Active packaging for topical cosmetic/drug products: a hot-melt extruded preservative delivery device.

A delivery device intended for the prolonged release of antimicrobial agents, able to enhance the stability profile of liquid/semi-solid cosmetic/pharmaceutical products for topical application, was proposed in the present study. With the aid of a simulation program based on compartment models, the relevant kinetic and formulation parameters were defined using dehydroacetic acid sodium salt (DHA.Na, Prevan) as the model preservative. Indeed, the overall DHA.Na degradation rate is increased in the presence of formaldehyde releasers that are often employed as co-preservatives. Inert matrices (3 g weight and 18 mm diameter) based on high-density polyethylene (HDPE), possibly consistent with the design of an active packaging meant for preservative delivery, were prepared by hot-melt extrusion. Units with satisfactory physical-technological properties could be obtained up to 50%w/w loads of antimicrobial agent. In an attempt to modify the relevant Fickian release profiles by varying the area exposed to the medium, matrix systems coated with an impermeable film except for one base (CMs) or for the inner surface of a central drilled hole (PCMs) were investigated. On the basis of the n exponent of power equation and the outcome of linear fitting, PCMs were proven able to yield the zero-order release behaviour needed to ensure constant DHA.Na levels over a predetermined time period, as indicated by the simulation process.

Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: an investigation into the mechanisms governing drug release.

When used as release-controlling coating agents for tableted core-based pulsatile delivery systems, three different hydroxypropyl methylcellulose (HPMC) grades, Methocel E5, E50, and K4M, provided lag phases of varying duration (Methocel K4M > E50 > E5) and a prompt and quantitative model drug release. Dissolution/mechanical erosion, permeability increase and disruption of the hydrated polymeric layer were assumed to participate in the definition of the overall release pattern. Based on these premises, we investigated what process(es) might prevail in the release-controlling mechanism for each HPMC grade. The polymers were evaluated for dissolution and swelling, while the finished systems were concomitantly evaluated for drug release and polymer dissolution. The obtained results indicated likely similarities between Methocel E5 and E50 performances, which we hypothesized to be mainly dissolution/erosion-controlled, and a clearly different behavior for Methocel K4M. This polymer indeed proved to yield higher viscosity and slower dissolving gel layer, which was able to withstand extensive dissolution/erosion for periods that exceeded the observed lag phases. The particular characteristics of swollen Methocel K4M were shown to be associated with possible drug diffusion phenomena, which might impair the prompt and quantitative release phase that is typical of pulsatile delivery.

Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: a study on process parameters and in vitro performances.

Currently, delayed/pulsatile release and colon delivery represent topics of remarkable interest. The present paper deals with the study and development of an oral dosage form devised to release drugs following a programmed time period after administration or, when opportune design modifications are introduced, to target the colon. The system is composed of a drug-containing core and a hydrophilic swellable polymeric coating capable of delaying drug release through slow interaction with aqueous fluids. An optional external gastroresistant film is applied to overcome gastric emptying variability, thus allowing colon delivery to be pursued according to the time-dependent approach. The aim of this work was to evaluate different hydroxypropyl methylcellulose (HPMC) viscosity grades as possible materials for the attainment of the system retarding hydrophilic layer. Both the relevant suitability for application onto tablet cores by aqueous spray-coating in fluid bed and capability of delaying drug release for a programmable period were explored and compared. Methocel E50 was found to afford the best balance among different important items, i.e. process time, retarding ability, dimensions of the coated units and possibility of finely tuning the delay duration. Further results pointed out the robustness of Methocel E50-based systems, which have shown to be practically unaffected by the concentration of the employed coating solution and the pH of the release medium, as well as only poorly influenced by ionic strength, at least with regard to values encompassed in the physiological range for gastrointestinal fluids.

Polymorphism of NCX4016, an NO-releasing derivative of acetylsalicylic acid.

