The safety of tattoo inks: Possible options for a common regulatory framework

Tattoo prevalence has been increasing in the last 25 years, but specific regulations on tattoo inks are still missing. In the European Union, no supranational regulation is available and only few national provisions cover them. In the United States, tattoo inks are classified as cosmetics but are not approved for injection into the dermis. Health risks for consumers may derive from microbiological contamination and the presence of toxic substances or nanomaterials. However, current regulations and non-binding recommendations, where present, only address the microbiological and chemical risks, completely overlooking nanotoxicity. The aim of this paper is to promote awareness of the risks associated with tattoo inks and the nanomaterials contained therein. In particular, the need for a harmonised regulation or, at least, a set of minimal requirements is highlighted to improve the safety of tattoo inks and market surveillance by regulatory authorities

Medicated foams and film forming dosage forms as tools to improve the thermodynamic activity of drugs to be administered through the skin

Medicated foams and film forming systems are dosage forms formulated to undergo to a controlled metamorphosis when applied on the skin. Indeed, due to the presence of propellant or a particular air-spray foam pump, a liquid can generate a foam when applied on the stratum corneum, or a liquid or conventional dosage form can form on the skin a continuous film as a consequence of the solvent evaporation. Thanks to these controlled modifications, the drug thermodynamic activity increases favoring the skin penetration and, therefore, the bioavailability with respect to conventional semi-solid and liquid dosage forms. Furthermore, the available clinical data also evidence that these dosage forms improve the patient's compliance. The main formulative aspects of medicated foams and film forming systems are reviewed with the aim to underline the possible advantages in terms of biopharmaceutical performances and patient's adherence

Regulatory framework of pharmaceutical compounding and actual developments of legislation in Europe

Pharmaceutical preparations are medicines that the pharmacist makes for the special needs of the patients that the pharmaceutical industry cannot comply for economic and logistic reasons. Pharmacy compounding is still an important component of pharmacy practice and a valuable therapeutical service that is an integrant part of the modern health care system, but its legislation is not harmonized among European and US countries.In 2011 the Committee of Ministers of the Council of Europe has adopted a Resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients. Aim of this resolution is to harmonize quality assurance and standards for pharmacy-made medicinal products among European countries and to pass the gap in quality assurance and standards between preparation in pharmacies and medicines prepared by the pharmaceutical industry. This article will analyze the actual rules and technical norms that regulate compounding activity and the expectations resultants from the new European and US laws

Glatiramer acetate : a complex drug beyond biologics

Complex drugs may be either biological, if the active ingredients are derived from a biological source, or non-biological, if obtained by chemical synthesis. In both cases, their quality depends considerably on the manufacturing process. In the case of Non Biological Complex Drugs (NBCDs), complexity may arise either from the active substance, as in the case of glatiramer acetate, or from other sources, such as the formulation, as in the case of liposomes. In this paper, the case of glatiramer acetate (GA) - a NBCD relevant for clinical and economic reasons - is considered and the differences between US and EU regulatory approaches to GA marketing authorization are highlighted. Indeed, though US and EU regulatory agencies have chosen a generic approach integrated with additional data the implementation is different in the two jurisdictions. In the US, the additional data required are listed in a product specific guideline and copies of Copaxone\uae have been approved as generics. In the EU, instead regulatory agencies followed a hybrid approach requiring an additional comparative study, and interchangeability policies and substitution schemes have been left to national agencies

Emulsion versus nanoemulsion : how much is the formulative shift critical for a cosmetic product?

The use of nanoemulsions in cosmetic products has been enlarged in the last decades because of several formulative advantages (e.g., the improved self-life stability, better texture properties). In addition, nanoemulsions seemed to improve the penetration of active ingredients through the human skin, comparing to conventional emulsion. In this contest, the risk of a higher systemic exposure of consumer to active ingredients, due to the ability of nanoemulsion to enhance permeation, results a critical attribute that should be evaluated for assuring the consumer safety. The aim of this work was the evaluation of how an oil-in-water (O/W) nanoemulsion can influence the in vitro skin permeation profiles of two model active ingredients with different polarity (i.e., caffeine and ethyl ximenynate). Preliminarily, since both selected molecules influenced the physical stability of nanoemulsion, formulative studies were carried out to identify the most stable formulation to perform in vitro permeation studies. The overall results demonstrated that nanoemulsions could significantly influence the permeation profiles of molecules as a function of their physicochemical properties. In particular, O/W nanoemulsions significantly improved the permeation profiles of apolar active ingredients in comparison to conventional emulsions, whereas no differences were observable for polar molecules. Considering such findings, it is worth observing that there is room for reconsidering the risk assessment of nanoemulsion-based cosmetic products

Regulatory aspects and quality controls of polymer-based parenteral long-acting drug products: the challenge of approving copies

