Model framework for off label use of medicines

Background The drug licensing regulatory system ensures that marketed drugs to be used, meet the high standards and requirements for quality, efficacy and safety. Unfortunately, in practice, prescribers are often obliged to deviate from granted medicine marketing authorisation, due to the lack of availability of appropriate medicines for patient’s therapeutic needs and progress. This concept of medicines use not mentioned in the approved labelling (FDA Modernization Act) or outside of the terms of Summary of Product Characteristics regarding indication, age, dosage, pharmaceutical form and route of administration (British NHS Guideline) is defined as off-label use of licensed medicines. On the global level, many supportive evidence and health care needs confirm that off-label medicines use occurs in every country and each level or specialty area of healthcare (Conroy, 2003). Moreover, it is an integral part of Good Medical Practice and may provide the best available option or even the standard of care in a particular health condition (Dresser and Frader, 2009). In general, this concept is legal and may be appropriate, but it can be associated with safety, clinical and ethical concerns, emphasizing the increased incidence of adverse events associated with off-label medicines uses in particularly vulnerable patient groups (Gazarian and Kelly, 2006). A concerning issue is that the majority of all off-label uses have limited to no scientific support (Radley et al., 2006) and a considerable number of prescribers have no or limited knowledge about off-label medicine use or do not meet regulations regarding off-label use, if they exist. (Piñeiro Pérez et al., 2014). Experience shows that to ensure the quality of off-label use of medicines, there should be a formal mechanism to assess the feasibility, monitoring the safety and efficiency of medication used based on this concept.Thus, in continuum, the off-label use of medicines has been an essential part of the ethical and legal considerations as well as, many regulatory initiatives. The overall objective is to present a model regulatory framework setting out guidelines and recommendations for quality use of off-label medicines within the national profile of health care policy. A literature search was undertaken to identify the issues and challenges related to off-label medicines use including clinical, safety and ethical concerns. Recommendations for model framework Principles of good practice for off-label use of medicines should include the following elements: identifying the medical needs; compilation of a consensus list of accepted, scientific based off-label uses; creating an official expert group for the evaluation and approval of specific offlabel uses; and, providing a safe and effective supply. The main guiding principles and developed activities to support a responsible decision-making with regard to off-label medicines include: 1) the medical need- the best avail- S7 OP 290 608 Maced. pharm. bull., 62 (suppl) 607 - 608 (2016) Oral presentations Continuing professional development able treatment in cases of specific characteristics when authorized medicines cannot meet the patients’ need; 2) sufficient scientific basis and/or clinical practice experience to justify their action. Distinguish the routine off-label use, which is the use of these medicines based on “high quality” evidence and the use in specific exceptional circumstances; 3) information duty and a high degree of respect for patient rights, involving the patient/carer in decisionmaking process; 4) monitoring and reporting the outcomes, efficiency and adverse reactions; 5) considering self-monitoring of prescribing practices, liability and accountability. An additional special responsibility which among others falls on pharmacists should be to ensure that the prescriber is conscious for off-label prescribing and the reasons for that 6) production of compendia of certain medicines, enlisting those off-label uses judged to be legitimate.7) financial sustainability of an off-label use in medical practice. Before deciding to compound a patient-specific preparation, a step by step evaluation of alternatives should be made. These alternatives include a therapeutic alternative, dose rounding or manipulation of licensed dosage forms (splitting tablets, crushing tablets/opening capsules, dispersing their content in water or food, splitting suppositories, the use of a preparation designed for another route of administration). Conclusion Prescription, compounding, dispensing and administration of off label use of medicines should be regulated within the national profile of health care policy. The regulation regarding the practice of off-label medicine use differs between countries. Some countries have this practice regulated by law, while in others it is covered by good practice regulations or general professional recommendations and ethical standards. Assuming that there is no any general rule to regulate the “accurate” offlabel use of medicines it is of paramount importance for the countries to find a national solution to fulfil the ethical and legal demand, especially in the areas of pharmaceutical law and health insurance law. The common elements of these regulatory frameworks are the physicians’ freedom to prescribe off-label medicines if the scientific evidence exists and the need to inform patients when making this decision. Making policy efforts, by adopting appropriate guidelines for off-label medicines use, based on scientific evidence, with specifications of healthcare professionals’ responsibilities and a registry of off-label drug use in every day practice, would make possible a valuable approach towards ensuring a quality use of these medicines. Recommended solutions, as practiced in some countries, would support prescribes in more direct and active approach to handle the ethical and legal phenomenon associated with the off-label use of medicines