NCX4016 [2-acetoxybenzoic acid 3'-(nitrooxymethyl)phenyl ester] is a recently developed nitrooxy-derivative of aspirin with improved antiinflammatory, analgesic, and antithrombotic activity as well as increased gastrointestinal safety. Systematic polymorphic screening performed with different solvents and preparation methods resulted in the identification of two polymorphs, designated Forms I and II. They were characterized by scanning electron microscopy, powder X-ray diffraction, thermal analyses, and infrared spectroscopy; the crystal structure of polymorph I was solved by single-crystal X-ray analysis and compared with that of aspirin. Finally, intrinsic dissolution rate studies and calculations according to the melting data method were performed to assess the thermodynamic relationship between the two polymorphs.

Influence of betacyclodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices.

The release behavior of poorly soluble drugs (naproxen and ketoprofen) from inert (acrylic resins) and hydrophilic swellable (high-viscosity hydroxypropylmethylcellulose) tableted matrices containing betacyclodextrin (betaCD) was investigated. The results demonstrated that, in both cases, betaCD can enhance the rate of drug release. Matrices obtained from formulations in which lactose replaced betaCD were also evaluated. BetaCD in inert matrices causes a dramatic increase in the rate of drug release, higher than that promoted by lactose which merely acts as a channelling agent. This result suggests that possible in situ formation of the drug-betaCD complex. which causes an improvement in apparent drug solubility, could have a greater influence on the rate of drug release than the possible increase of water uptake by a soluble filler. Indeed, if the opposite were true, lactose would be more effective in increasing the rate of drug release than betaCD, because of its greater solubility in water. On the contrary, in the case of hydrophilic matrices, lactose proves to be much more effective in promoting drug release than betaCD. It seems that, while the bulky interaction compound can freely diffuse through water-filled pores of inert systems, its diffusion through swollen macromolecular chains of hydrophilic matrices may be hindered. This hypothesis was supported by data obtained from binary (drug/polymer) and ternary (drug/polymer/betaCD) hydrophilic matrices using a betaCD-containing dissolution media.

In vitro and in vivo evaluation of an oral system for time and/or site-specific drug delivery.

Aim of this work was the evaluation of an oral system (Chronotopic) designed to achieve time and/or site-specific release. The system consists in a drug-containing core, coated by a hydrophilic swellable polymer which is responsible for a lag phase in the onset of release. In addition, through the application of an outer gastroresistant film, the variability in gastric emptying time can be overcome and a colon-specific release can be sought relying on the relative reproducibility of small intestinal transit time. For this study, cores containing antipyrine as the model drug were prepared by tableting and both the retarding and enteric coatings were applied in fluid bed. The release tests were carried out in a USP 24 paddle apparatus. The in vivo testing, performed on healthy volunteers, envisaged the HPLC determination of antipyrine salivary concentration and a gamma-scintigraphic investigation. The in vitro release curves presented a lag phase preceding drug release and the in vivo pharmacokinetic data showed a lag time prior to the detection of model drug in saliva. Both in vitro and in vivo lag times correlate well with the applied amount of the hydrophilic retarding polymer. The gamma-scintigraphic study pointed out that the break-up of the units occurred in the colon. The obtained results showed the capability of the system in delaying drug release for a programmable period of time and the possibility of exploiting such delay to attain colon-targeted delivery according to a time-dependent approach.

In vitro and in vivo evaluation of oral systems for time and site specific delivery of drugs (Chronotopic technology).

This paper reports the in vivo and in vitro evaluation of an oral system for time and/or site specific drug delivery prepared according to Chronotopic technology. The proposed device consists of a drug containing core coated by a hydrophilic polymeric layer, which determines the delay in release onset. By applying an outer gastroresistant film, and by properly modulating the delay duration, a colon-specific release can be achieved. The obtained results show that the proposed delivery system is capable of releasing drug after a programmed time (time-specific release) and of targeting the colon (site-specific release) when an external gastroresistant film is applied on units coated with an appropriate amount of a hydrophilic retarding polymer.

