentrations with the concomitant formation of a visible particulate sizing bigger than 1 μm after 24 h of storage at 25°C. This behavior was mainly driven the pH reduction induced by the pH value of the cytarabine solution used; the shear stress also caused the drug precipitation. In case of the hydrocortisone based mixtures, the formation of a precipitate occurred at a slow rate. To improve the physical stability, a better control of the mixture pH (optimal value ≈ 7) is required or the addition of the cytarabine solution to a pre-mixed binary mixture containing MTX and a corticosteroid should be preferred

β-galactosidase orodispersible dosage forms for the treatment of lactose intolerance

Lactose intolerance is associated with the insurgence of mild to severe gastrointestinal symptoms. The administration of beta-galactosidase (beta-gal) tablets or capsules, which are unsuitable for the dysphagic population, is the main symptomatic treatment. This work aimed to demonstrate the feasibility of beta-gal orodispersible films (ODF) prepared by solvent casting technique. Since the preparation involves thermal and mechanical stresses, which can compromise the enzyme stability, in vitro performances of ODF were compared to those of oral lyophilizates (OL). ODF were made of maltodextrin DE6, glycerol and Capryol90. OL made of different grades of maltodextrins, and sorbitol or trehalose were prepared in aluminium blisters. ODF and OL were assayed for disintegration time and beta-gal activity. The hydrolysis rate of lactose was determined using: a) a placebo capsule (500 mg lactose) disintegrated in a glass of water; b) 150 mL milk in biorelevant media. ODF (6 cm2) and OL (made of maltodextrin DE19 and trehalose). ODF and OL loaded with about 4000 UI of beta-gal were stable over 3 months of storage at 25 °C/60% RH. Both of them allowed the hydrolysis of lactose in water within 15 min. The complex composition of milk affected the hydrolysis rate (K) of lactose: the reaction was faster in fasted-state media (K ≈ −0.07 min−1) than in those simulating the fed state of subjects with physiologically appreciable residual gastric fluid in the stomach (grade 1 antrum: 20 mL, K ≈ −0.005 min−1; grade 2 antrum: 180 mL, K ≈ −0.01 min−1). No significant differences were noticed between ODF and OL. Overall, ODF can be proposed to hydrolyse lactose contained in immediate release dosage forms, improving the patient's adherence to therapy. Moreover, the dependence of the lactose degradation kinetic not only on the fed or fasted conditions, but also on the antrum phenotype may allow the development of ODF in a more patient-centric perspective

Biodegradable composite porous poly(dl-lactide-co-glycolide) scaffold supports mesenchymal stem cell differentiation and calcium phosphate deposition

In recent decades, tissue engineering strategies have been proposed for the treatment of musculoskeletal diseases and bone fractures to overcome the limitations of the traditional surgical approaches based on allografts and autografts. In this work we report the development of a composite porous poly(dl-lactide-co-glycolide) scaffold suitable for bone regeneration. Scaffolds were produced by thermal sintering of porous microparticles. Next, in order to improve cell adhesion to the scaffold and subsequent proliferation, the scaffolds were coated with the osteoconductive biopolymers chitosan and sodium alginate, in a process that exploited electrostatic interactions between the positively charged biopolymers and the negatively charged PLGA scaffold. The resulting scaffolds were characterized in terms of porosity, degradation rate, mechanical properties, biocompatibility and suitability for bone regeneration. They were found to have an overall porosity of ∼85% and a degradation half time of ∼2 weeks, considered suitable to support de novo bone matrix deposition from mesenchymal stem cells. Histology confirmed the ability of the scaffold to sustain adipose-derived mesenchymal stem cell adhesion, infiltration, proliferation and osteo-differentiation. Histological staining of calcium and microanalysis confirmed the presence of calcium phosphate in the scaffold sections

Preclinical pharmacology of patient-derived extracellular vesicles for the intraoperative imaging of tumors

Extracellular vesicles (EVs) derived from the plasma of oncological patients exhibit significant tumor-targeting properties, unlike those from healthy individuals. We have previously shown the feasibility of formulating the near-infrared (NIR) fluorescent dye indocyanine green (ICG) with patient-derived extracellular vesicles (PDEVs) for selective delivery to neoplastic tissue. This staining protocol holds promise for clinical application in intraoperative tumor margin imaging, enabling precise neoplastic tissue resection. To this end, we propose the ONCOGREEN protocol, involving PDEV isolation, ICG loading, and reinfusion into the same patients. Methods: By in vivo studies on mice, we outlined key pharmacological parameters of PDEVs-ICG for intraoperative tumor imaging, PDEV biodistribution kinetics, and potential treatment-related toxicological effects. Additionally, we established a plasmapheresis-based protocol for isolating autologous PDEVs, ensuring the necessary large-scale dosage for human treatment. A potential lyophilization-based preservation method was also explored to facilitate the storage and transport of PDEVs. Results: The study identified the effective dose of PDEVs-ICG necessary for clear intraoperative tumor margin imaging. The biodistribution kinetics of PDEVs showed favorable targeting to neoplastic tissues, without off-target distribution. Toxicological assessments revealed no significant adverse effects associated with the treatment. The plasmapheresis-based isolation protocol successfully yielded a sufficient quantity of autologous PDEVs, and the lyophilization preservation method maintained the functional integrity of PDEVs for subsequent clinical application. Conclusions: Our research lays the groundwork for the direct clinical application of autologous PDEVs, initially focusing on intraoperative imaging. Utilizing autologous PDEVs has the potential to accelerate the integration of EVs as a targeted delivery tool for anti-neoplastic agents to cancerous tissue. This approach promises to enhance the precision of neoplastic tissue resection and improve overall surgical outcomes for oncological patients

When authorized medicinal products are not available: possible alternatives to meet legitimate expectations of patients

Objectives: Authorized medicinal products placed on the market do not cover all therapeutic needs. In order to meet the patient's legitimate right, a physician can prescribe other pharmacological treatments in other ways: off-label prescriptions, compounded medicinal products, compassionate use of medicinal products and medicinal products authorized in foreign countries. This is a critical review of the actual regulations which govern these alternatives, with particular attention to the Italian situation. Key findings and summary: The legality of prescribing and dispensing approved drugs or devices for uses not included in their official labelling is sometimes a cause for concern and confusion. The public administration should always safeguard patients' rights and health, evaluating the appropriateness of medical prescriptions. Off-label use should be based on sound scientific evidence, expert medical judgement and published literature. In its attempt to avoid misuse, the public administration should not limit prescribing activity by issuing rigid the rules to be followed. The physician and the pharmacist have to be trained to assess the risks associated with a single therapy and/or absence of therapy to evaluate the best practice case by case

Accelerated polymer biodegradation of risperidone poly(D, L-lactide-co-glycolide) microspheres

The influence of a tertiary amine, namely risperidone (pKa = 7.9) on the degradation of poly(D, L lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drug-loaded microspheres and blank microspheres in presence of free risperidone in 0.02 M PBS containing 0.02% Tween®80 at 37°C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration-dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs