Antonella Casiraghi

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.

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.

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.

Measuring adhesive performance in transdermal delivery systems

The therapeutic performance of a transdermal delivery system (TDS) can be affected by the quality of contact between the patch and the skin. The adhesion of a TDS to the skin is obtained by using pressure-sensitive adhesives (PSAs), which are defined as adhesives capable of bonding to surfaces with the application of light pressure. The adhesive properties of a TDS can only be fully and correctly characterized by considering the following factors: (i) the property that enables an adhesive to form a bond with the surface of another material upon brief contact and under light pressure (tack); (ii) the resistance of the matrix to flow that could be considered as an expression of the cohesiveness of the matrix itself (creep resistance); and (iii) the force required to peel away a patch from a surface (peel adhesion). In this paper, attention is focused on the most widely used methods for the measurement of TDS adhesive properties in development studies and in the quality control of TDSs. The most critical formulative variables in the development of TDSs are the type and concentration of additives used, the drug loaded, the PSA thickness, the composition and thickness of the backing layer, and the solvent residue. There is a lack of evidence for a relationship between the results obtained in in vitro adhesion tests and the in vivo adhesion performance of TDSs. Therefore, an analysis of the percentage of TDSs that lifted and/or detached during pharmacokinetic and clinical studies should be performed during development studies. No official tests for adhesive strength are currently included in the TDS monographs of the most authoritative pharmacopeias. At present, the medical application of TDS relies on tests standardized by the adhesive tape industry or prescribed in the adhesive tape monographs of US and Japanese Pharmacopoeias, or adaptations of these. The development of new methods is recommended to meet the specific requirements of evaluating TDSs, and to improve the correlation between in vitro tests and in vivo performance.

Development of local patches containing melilot extract and ex vivo-in vivo evaluation of skin permeation

Melilot extract could be effective in treating localised varicose syndrome or capillary fragility. The monolayer patch was selected to obtain a prolonged release of coumarin contained in the phytocomplex. Two types of methacrylic patches (patch 1 based on a blend of Eudragit E100 and Eudragit NE; patch 2 based on Eudragit L100) were prepared. Both patches were equivalent in terms of coumarin release and ex vivo skin permeation profiles. The two patches differed significantly as regards respective adhesive properties. At low peel rate only patch 1 showed adhesive failure as confirmed by the in vivo performance. When comparing the behaviour of the patches containing melilot extract with analogous patches containing synthetic coumarin, no melilot phytocomplex enhancer effect was shown. The data of the ex vivo coumarin skin permeation and those obtained by the in vivo stripping technique showed a good correlation (r(2)=0.9727 for patch 1, r(2)=0.9835 for patch 2).

Effect of drug chirality on the skin permeability of ibuprofen

The in vitro passive diffusion of S-ibuprofen (S-IB) and RS-ibuprofen (RS-IB) through human epidermis was determined to study the effects of drug chirality. S-IB has a lower melting point (T(m)=54 degrees C) than RS-IB (T(m)=77 degrees C) and, therefore, a greater solubility (S-IB: 127+/-1 microg/mL; RS-IB: 81+/-1 microg/mL). Supersaturated plasters were prepared by using a poly(dimethylsiloxane) adhesive and Eugragit RL and propylene glycol as antinucleant agents. The in vitro skin permeation profiles were determined by Franz cells and human epidermis obtained from three different donors. The permeation profiles of S-IB from saturated solutions resulted statistically higher than those of RS-IB (p<0.002). When plasters were used, no differences were noticeable between the enantiomer and racemate (p>0.17). The latter unexpected results could be explained considering that the RS-IB or S-IB in vitro release rate constants, determined using 3% w/w or 6% w/w loaded plasters, were not statistically different, suggesting that the drug diffusivity within the adhesive matrix represented the rate limiting step to the skin absorption.

Comparison of Different Membranes with Cultures of Keratinocytes from Man for Percutaneous Absorption of Nitroglycerine

The permeability barrier function of cell‐culture membranes to the permeation of nitroglycerine was evaluated to find an alternative to skin from man for ex‐vivo skin‐permeation tests.