Micro-Raman Spectroscopy for Detection of Label-Free and Oil Red O Labeled PEGylated Nanoliposomes in hCmec/D3 Cell Internalization Studies

Rapid development of nanomedicines necessitates advancement in internalization techniques which can accurately distinguish between the complex environments of cells and nanocarriers. Internalization (or endocytosis) studies of oil red O labeled and label-free PEGylated-lecithin/cholesterol nanoliposomes was performed using micro-Raman spectroscopy. The C.O stretching vibrations and CCH scissoring bendings of naphthalene ring around 1225 cm.1 as well as the N=N stretching vibrations at 1377 cm.1 are prominent peaks absent from the label-free spectra which can be used for detection of internalized oil red O labeled nanoliposomes. Suitability of oil red O as a liposome marker was confirmed by stability studies of the incorporated dye and automated fluorescence cell counting. The C.C stretching region with a prominent wide band centered at 1080 cm.1 indicative of larger gauche conformer content typical for the lecithin-cholesterol nanoliposomes and the strong maximum at 980 cm.1 associated with O.C.C.N+ stretching vibrations of the liposome polar head groups are important for studying label-free nanoliposome cell internalization

Digital light processing 3D printing of Hydrochlorothiazide with modified release

Additive manufacturing also known as 3D printing gains more attention in scientific research due to its great advantages in simple and fast producing custom-designed products. 3D models created with computer-aided design (CAD) are presented to the printers and with different techniques, printing layer-by-layer desired products are made. Most used techniques in additive manufacturing are fused deposition modeling (FDM), material and ink jetting, sintering and vat polymerization techniques. Stereolithography (SLA) and digital light processing (DLP) are the most frequently used techniques in vat polymerization due to their advantages. In DLP technique, a digital micromirror is used for gradually exposing and solidifying a layer of liquid photopolymer solution following a layer-by-layer mechanism (Adamov et al., 2022; Zhu et al., 2020). Nowadays additive manufacturing finds its place in medicine by producing medical devices, implants, prostheses and medical equipment. 3D printing has enormous potential in personalized medicine as a result of different possibilities in production of dosage forms with desired shapes that contain one or more active compounds that can have different release profiles. 3D printing helps in overcoming the problem with permeability and solubility of some drugs and enables using drugs from different BCS classes.14th Central European Symposium on Pharmaceutical Technology, 28th - 30th September, Ohrid, N. Macedonia, 202

Comparative risk assessment study of elemental impurities in Montelukast chewable tablets and film-coated tablets

It is well documented that elemental impurities (EIs) are critical in the field of pharmaceutical development since they could affect the quality, efficacy and safety of the finished dosage form (FDF). The responsibility of pharmaceutical manufacturers is to demonstrate via assessment approach, risk-based control strategy and/or required data analysis that the FDFs are compliant with ICH Q3D (R2). The aim of this research is to conduct a comprehensive comparative EIs risk assessment study of three different Montelukast dosage forms produced as chewable tablets (4 mg and 5 mg) and film-coated tablets 10 mg. The inductively coupled plasma-mass spectrometry (ICP-MS) system was used for the determination of EIs in samples of Montelukast sodium as the active pharmaceutical ingredient (API), placebos for all FDFs, and FDFs. Moreover, the analyses were also conducted on three batches from all three studied FDFs. Based on ICH Q3D (R2) guidelines, the tested products for EIs Class 1 and Class 2A showed that EIs levels in the API and placebos are well below the ICH Option 1 oral and parenteral limits. For the examined batches of each FDF strength (total of 9), none of the EI exceeds their concentration limits

Evaluation of the in vitro bee venom release and skin absorption from bioadhesive gel formulation

