Paola Minghetti

Fast dissolving films made of maltodextrins

This work aimed to study maltodextrins (MDX) with a low dextrose equivalent as film forming material and their application in the design of oral fast-dissolving films. The suitable plasticizer and its concentration were selected on the basis of flexibility, tensile strength and stickiness of MDX films, and the MDX/plasticizer interactions were investigated by ATR-FTIR spectroscopy. Flexible films were obtained by using 16-20% w/w glycerin (GLY). This basic formulation was adapted to the main production technologies, casting and solvent evaporation (Series C) or hot-melt extrusion (Series E), by adding sorbitan monoleate (SO) or cellulose microcrystalline (MCC), respectively. MCC decreased the film ductility and significantly affected the film disintegration time both in vitro and in vivo (Series C<10s; Series E approximately 1min). To assess the film loading capacity, piroxicam (PRX), a water insoluble drug, was selected. The loading of a drug as a powder decreased the film ductility, but the formulation maintained satisfactory flexibility and resistance to elongation for production and packaging procedures. The films present a high loading capacity, up to 25mg for a surface of 6cm(2). The PRX dissolution rate significantly improved in Series C films independently of the PRX/MDX ratio.

Fabrication of Polymer Microneedles Using a Two-Photon Polymerization and Micromolding Process

Background: Microneedle-mediated drug delivery is a promising method for transdermal delivery of insulin, incretin mimetics, and other protein-based pharmacologic agents for treatment of diabetes mellitus. One factor that has limited clinical application of conventional microneedle technology is the poor fracture behavior of microneedles that are created using conventional materials and methods. In this study polymer microneedles for transdermal delivery were created using a two-photon polymerization (2PP) microfabrication and subsequent polydimethylsiloxane (PDMS) micromolding process. Methods: Solid microneedle arrays, fabricated by means of 2PP, were used to create negative molds from PDMS. Using these molds microneedle arrays were subsequently prepared by molding eShell 200, a photo-reactive acrylate-based polymer that exhibits water and perspiration resistance. Results: The eShell 200 microneedle array demonstrated suitable compressive strength for use in transdermal drug delivery applications. Human epidermal keratinocyte viability on the eShell 200 polymer surfaces was similar to that on polystyrene control surfaces. In vitro studies demonstrated that eShell 200 microneedle arrays fabricated using the 2PP microfabrication and PDMS micromolding process technique successfully penetrated human stratum corneum and epidermis. Conclusions: Our results suggest that a 2PP microfabrication and subsequent PDMS micromolding process may be used to create microneedle structures with appropriate structural, mechanical, and biological properties for transdermal drug delivery of insulin and other protein-based pharmacologic agents for treatment of diabetes mellitus.

Diclofenac fast-dissolving film: suppression of bitterness by a taste-sensing system

Context: The selection of a proper taste-masking agent (TMA) is a critical issue in the development of fast‐dissolving films containing bitter drugs. Objective: This work is aimed to evaluate the suppression of the bitter taste of a maltodextrin fast-dissolving film loaded with 13.4 mg sodium diclofenac (DS) by adding TMAs. Methods: The films were prepared by casting and drying aqueous mixtures of maltodextrin (DE = 6), glycerin, sorbitan oleate, and DS. Films were characterized in terms of thickness, tensile properties, film disintegration time, and drug dissolution time. The bitterness intensity of DS and the masking effect of TMAs were evaluated by an electronic tongue. Results: The ‘mint’ and ‘licorice’ flavors and sucralose mixture resulted appropriate to mask DS bitterness as confirmed by a panel of volunteers. The addition of these TMAs did not significantly affect the film disintegration time (15–20 seconds) and DS dissolution rate (about 5 minutes). Conclusion: The electronic tongue was allowed to discriminate the effect of the TMA also in the presence of other hydrosoluble constituents of the film. Therefore, because of its simplicity and rapidity, this technique could assist or even replace the sensory evaluation in the development of fast‐dissolving films.

Polymethacrylate salts as new low-swellable mucoadhesive materials

The sodium and potassium salts of the methacrylic copolymers Eudragit L100 and Eudragit S100 were prepared with the aim to develop new low-swellable mucoadhesive materials intended for the preparation of buccal dosage forms. The physico-chemical characterization of the copolymers and the corresponding sodium and potassium salts was performed by using Fourier-transform infrared (FT-IR) spectroscopy and thermal analysis. When ionization occurred, the carboxylic acid group absorption band (1730 cm(-1)) was replaced by another characteristic band at 1560 cm(-1). After salification the T(g) of the two polymers shifted towards higher values and it was not significantly influenced by the contraion nature. The intrinsic dissolution rate at infinite rotation speed (7.354<G( infinity )<9.196) was about 6- to 7-fold higher than that of a low nominal viscosity hydroxypropylmethylcelluloses (HPMC). Moreover, the Eudragit salts did not show an evident swelling layer and their dissolution is governed by erosion. The adhesion properties of these materials, evaluated by texture analysis, overlapped with those of Carbopol 934P. On the basis of the in vivo bioadhesion test, the prepared methacrylic salts can be considered interesting for the preparation of both buccal tablets and patches with good patient compliance due to their low swelling properties.