To assure the safety and the efficacy of a medicinal product, quality and batch-to-batch reproducibility need to be guaranteed. In the case of parenteral long-acting products, the European Union (EU) and US Regulatory Authorities provide different indications, from the classification to the in vitro release assays related to such products. Despite their relevance, there are few in vitro experimental set-ups enabling researchers to discriminate among products with different in vivo behavior. Consequently, most copies are authorized through hybrid instead of generic applications. Here, we review the actual regulatory frameworks to evaluate the in vitro release tests of polymer-based long-acting parenterals to highlights the directions followed by the Regulatory Agencies in the USA and EU

Diclofenac orodispersible films by hot melt ram extrusion 3D printing

Background: Hot melt ram extrusion 3D printing was recently proposed to prepare small batches of orodispersible films (ODF), but the feasibility of loading thermosensitive drugs with low palatability has not been investigated. Among the possible candidates, diclofenac sodium (DNa) at a dose of 25 mg could be loaded in ODF, despite the limited formulative space, when an immediate release is required. However, the addition of taste masking agents (TMA) should be carefully evaluated as they can compromise the ODF processability and handling. Purpose: This study aims to design ODF loaded by DNa and TMA by hot melt ram extrusion 3D printing and to study their influence on the mechanical and physico-chemical properties of ODF. Methods: ODF made of maltodextrins with a dextrose equivalent of 6 containing DNA and TMA (i.e. mint, licorice-mint and sucralose) or a combination thereof were characterized in terms of drug content, disintegration time, in vitro dissolution test and tensile properties. Results: All ODF disintegrated within 2 min complying the compendial specification. Impurity A of DNa was detected below the Ph. Eur. limits (< 0.2%). The in vitro dissolution profiles of DNa from ODF with and without TMA were superimposable (t80%\uf07e3 min) in deionized water; t80% decreased about 1-fold for ODF containing TMA in artificial saliva at pH=5.7 (t80%\uf07e2 min). Independently of the presence of TMA, drug loaded ODF were flexible and easy to handle without fracture, even if the presence of DNa significantly increased the tensile strength (placebo ODF=0.17\ub10.03 MPa vs DNa loaded ODF=2.21\ub10.54 MPa). Conclusion: Hot melt ram extrusion 3D printing can be also proposed to prepare palatable ODF loaded by a thermosensitive drug

Olanzapine orodispersible films: the impact of preparation method on drug dissolution

Background: Olanzapine (OLZ) can take the advantage of administration as orodispersible films (ODF) to improve adherence in psychiatric patients as ODF disintegrate quickly in the mouth without need of water. ODF can be prepared by solvent-casting or extrusion-based technologies. However, the preparation method needs to be carefully selected since water can influence the OLZ solid state and, consequently, the drug dissolution properties. Purpose: This study aims to compare the OLZ dissolution from ODF obtained by an aqueous-based solvent casting and a novel hot-melt ram-extrusion 3D printing. Methods: The ODF were prepared by casting and drying aqueous slurry of OLZ, maltodextrin (DE = 6), glycerine and sorbitan oleate; while the hot-melt ram-extrusion 3D ODF were obtained by printing a paste containing OLZ, maltodextrins (DE=6) plasticized with glycerine. In each case, 10 mg OLZ was loaded in 6 cm2 ODF. ODF were characterized for thickness, loss on drying, disintegration time and in vitro dissolution in deionized water. Results: ODF appeared homogeneous and easy to handle without cracks. The cast and printed ODF thicknesses were 140\ub14.5 \u3bcm and 278\ub113.2 \ub5m respectively. Residual water content in ODF was in the 6-8% w/w range. In both cases, ODF disintegrated within 60 s, complying the Pharmacopeia specifications. For in vitro dissolution, about 90% OLZ was released in \uf07e3 min for the 3D printed films; in contrast, an erratic drug release was observed for the OLZ ODF made by casting with a concomitant formation of a yellow precipitate after 3 min, which suggest a change in the OLZ solid state. Conclusion: The solvent-free hot melt ram extrusion 3D printing technique can be suitable for ODF preparation for drugs sensitive to solvent system

Nanofiller for the mechanical reinforcement of maltodextrins orodispersible films

One of the most critical quality attributes of orodispersible films (ODFs) is related to the development of dosage forms with tensile properties suitable for the packaging and patient's handling. Aiming to develop a strategy to reinforce the tensile properties, the current work reported the feasibility to improve the tensile strength of maltodextrins (MDX) based ODFs by adding an amorphous water insoluble nanofiller, namely polyvinylacetate (PVAc). The possible interactions between components investigated by DSC and ATR-FTIR spectroscopy revealed that MDX and PVAc were immiscible; even if, the presence of plasticizers permitted the homogeneous dispersion of PVAc in the film until the 10% w/w concentration was reached. As a consequence, PVAc nanoparticles was found to be an effective reinforcing agent only at the concentrations of 3 and 5% w/w. In this optimal range, the tensile strength increased at least 1.5 fold and the elastic modulus increased at least 4 times