The use of beta-cyclodextrin as a pelletization agent in the extrusion/spheronization process.

The use of beta-cyclodextrin for the preparation of pellets by the extrusion/spheronization process is described for different formulations and processing conditions. Sieve analysis and friability tests were performed to assess the physical and technological characteristics of pellets. Satisfactory products were obtained with beta-cyclodextrin contents up to 90% by weight.

Rotary tangential spray technique for aqueous film coating of indobufen pellets.

Indobufen pellets, previously prepared by direct pelletization employing the rotary tangential spray fluidized bed (Rotoprocessor), were coated using the same equipment setup as for the film coating process. Different amounts of the aqueous-based ethylcellulose dispersion (Aquacoat) were easily applied on the active cores of different compositions with no spray blocking or pellet sticking. The coating process was not influenced by changing the ethylcellulose (Aquacoat ECD-30) formulation with soft acrylic resin (Eudragit NE 30D) or by adding water-soluble polymers (Pharmacoat 606 and PEG 6000) to the coating dispersions. Simple setup, flexibility of operation, and short manufacturing times were the advantageous features of the tangential spray equipment. These benefits were verified during the pellet coating process. The composition of the cores and membranes were confirmed as the determining parameters with respect to the performances in terms of the drug release rate. The morphological and functional results clearly demonstrated the tangential spray rotary system as a promising one-step technique for the preparation of indobufen prolonged-release multiple-unit dosage forms.

Ocular mini-tablets for controlled release of timolol: evaluation in rabbits.

Topical delivery of timolol by inserts or similar controlled-release devices may offer distinct advantages over administration by eyedrops. The purpose of this investigation was the evaluation in rabbits of ophthalmic inserts (denominated mini-tablets, MT) for sustained/controlled release of timolol maleate (TiM). The MTs (diameter 3.5 mm, thickness 1.5 mm, average TiM content 0.34 or 0.68 mg) were prepared by compressing appropriate mixtures of powders with a standard tabletting machine. A thin, rate-controlling membrane was applied over the devices by spraying aqueous dispersions of acrylic copolymers. A first series of different (uncoated and coated) MTs were tested for release of TiM to the lacrimal fluid, using commercial eyedrops (Timoptol 0.5%) as a reference standard. Two MTs (one of which was coated) and the same reference solution were then selected for an ocular absorption study. Analysis of TiM in the aqueous humor indicated that the coated MT was capable of maintaining low and steady levels of TiM for at least 19 h, while the other device, identical but uncoated, produced a prolonged-pulse effect lasting about 8 h. The apparent mean residence time (MRT) of TiM in the aqueous humor was 1.3 h for the reference solution, 3.2 h for the uncoated MT, and 5.7 h for the coated one. The present preliminary results point to the potential validity of coated mini-tablets as simple systems for controlled ocular delivery of timolol.

Chemico-physical and functional properties of inorganic sunscreens in cosmetic products.

Synopsis This paper reports preliminary results of a study carried out on liquid crystal emulsions added to three different inorganic sunscreens: ultrafine zinc oxide, ultrafine titanium dioxide (inorganic-treated) and ultrafine titanium dioxide (organic-treated hydrophobically). The aim of the work was to investigate the influence of chemico-physical properties of inorganic sunscreens on the microstructure of cosmetic emulsions. The study was carried out using three different techniques: rheological measurements performed in dynamic conditions, to study the homogeneity of samples and their structural features; dispersion of powders in emulsions by optical microscopy and SEM/EDX analysis; and functionality of emulsions by UV spectroscopy, with adhesive tape as substrate. Results show that the different chemico-physical properties of the micropigments lead to different interactions with emulsion components; these interactions may affect the functionality and microstructure of the whole system, with loss of stability.