Newborn pig skin as model membrane in in vitro drug permeation studies: A technical note

Summary and ConclusionsThe suitability of newborn pig skin as an alternative to human epidermis in in vitro permeation studies was investigated. A set of 7 benzoxazinones was used to perform in vitro experiments by using a modified Franz diffusion cell and excised newborn pig skin as a membrane. The maximum flux through newborn pig skin (Jmax,p) was compared with the maximum flux through excised human epidermis (Jmax,h), available from the literature, by means of the factor of difference value FoD=Jmax,p/Jmax,h. The FoD values ranged from 0.48 to 1.91, indicating thatJmax,p andJmax,h were in the same order of magnitude.This result confirmed the suitability of this membrane to assess the permeability of not completely freely water soluble drugs, such as the set of benzoxazinones used in the present study and propranolol hydrochloride.3 Considering that the skin was withdrawn from animals that died of natural causes, the ethical problems connected with the use of animal skin in preliminary permeation screenings can be bypassed.

Characterization of nifedipine solid dispersions.

The sublingual administration of nifedipine (NIF) is currently used in clinical practice. The sublingual administration of NIF solid dispersions (SD), by using a suitable dispenser, appears an interesting approach in the treatment of moderate and severe hypertensive emergencies. With this aim nine SD made of NIF and a low viscosity hydroxypropylmethylcellulose (HPMC) in different ratio were prepared by means of spray-drying technique and their structure was studied. Moreover, the drug dissolution properties from SD were verified. The characteristic peaks of crystalline NIF were not detectable by using the X-ray analysis when the NIF/HPMC ratios were lower than 50/50 w/w. In thermograms obtained from SD, the NIF melting endothermic peak disappeared when NIF/HPMC ratios were lower than 30/70 w/w; the experimental Tg values of SD were lower than the Tg values predicted by Gordon Taylor equation suggesting some type of non-ideality of mixing. In the SD FTIR spectra the NH stretching vibrations and the C=O stretch in esteric groups of NIF shift to free NH and C=O regions indicating the rupture of intermolecular hydrogen bond in the crystalline structure of NIF. The prepared SD improved the NIF dissolution rate in comparison with that of commercial NIF or NIF/HPMC physical mixtures. Moreover, the concentration of NIF in the dissolution medium increased decreasing the NIF content.

The regulatory framework of biosimilars in the European Union

In the European Union (EU), the regulatory policy for biosimilars has enabled different biosimilar products to be marketed through an abridged application, which allows the applicant to submit a reduced dossier. Nevertheless, some manufacturers of biological products that share some characteristics with copies have opted for a full application; therefore, the number and extent of clinical studies required in these cases is increased. Here, we focus on a comparison of recombinant human erythropoietin medicinal products. We analyse and discuss clinical studies submitted to the European Medicines Agency that relate to available biosimilars and biological medicinal products that are authorised with a full dossier. We also discuss the issues of interchangeability and substitution, given that the EU allows each Member State to set their own substitution policies.

Adhesive properties: a critical issue in transdermal patch development

Introduction: Transdermal patches and medicated plasters (patch) represent well-established prolonged release dosage forms. Even if satisfactory adhesion to the skin is strictly linked to the efficacy and safety of the therapeutic treatment, nowadays numerous reports of in vivo ‘adhesion lacking’ are still addressed to regulatory agencies. The adhesive properties of a patch should be characterized considering i) the ability to form a bond with the surface of another material on brief contact and under light pressure (tack); ii) the resistance of the adhesive to flow (shear adhesion); and iii) the force required to peel away a patch from a surface (peel adhesion). Areas covered: In this manuscript, the most widely used methods to measure adhesive properties during development studies are described, along with the quality control of patches. The influence of formulative variables on patch adhesive properties, and their possible relationship with the in vivo adhesion performances, is also discussed. Expert opinion: The Pharmacopoeias should consider the opportunity of introducing compendial testing to assay the quality of adhesive patch properties, and regulatory agencies should issue proper guidelines to evaluate these features during development.

Design of a new water-soluble pressure-sensitive adhesive for patch preparation

This work was intended to improve the adhesion properties of an available medical water-soluble pressure-sensitive adhesive (PSA) through the addition of cellulose ethers or polyvinylpyrrolidone (PVP). The adhesion properties were evaluated by means of peel adhesion test and creep resistance test. Possible interactions between the polymethyl methacrylate (PMMA) and hydrocolloid were investigated by Fourier-transformed infrared spectroscopy. Moreover, a central composite design was used to estimate the effects of hydrocolloids and plasticizers and their interactions on the PSA performance. The addition of PVP made it possible to obtain a patch with a 40-fold improved creep compliance and a reduced peel adhesion. The significant increase of the matrix cohesion was due to attractive interactions between the amide group of PVP and the carboxylic acid group of PMMA. The water vapor permeability of the prepared systems was very high. Furthermore, no primary skin irritation was observed. The presence of plasticizers at high level increased both the peel values and creep compliance, showing an opposite behavior with respect to PVP. The new PSA system can be easily removed from the skin, is suitable for repeated applications on the same site, and has adhesive properties that can be modified by changing the component ratios.

Biosimilars and regulatory authorities.

The patent expirations for many biotechnological medicines have prompted the development of copies of biological medicinal products. Unlike generics, biosimilars are similar but not identical to their reference product, because their chemical characteristics are directly related to the manufacturing process which cannot be precisely duplicated. The regulatory policy for biosimilars is complex and in Europe it is regulated mainly by guidelines issued by the European Medicines Agency (EMEA); additional product-class specific guidelines have been developed as in the case of recombinant human erythropoietin (rHuEPO). In 2008, the experience gained with this drug has prompted the development of a new guideline, currently in draft. In this review we critically discuss aspects related to EMEA guidelines, particularly focusing on rHuEPO.