Topical and transdermal drug delivery are one of the most suitable alternative, non-invasive routes for administration of drugs in clinical practice mainly due to the increased patient compliance and reduced systemic drug side effects. Many drug products applied to the skin surface may penetrate to some extent into the skin layers, where their effects are expected, as for example, topical formulations for the treatment of different local skin disorders. Also, significant concentrations of drug could be absorbed by the body regions close to the site of delivery, where regional effects are expected, for e.g., in the muscles, local blood vessels and articulations. Arthritis is a systemic, autoimmune disease characterized by inflammation of joints. Inflammatory cytokines cause activation of the macrophages which leads to swelling of joints, damage to cartilage, bone erosion , functional impairment and stiffness. Bee venom (BV) contains a variety of peptides, including melittin, apamin, adolapin, the mast-cell degranulating peptide, enzymes (phospholipase [PL] A2), biologically active amines (histamine and epinephrine) and nonpeptide components with anti�inflammatory, anti-arthritis, anticoagulant, antimicrobial, anticancer and anti-nociceptive properties. Melittin, a major peptide component of BV shown to have anti-inflammatory and anti�arthritis properties and inhibitory activity on nuclear factor kappaB which is involved in the synthesis of inflammatory mediators and may be essential for the treatment of arthritis using BV. The aim of this study was to evaluate the stability of crude BV as an active ingredient, as well as to evaluate the in vitro release and skin absorption of BV from a designed topical gel formulation

Nanotechnology in medicine – our experiences

The success of design criteria for long-circulating drug delivery systems to support membrane receptor-ligand interaction and internalization has been limited and there is a need to develop smarter approaches for efficient drug tumor targeting. In order to overcome some of the current limitations, stimulus-responsive targeting has been combined with passive and active targeting strategies. More innovative nanocarriers that hold promise to optimize targeted drug delivery are systems with the ability for transformation from the stealth long-circulating form to cell interactive form in the complex tumor environment, exposing ligands at their surface for improved ligandreceptor interaction and cell internalization. This short review will be an overview of several nanomedicines designed and characterized by our research group, and the interplay between their physicochemical characteristics and biological fate

Nanotechnology – a robust tool for fighting the challenges of drug resistance in non-small cell lung cancer

Genomic and proteomic mutation analysis is the standard of care for selecting candidates for therapies with tyrosine kinase inhibitors against the human epidermal growth factor receptor (EGFR TKI therapies) and further monitoring cancer treatment efficacy and cancer development. Acquired resistance due to various genetic aberrations is an unavoidable problem during EGFR TKI therapy, leading to the rapid exhaustion of standard molecularly targeted therapeutic options against mutant variants. Attacking multiple molecular targets within one or several signaling pathways by co-delivery of multiple agents is a viable strategy for overcoming and preventing resistance to EGFR TKIs. However, because of the difference in pharmacokinetics among agents, combined therapies may not effectively reach their targets. The obstacles regarding the simultaneous co-delivery of therapeutic agents at the site of action can be overcome using nanomedicine as a platform and nanotools as delivery agents. Precision oncology research to identify targetable biomarkers and optimize tumor homing agents, hand in hand with designing multifunctional and multistage nanocarriers that respond to the inherent heterogeneity of the tumors, may resolve the challenges of inadequate tumor localization, improve intracellular internalization, and bring advantages over conventional nanocarrier

Design of Experiments (DoE)-based approach for improvement of dry mixing processes in the production of low-dose Alprazolam tablets using Raman spectroscopy for content uniformity monitoring

