Comparison of the coating process and in vitro dissolution of 3 mm gastro-resistant minitablets and 5 mm gastro-resistant tablets with pantoprazole.

Minitablets are solid oral forms, which, due to their size (1-3 mm), may be easily swallowed by children. The administration of minitablets in a certain number of units allows for flexible dosing for a broad age group of paediatric patients, which is particularly important for modified-release drugs. In this study, enteric-coated minitablets (3 mm) with pantoprazole were developed and compared to conventional tablets (5 mm). Eudragit L 30D 55® and Acryl Eze II® films, which were 50 and 80 µm thick, respectively, were applied using two different fluid bed systems. The increase in the pantoprazole release rate occurred not only due to the application of a thinner film but also due to the reduction in the size of the core independent of the coating apparatus that was used. In contrast to minitablets, the thin film's thickness was insufficient for 5 mm tablets and a loss of gastro-resistance was observed. The insertion of minitablets into a hard gelatine capsule did not affect drug release from the minitablets under in vitro conditions.

Gastroresistant gelatin films prepared by addition of cellulose acetate phthalate.

Gastroresistant capsules are obtained mostly by using modified-release fill in hard capsules, or by coating the gelatin shell with acid-resistant polymers. Modification of the material used at the stage when the capsule shell is produced would reduce the complexity and cost of introducing new products to the market. Gastroresistant gelatin films were obtained by using commercial cellulose acetate phthalate (aqueous dispersion Aquacoat® CPD). Only films casted from non-alkalized mixtures showed no visible disintegration at pH from 1.2 (simulated gastric fluid) to 4.5 (phosphate buffer). Elasticity of the dry films was comparable with the one determined for non-modified gelatin films, however tear resistance was 2-fold smaller, but still acceptable for practical application.

Can preschool-aged children swallow several minitablets at a time? Results from a clinical pilot study.

Minitablets are a novel, multi-compartment solid drug formulation, particularly intended for children between 1 and 6 years of age. Available literature shows that even infants are capable of swallowing a single minitablet. In this study, we have explored the level of acceptance of minitablets administered in units of 5 or 10. A group of thirty two 2-year-old children (2-years) and twenty eight 3-year-old children (3-years) have been enrolled in the study. Each child was asked to swallow placebo minitablets (2mm or 3mm) suspended in a fruity jelly on a spoon. The swallowing of minitablets (with or without chewing) was registered for 75% of 2-year-olds and for 93% of 3-year-olds. Moreover, most of the children (57% of all participants) were fully capable of swallowing all units without chewing (2-years: 50%; 3-years: 64%). However, no statistically significant differences in the swallowing ability were observed in gender and age groups. None of the children choked. Neither the number, nor the diameter of the administered minitablets have significantly influenced the ability to swallow units. The results show that minitablets administered in several units mixed with jelly food are safe and could be accepted by a pediatric population.

Dissolution test for ivermectin in oral veterinary paste.

A dissolution test for oral veterinary pastes with ivermectin using the Ph. Eur. paddle apparatus was developed. Sink conditions were achieved with sodium lauryl sulphate in a concentration of 0.5% as dissolution medium. By means of HPLC fast degradation of ivermectin was observed in HCl 0.1 M solution. Rotation speed of the paddle at 75 rpm was appropriate as demonstrated in a study comparing two different products.

The choice of lipids and surfactants for injectable extravenous microspheres.

Suspensions of lipid microspheres sizing from 1 to 30 microm, whose fluidity and lipid/surfactant composition is suitable for parenteral administration were developed. None of the formulations prepared with Precirol (palmitostearate), as the only lipid, was physically stable during storage, because liquid suspensions formed semisolid gels within one week. Stable 10% (w/w) suspensions of lipid microspheres were produced using saturated triglycerides in combination with medium chain unsaturated triglycerides (Miglyol) as lipids and polysorbate 80 (2% w/w) as a surfactant.

Lithium carbonate 24-hour extended-release capsule filled with 6 mm tablets.

A 24-h extended-release multiparticulate capsule containing a dose of 500 mg of lithium carbonate divided into 6 tablets 6 mm in size was produced. In order to achieve an immediate and prolonged drug release profile one uncoated tablet and 5 tablets coated with methacrylic acid/ethyl acrylate copolymer Kollicoat MAE30DP were filled into a capsule. The core of tablets consisted of microcrystalline cellulose, lactose, povidone, macrogol and magnesium stearate.

Studies on the effect of pH on the lipoidal route of penetration across stratum corneum.

The effect of pH on the excised skin permeability towards two model lipophilic compounds was studied in the range of pH 1.0-10.0 and 1.0-12.0, for hydrocortisone and testosterone, respectively. Suspensions of the model compounds in appropriate buffers (0.1-0.2 M) were applied to the intact skin, delipidized skin, skin pretreated with Azone or sodium lauryl sulfate solution and the percutaneous penetration was observed for 28 h. Within the studied pH range, up to pH 11.0 no change in the penetration through the skin and skin accumulation was observed for both compounds. Significant, 3-4-fold, increase of penetration of testosterone was noted only at pH 12.0, however the change was neither fast not progressing with time. None of the pretreatment procedure influenced the observed relationship between pH and skin permeability. It is concluded that the lipoidal route of penetration is not affected by solutions at pH within the range 1.0-11.0.

Bioavailability of diazepam from aqueous-organic solution, submicron emulsion and solid lipid nanoparticles after rectal administration in rabbits.

The bioavailability of diazepam in rabbits after rectal administration of three formulations: organic-aqueous Relsed rectal solution (containing ethanol, benzyl alcohol and propylene glycol), submicron emulsion and solid lipid nanoparticles (SLN), was studied. Submicron emulsion contained MCT oil (20% w/w), egg lecithin and poloxamer; SLN were prepared with cetyl palmitate 10% w/v and non-ionic emulsifying agent, Plantacare. All formulations contained 4 mg/ml of diazepam and the dose administrated to rabbits was 2 mg/kg. In both submicron preparations nearly the same mean size of the dispersed particles (201-206 nm) and the fraction of the free drug in aqueous phase (0.9-1.5%) was determined. Besides very moderate prolongation of drug release, the submicron emulsion as a vehicle did not alter pharmacokinetics of diazepam when compared with the solution: the mean C(max) was 48.9+/-24.0 and 49.5+/-17.0 ng/ml, and area under the curve was 134.0+/-42.3 and 186.8+/-59.8 ng h/ml, for solution and emulsion, respectively. The low relative bioavailability, 47% compared to the solution, was observed after administration of SLN. Transmission electron microscopy pictures revealed that some of diazepam is present on the surface of the SLN and this fraction was immediately absorbed, while the diffusion of the drug in the solid core was not efficient enough to allow a complete release. It may be concluded that submicron emulsion may be a good choice of an ethanol-free drug formulation, but lipid matrix, which is solid at body temperature, is not advantageous system for diazepam rectal delivery, even if delivered as a submicron dispersion.

Evaluation of paracetamol suppositories by a pharmacopoeial dissolution test--comments on methodology.

Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of paracetamol suppositories was evaluated and the effect of experimental conditions on dissolution profiles was studied. Paracetamol suppositories containing 80-500 mg of the drug, on fatty base, were obtained from four manufacturers (A, B, C, D). The diffusion cell was modified by incorporation of an in-built thermoprobe and large difference (up to 1.7 degrees C) between temperature in the water-bath and in the dissolution chamber was observed. This effect was avoided by increasing the length of tubing immersed in the thermostat at the inlet of the cell. The most reproducible results were observed for A and C suppositories, however from suppository C the total dose of paracetamol was released after 3.5-4.5 h while the release from suppository A was slow with only 40-87% of the total dose liberated during 6 h. Suppositories B did not melt at 37 degrees C and less than 5% of the drug was released. Fast release was observed after melting when the temperature was elevated to 39.5 degrees C. The results demonstrate clearly that essentially complete melting of a suppository in the dissolution chamber is required for an appropriate dissolution of paracetamol in vitro. Disintegration time, softening time, drop point and particle size of the suspended drug were measured and the relevance of these parameters for dissolution behaviour of the preparations was discussed.

In vitro studies on penetration of terpenes from matrix-type transdermal systems through human skin.

Polyurethane matrices containing up to 39% of the terpenes eucalyptol, L-limonene, D-limonene, dipentene or terpinolene were produced. Release of the terpenes directly to the acceptor fluid, as well as through isolated human epidermis and dermis, was studied. In the presence of dermis the penetration profiles were very similar to the release profiles, indicating that dermis does not present a barrier for penetration of terpenes. For all terpenes the penetration was slower in the presence of epidermis (K(p) was in the range 0.21-1.8x10(-3) cm/h). Release and penetration through the epidermis and dermis were fastest for dipenetene (mixture of D-limonene and L-limonene), being at least 3-4 times faster than for D-limonene and L-limonene. Large amounts of terpenes found in epidermis (approximately 1.5 mg/cm(2)) indicate that affinity of these compounds to the stratum corneum is very high.

Diazepam submicron emulsions containing soya-bean oil and intended for oral or rectal delivery.

Physically stable diazepam submicron emulsions were prepared using soya-bean oil. Diazepam concentration 4 mg/ml, suitable for rectal or oral delivery, was achieved in 20% emulsions. Mixture of egg lecithin (1.2%) and poloxamer (2.0%) has been chosen as the most suitable emulsifying agent. Composition of the emulsion may be supplemented with alpha-tocopherol and parabens. However, the system was not stable when either phenylethanol or chlorhexidine gluconate was added. Taste masking agents commonly used as food additives decreased stability of the preparation and were not efficient in elimination of a bitter taste of the drug-loaded emulsions.

In vivo evaluation of submicron emulsions with pilocarpine: the effect of pH and chemical form of the drug.

Submicron emulsions containing 2.0% w/v pilocarpine as pilocarpine HCl, soybean oil (10% w/v) and egg lecithin (1.2% w/v) were formulated. Emulsions at pH 5.0, 6.5 and 8.5 were applied to the rabbit's eye, and the reduction in pupil diameter was measured for 6 h. The miotic effect was compared with that obtained with aqueous solutions at the same pH. A prolonged miotic effect was observed when the submicron emulsion was used as a vehicle. After application of emulsions at pH 5.0, 6.5 or 8.5, the time when 20% reduction of pupil diameter was still observed was 3.9 +/- 1.1 h, 4.3 +/- 1.3 h and 5.3 +/- 0.8 h, respectively, while, after application of a solution, this parameter was shorter by 30-40%. AUC(0-6h) values were larger after application of the submicron emulsions in comparison to aqueous solutions; however, statistically significant differences were only observed for emulsions at pH 6.5. Although the bioavailability of the drug is pH dependent, emulsions at higher pH cannot be considered for clinical use because of pilocarpine degradation which occurs with a similar rate as in aqueous solutions. Introduction of pilocarpine into the oily phase in the form of pilocarpine base or its oleate did not improve either the physicochemical or the pharmacological properties of the formulations. Irrespective of the pH and chemical form of pilocarpine used for emulsion preparation, practically all drug was found in the aqueous phase of the emulsion; thus, partitioning to the oily phase was negligible.

Submicron emulsions as drug carriers. Studies on destabilization potential of various drugs.

Few drugs have been successfully formulated as submicron emulsions. The physicochemical stability of submicron emulsions on admixture of drugs is the main factor limiting a wider use of this type of vehicle for parenteral or other routes of administration. In a short-term stability studies we have investigated 35 drugs with regard to their compatibility with 20 or 5% parenteral fat emulsions. The study has shown that interaction of drugs with submicron emulsions is complex in nature. Taking into consideration the physicochemical properties of a drug e.g. lipophilicity or ionization, it is difficult to predict changes in the physical stability of the system. If destabilization occurs it is maximal at saturated concentrations and the presence of even significant amounts of the solid phase formed by undissolved drug does not influence the short-term stability of the system. Due to the increased ratio of emulgator to oil, emulsions containing 5% of oily phase are less susceptible to destabilization than 20% emulsions.

Increased partitioning of pilocarpine to the oily phase of submicron emulsion does not result in improved ocular bioavailability.

Submicron emulsions containing pilocarpine as ion-pair with mono-dodecylphosphoric acid were prepared. Physical stability of these preparations was confirmed during 4 months of storage at 4 degrees C. Approximately 50% of the drug was found in the aqueous phase of emulsion separated using an ultrafiltration technique, while the rest was present in the oily phase and interphase. The miotic effect observed in rabbits after application of the ion-pair in aqueous solution or in submicron emulsion was the same; indicating that the drug distribution into the oily phase of the colloidal vehicle does not improve ocular bioavailability.

Investigation of diazepam lipospheres based on Witepsol and lecithin intended for oral or rectal delivery.

Diazepam was incorporated in lipospheres prepared by high pressure homogenization of melted Witepsol (10%) dispersed in aqueous lecithin (2.4%). Diazepam content was 0.4% and more than 98% of the dose was found to be encapsulated in the lipospheres. Although the initial mean particle size was 0.3 micron, the liposhperes agglomerated during storage and this phenomenon was not eliminated by increasing lecithin concentration to 4% or incorporation of oleic acid (0.1%) and co-surfactants, polysorbate 80 (0.5%) or poloxamer (up to 6%). The formulation was not able to mask effectively bitter taste of diazepam, even when lipids of higher melting temperature, namely glyceryl tripalmitate or stearic acid, were introduced.

[Percutaneous absorption of heparin: a critical review of experimental results]. / Wchlanianie heparyny przez skóre--krytyczna ocena wyników badan.

Percutaneous penetration of heparin is limited by its large molecular weight, negative charge and hydrophilicity. Although some authors did not find any significant anticoagulant effect of transdermally delivered heparin but several other papers indicate that heparin penetrates the skin barrier. The actual article provides a critical review of the in vitro and in vivo studies on percutaneous absorption of heparin and heparinoids. It is concluded that there is no sufficient evidence that heparin is able to penetrate intact skin. However under clinical conditions the integrity of the skin barrier may be changed what results in promotion of heparin penetration and justifies usage of topical drug formulations like ointments and gels.

Miotic effect and irritation potential of pilocarpine prodrug incorporated into a submicron emulsion vehicle.

Pilocarpine prodrug, O,O'-dipivaloyl(1,2-ethylene) bispilocarpic acid diester, was introduced to a submicron emulsion vehicle in a dose equivalent to 0.5% pilocarpine base, and the formulation was studied in albino rabbits using miotic assay. Compared with pilocarpine HCl 0.5% solution delayed and prolonged miosis was observed after application of the prodrug emulsion. AUC(0-6 h) values for the prodrug emulsion and pilocarpine solution were 9252+/-1345 and 6845+/-1967%xmin, respectively. The prodrug was also administered twice daily for 5 days in the form of aqueous solution or submicron emulsion in order to study ocular irritation. Irritation potential of the prodrug was significantly reduced when submicron emulsion was used as a vehicle.

Studies on the effect of pilocarpine incorporation into a submicron emulsion on the stability of the drug and the vehicle.

In order to obtain a novel ocular formulation with a potential for prolonging pilocarpine activity, the drug (2.0%) was incorporated into a submicron emulsion containing soya-bean oil and lecithin as emulgator. The effect of drug incorporation into the emulsion on its physical stability and on the other hand, the potential of the vehicle to reduce drug degradation at pH higher than 5.0 was studied. The pH was adjusted to 6.5 or 5.0 and the physicochemical stability of the formulations was observed. The mean diameter of oily particles in the resulting emulsions measured by a laser diffractometer was 0.6-0.7 micron and this was larger than in a drug-free emulsion where a 0.33 micron value was measured. The formulations were physically stable for 6 months at 4 degrees C, but progressing chemical degradation of pilocarpine was noted at pH 6.5. At that pH nearly 8% of pilocarpine was degraded to isopilocarpine and pilocarpic acid, both in the emulsion and in the solution. Thus, it may be concluded that pilocarpine in submicron emulsion is not protected against degradation. The presence of pilocarpine changes the physical stability of the vehicle since the formulation was easily destabilized during autoclaving or at room temperature. In the presence of higher concentration of lecithin (2.4%) or co-emulgators (poloxamer 2.0% or Tween 80 0.5%) the mean droplet size in the emulsions was the same as in a drug-free system. However the emulsions containing poloxamer were not stable during storage. Viscosity of pilocarpine emulsions can be increased by addition of methylcellulose or sodium carmellose (1.0%), but an intensive creaming occurs in these systems. Pilocarpine base is less suitable for emulsion preparation than hydrochloride salt, and emulsions prepared at pH 5.0 show the most satisfying stability.

Intracellular or intercellular localization of the polar pathway of penetration across stratum corneum.

A pharmacokinetic hypothesis of stratum corneum with two parallel pathways, lipophilic and porous hydrophilic, is not well documented yet. Still questionable is the localization of the pores, and the present experiments were designed to elucidate the contribution of extracellular lipids and intracellular keratin to the structure of this pathway. Percutaneous penetration of baclofen, a model zwitterion, was studied in vitro using human cadaver skin. Aqueous or ethanolic saturated solutions of the drug (Cs = 4.6 and 0.4 mg/mL, respectively) were applied on the skin that was pretreated with: methanol/chloroform (Me/Ch) or acetone-chloroform (Ac/Ch) (1:1) mixtures, or with these solvents followed by 0.2% solution of sodium lauryl sulfate (SLS). As controls, baclofen penetration through the intact full-thickness skin was determined, and the fluxes were 0.18 +/- 0.08 and 0.14 +/- 0.07 microg/cm2/h for aqueous and ethanolic solutions, respectively. When Me/Ch was used for 1 h, an expected increase of the penetration was observed, but the lag time, Tlag, was still nearly 20 h. When the less polar mixture, Ac/Ch, was used, no flux enhancement was observed, and with ethanol as the vehicle, decreased penetration was even noted. No effect on baclofen penetration was observed when SLS was used for 1 h after delipidization of the skin was done with either the Me/Ch or Ac/Ch mixture. The results suggest that the polar pathway may be located intercellularly and comprises aqueous regions surrounded by polar lipids, which create the walls of such microchannels.