Controlled release of dehydroacetic acid sodium salt for the stability improvement of cosmetic formulations*.

Synopsis The kinetics of decomposition of the sodium salt of dehydroacetic acid (DHA.Na) in presence of formaldehyde and formaldehyde donors was investigated. The possibility of preparing systems capable of providing the cosmetic preparation with increasing amounts of DHA.Na corresponding to portions interacted with formaldehyde was explored. Data relevant to matrices prepared from ethylcellulose and polyethylene by casting and moulding process, respectively, are reported and discussed. Experimental data demonstrate the possibility of preparing polymeric systems able to control in terms of rate and duration the relase of DHA.Na, according to time and concentration needs of a typical cosmetic formulation.

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCI.

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and td of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and td between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t1/2 (7.12 h), while apparent t1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for Cmax and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p < 0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the 'Levy's plot' (per cent released versus per cent absorbed) approach and provided further support for the correlation found.

Swelling-restricted minimatrices for controlled release of drugs. Preliminary in-vivo studies.

A preliminary in-vivo study was performed on a new modified release system which contained diltiazem hydrochloride. The system consisted of swellable minimatrices that were coated with an acrylic polymeric film. The film thickness, because of its pH-dependent solubility, might represent a critical variable with regard to in-vivo release. In order to evaluate the influence of such a variable on in-vivo behaviour, two minimatrices formulations with differing film thickness were tested versus a commercial tablet. The in-vivo study, which was based on a balanced incomplete block design, involved six volunteers in two sequences. The drug was quantified in plasma by an HPLC method. Computation and statistical analysis of pharmacokinetic parameters were performed by means of SIPHARR package (Simed, F). The results show that the approach of film coating, in order to modify the release rate from minimatrices, is feasible, but it must be improved; in particular the results point to the necessity of reducing the film susceptibility to pH changes.

Cross-linked sodium carboxymethylcellulose as a carrier for dissolution rate improvement of drugs.

The dissolution rate is often the limiting step in gastrointestinal absorption of water insoluble drugs from solid oral dosage forms. The aim of this work was to use a swellable polymer chosen among superdisintegrants, for improving the dissolution rate of a sparingly soluble drug, loaded on its surface. Nifedipine, which has a very low water solubility, was chosen as a model drug, while cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) was chosen as the swellable polymer. The Nifedipine/Ac-Di-Sol systems were prepared using two different techniques: evaporation and spraying; in some preparations polyethylene glycol (PEG 1500), or sucrose palmitate (Sucrodet), or dioctyl sodium sulfosuccinate (Aerosol OT) were added. The results of the dissolution tests showed that the dissolution rate of Nifedipine from the systems prepared increases, particularly in the case of the preparation composed of Ac-Di-Sol plus surfactant agents.

Swelling-activated drug delivery systems.

A previous paper dealt with the preparation of an in vitro programmable zero-order drug delivery system in which the area of the surface exposed to the dissolution medium and the macromolecular relaxation of polymer controlled the release of the drug. In the present study, the preparation of similar delivery systems is described, in which differing drugs and polymers were used to ascertain the mechanism governing the drug-release kinetics. The movement of the interfaces between solvent and system was measured during drug release in systems with varying composition. The results indicate that the synchronization of the movement of swelling and eroding fronts at the solvent-system interface determines the achievement of the linear-release kinetics of such swelling activated systems and that the swelling and dissolution characteristics of the polymer employed for core preparation govern front movement.

Drug/polymer matrix swelling and dissolution.

The swelling and dissolution behavior of pharmaceutical systems containing a drug and a polymer can be analyzed by a mathematical model which predicts the drug released and the gel layer thickness as a function of time. It is possible to approximate the values of several of the physicochemical parameters of this model in order to obtain an order-of-magnitude analysis of the tablet dissolution process. Selected experimental results of tablet dissolution and drug release are analyzed and conclusions are made about the importance of the drug and polymer content and solubility in the release behavior.