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

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

Maltodextrins as drying auxiliary agent for the preparation of easily resuspendable nanoparticles

The drying of biodegradable polymeric nanoparticles (NP) is mandatory to improve their physical and chemical stability over time. Spray- or freeze-drying can induce irreversible aggregation of NP and therefore the use of drying auxiliary agents is required. The ability of four grades of maltodextrins differing in dextrose equivalent (DE) (i.e. DE2, DE6, DE12 and DE38) to protect PLGA NP from stresses was studied. High Mw maltodextrins (DE2) was not functional for obtaining an easily resuspendable dried product, since it needs a prolonged time to fully hydrate. Maltodextrins at intermediate DE showed a poor ability to protect NP from irreversible aggregation probably because too sensitive to environmental variation. DE38, which did not alter \u3b6-potential of NP, allowed to obtain an easily resuspendable nanosuspension independently of the drying process. The effectiveness of such material was attributed to the easiness of spray-dry a low viscous solution and to the ability of substitute the water molecules\u2019 hydrogen bonds with NP during freeze-drying

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

Preserving the Integrity of Liposomes Prepared by Ethanol Injection upon Freeze-Drying: Insights from Combined Molecular Dynamics Simulations and Experimental Data

The freeze-drying of complex formulations, such as liposomes, is challenging, particularly if dispersions contain residual organic solvents. This work aimed to investigate the effects of possible protectants, namely sucrose, trehalose and/or poly(vinyl pyrrolidone) (PVP), on the main features of the dried product using a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-based liposomal dispersion prepared by ethanol injection and containing ethanol up to 6%, as a model. The interactions among vesicles and protectants were preliminary screened by Molecular Dynamics (MD) simulations, which have been proved useful in rationalizing the selection of protectant(s). The freeze-drying protocol was based on calorimetric results. Overall data suggested a stronger cryo-protectant effect of trehalose, compared with sucrose, due to stronger interactions with the DPPC bilayer and the formation of highly ordered clusters around the lipids. The effect further improved in the presence of PVP. Differently from the other tested protectants, the selected trehalose/PVP combination allows to preserve liposome size, even in the presence of 6% ethanol, as demonstrated by Nanoparticle Tracking Analysis (NTA). Nevertheless, it should be also underlined that cakes blew out at an ethanol concentration higher than 1% v/v, probably due to the poor cohesion within the cake and solvent vapour pressure upon sublimation

Design of in vitro skin permeation studies according to the EMA guideline on quality of transdermal patches

Transdermal patches and medicated plasters are designed to sustain efficacious systemic or loco-regional drug concentrations, respectively. In both cases, drug skin permeation is a critical attribute from the early stage of the pharmaceutical development. In 2014, the EMA introduced the "Guideline on the quality of transdermal patches", in which the importance of equivalence of drug fluxes in in vitro skin permeation study was particularly emphasized to generic or abridged applications for the marketing authorization or manage dossier variations during the product cycle life. Moving from experimental data, this work provides information on the set-up of such studies and the statistical evaluation of obtained fluxes. In particular, the impact of the inter-sample variability on the equivalence assessment was deeply investigated by using formulation pairs containing propranolol, diclofenac or nitroglycerine. The main outputs of the work were attributable to the definition of the acceptability interval and number of replicates to be performed. As an example, the equivalence of two propranolol patches (flux variability lower than 25%) can be assessed using six replicas and a confidence limit within the 0.8-1.25 range (alpha = 0.05; power 90%). In contrast, the equivalence of diclofenac plasters, which exhibit a variability near the 50%, can be demonstrated increasing the number of replicas (i.e., 20 skin samples) for each formulation and widening the acceptance range according to the statistical approach proposed in the work

A new mucoadhesive dosage form for the management of oral lichen planus : formulation study and clinical study

The work aimed at studying a new mucoadhesive prolonged release tablet containing 24\u3bcg clobetasol-17 propionate (CP) suitable for the management of oral lichen planus. Low swellable dosage forms were designed by combining a mucoadhesive polymer, i.e. poly(sodium methacrylate, methylmethacrylate), with hydroxypropylmethylcellulose and MgCl2. This formulation was selected to modify the tablet erosion rate in order to obtain a release of CP over a 6-h period. A double-blind, controlled study was performed using three groups of patient (n=16) who received three applications-a-day over 4weeks of the developed CP tablets (group CP-T), placebo tablets (group CP-P) or commercial CP ointment for cutaneous application (123\u3bcg/application) extemporary mixed with Orabase\u2122 (group CP-O). At the end of the study, pain and ulceration resolved in 13/16 and 11/16 patients of group CP-T and group CP-O, respectively. In the group CP-O, a transient acute hyperaemic candidosis (n=2) and taste alteration (n=4) were also observed. No changes in clinical signs of patients in the group CP-P were evident. The application of mucoadhesive tablet containing 24\u3bcg CP 3 times a day appeared to be effective, avoiding the side effects of the generally used treatment

Design of pressure-sensitive adhesive suitable for the preparation of transdermal patches by hot-melt printing

This work aimed to design low-melting pressure sensitive adhesives and to demonstrate the feasibility of the preparation of (trans)dermal patches by hot-melt ram extrusion printing. This approach allows defining both the geometry of (trans)dermal patch and the drug strength easily according to patient needs. The preparation steps are the mixing of a poly-ammonium methacrylate polymer (i.e. Eudragit RL and RS) with a suitable amount of plasticizer (triacetin or tributyl citrate) and drug (ketoprofen or nicotine), the melting in the ram extruder, and the printing on the backing layer foil. The formulations were characterized in terms of rheological and adhesive properties, in vitro drug release and skin permeation profiles. The (trans)dermal patches made of Eudragit RL or Eudragit RS plasticized with the 40% triacetin could be printed at 90 \ub0C giving formulations with suitable adhesive properties and without cold flow after 1 month of storage at 40 \ub0C. Furthermore, the overall results showed that the performances of printed (trans)dermal patches overlapped those made by solvent casting, suggesting that the proposed solvent-free technology can be useful to treat cutaneous pathologies when the availability of (trans)dermal patches with size and shape that perfectly fit with the skin area affected by the disease improves the safety of the pharmacological treatment