A low-dose tablet formulation, containing a potent Benzodiazepine derivative Alprazolam was developed, considering the achievement of appropriate content uniformity of the active substance in powder blends and tablets as a major challenge. Two different types of lactose monohydrate (Tablettose 80 and Granulac 200) and two different types of dry mixing processes (high-shear mixing and "in bulk" mixing) were employed. To evaluate the influence of the variables (mixing speed, mixing time, filling level of the high-shear and cube mixer, lactose monohydrate type) and their interactions upon the response (content uniformity of Alprazolam in the powder blends), a Factorial 2 4 design (with 4 factors at 2 levels in 1 block) was generated for each type of mixer. For high-shear dry mixing the Response Surface, D-optimal Factorial 2 4 design (with 2 replications and 31 experiments) was used, while for the "in bulk" dry mixing the Response Surface, Central Composite Factorial 2 4 design (with 34 experiments) was used. The process parameters for the high-shear mixer were varied within the following ranges: filling level of 70-100%, impeller mixing speed of 50-300 rpm and mixing time of 2-10 minutes. For the cube mixer the following process parameter ranges were employed: filling level of 30-60%, mixing speed of 20-390 rpm and mixing time of 2-10 minutes. Raman spectroscopy in conjunction with a validated Partial Least Square (PLS) regression model was used as a Process Analytical Technology (PAT) tool for Alprazolam content determination and content uniformity monitoring. The DoE model was further employed to optimize the powder blending process in regard to the achievement of appropriate Alprazolam content uniformity using high-shear mixing and Tabletosse 80 as filler. The desirability function revealed that the following process parameters: a mixing time of 2 minutes, a mixing speed of 300 rpm and a 70% filling level of the mixer would produce powder blends with the lowest variability in Alprazolam content. The three independent lab batches of low-dose Alprazolam tablets, produced with high-shear mixing using these process parameters, conformed to the requirements of the European Pharmacopoeia for content (assay) of Alprazolam and uniformity of the dosage units

Mikroinkapsuliranje bakterije Lactobacillus casei u izolatu sojinog proteina i alginata pomoću sušenja raspršivanjem

This article presents a novel formulation for preparation of Lactobacillus casei 01 encapsulated in soy protein isolate and alginate microparticles using spray drying method. A response surface methodology was used to optimise the formulation and the central composite face-centered design was applied to study the effects of critical material attributes and process parameters on viability of the probiotic after microencapsulation and in simulated gastrointestinal conditions. Spherical microparticles were produced in high yield (64 %), narrow size distribution (d50=9.7 µm, span=0.47) and favourable mucoadhesive properties, with viability of the probiotic of 11.67, 10.05, 9.47 and 9.20 log CFU/g after microencapsulation, 3 h in simulated gastric and intestinal conditions and four-month cold storage, respectively. Fourier-transform infrared spectroscopy confirmed the probiotic stability after microencapsulation, while differential scanning calorimetry and thermogravimetry pointed to high thermal stability of the soy protein isolate-alginate microparticles with encapsulated probiotic. These favourable properties of the probiotic microparticles make them suitable for incorporation into functional food or pharmaceutical products.U radu je prikazan novi način pripreme mikrokapsula bakterije Lactobacillus casei 01 u izolatu sojinog proteina i alginata pomoću sušenja raspršivanjem. Metodologijom odzivnih površina optimiran je sastav mikrokapsula, a korištenjem plošno centriranog plana ispitan je utjecaj glavnih sastojaka kapsula te parametara procesa na preživljavanje mikroinkapsuliranog probiotika u simuliranim uvjetima gastrointestinalnog trakta. Najviše je proizvedeno kuglastih mikročestica (64 %), s raspodjelom veličina od d50=9,7 μm (raspon od 0,47) i povoljnim mukoadhezivnim svojstvima. Nakon mikroenkapsulacije preživjelo je 11,67 log CFU/g probiotika, nakon 3 sata u simuliranom želučanom soku 10,50 log CFU/g, u simuliranom soku tankog crijeva 9,47 log CFU/g, a nakon četiri mjeseca hladnog skladištenja 9,20 log CFU/g. Stabilnost probiotika nakon mikroinkapsulacije potvrđena je infracrvenom spektroskopijom s Fourierovom transformacijom, a toplinska stabilnost mikrokapsula probiotika u izolatu proteina soje i alginatu diferencijalnom pretražnom kalorimetrijom i termogravimetrijom. Zaključeno je da se zbog njihovih povoljnih svojstava mikrokapsule probiotika mogu upotrijebiti u proizvodnji funkcionalne hrane i farmaceutskih proizvoda