Application of viscometry and solubility parameters in miconazole patches development

Nine binary mixtures of seven different methacrylic copolymer systems (Plastoid((R)) E 35 L (PLE) and Plastoid((R)) L 50 (PLL); Eudragit((R)) (Eu) NE, RL, RS, L, S) were tested as components of monolayer patches containing miconazole. Only three mixtures (PLE:EuNE, PLE:EuRL and PLE:EuRS) were suitable for the preparation of placebo matrices. Miconazole patches with good technological characteristics were obtained by using mixtures of PLE:EuNE and PLE:EuRL. The in vitro miconazole release rate from the two patches and from the patch prepared using only PLE were significantly different. The amounts of drug released in 24 h were quite satisfactory. A mathematical model based on capillary viscometry data was used for the evaluation of interactions between copolymers. This was useful to predict and understand the mechanisms related to the instability of the prepared mixture. The solubility parameters of the drug and of the matrix were also calculated. Miconazole release was faster when the difference between the solubility parameters of the matrix and of the drug was higher. A relationship between miconazole release rate and the difference of drug and matrix solubility parameters was found. Therefore, the solubility parameter could be applied in formulation studies of patches.

Dermal patches for the controlled release of miconazole : Influence of the drug concentration on the technological characteristics

The aim of this work was to evaluate the effect of different amounts of miconazole nitrate (MIC) on the technological characteristics (drug release profile, adhesiveness, and water vapor permeability) of a nonocclusive dermal therapeutic system (DTS) for the treatment of tinea unguium infection. Artificial silk was used as a backing layer. The self-adhesive matrix was made of a mixture of Plastoid E 35 L (PL L), an adhesive hydrophilic polymer, and Eudragit NE 40 D (EU NE), a nonadhesive hydrophobic polymer able to modify the drug release. Plastoid E 35 L is a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic ester. Eudragit NE 40 D is a copolymer of ethylacrylate and methylmethacrylate. Formulations containing different amounts of MIC, ranging from 2% to 16% w/w of the dried matrix, were designed. Drug crystals were observed by polarizing light microscopy, proving the incomplete solubilization of MIC only in the matrices containing 8% w/w or more of this compound. All systems provided an in vitro control of drug release for at least 24 hr. The amount of the drug released increased with drug loading in all DTS. The percentage of the drug released was the same in all the DTS containing detectable crystals of MIC. When the MIC was completely dissolved in the matrix, the released percentage decreased when drug loading increased. The water vapor permeability and the adhesive properties of the DTS were excellent.

Design and characterization of an adhesive matrix based on a poly(ethyl acrylate, methyl methacrylate).

The main issue in the development of transdermal patches made of poly(ethyl acrylate, methyl methacrylate) (Eudragit® NE 40D, PMM) is the shrinkage phenomenon during the spreading of the latex onto the release liner. To solve this problem, the latex is usually freeze-dried and then re-dissolved in an organic solvent (method 1). To simplify the production process, we prepared an adhesive matrix by adding to the commercial PMM latex a plasticizer and an additive (anti-shrinkage agent) that avoids the shrinkage of the water dispersion spread onto the release liner (method 2). In some cases the active ingredient itself, such as potassium diclofenac (DK) and nicotine (NT), works as anti-shrinkage agent. In this work, the effects of the preparation method, types and concentrations of the plasticizer (triacetin and tributyl citrate) on the adhesive properties of the transdermal patches were investigated. The adhesive properties of the prepared patch were determined by texture analysis, peel adhesion test and shear adhesion. The PMM/plasticizer interactions were evaluated by ATR-FTIR spectroscopy. Furthermore, the in vitro skin permeation profiles of DK and NT released from the patch were determined by Franz cell method. Generally speaking, the variables that mainly modify the adhesive properties are the concentration and type of the plasticizer. The skin permeation profiles of DK and NT from the patch prepared by method 2 overlapped with those obtained with the commercial products. The results underline that the PMM latex can be used conveniently in the development of transdermal patches.