Effect of pressure sensitive adhesive and vehicles on permeation of terbinafine across porcine hoof membrane.

The purpose of this study was to investigate characteristics of transungual drug delivery and the feasibility of developing a drug-in-adhesive formulation of terbinafine. The permeation of terbinafine from a PSA matrix across porcine hoof membrane was determined using a plate containing poloxamer gel. The permeation rate of terbinafine across hairless mouse skin was evaluated using a flow-through diffusion cell system. The permeation of terbinafine across the hoof membranes was the highest from the silicone adhesive matrix, followed by PIB, and most of the acrylic adhesives, SIS, and SBS. The rank order of permeation rate across mice skin was different from the rank order across porcine hooves. The amount of terbinafine permeated across the porcine hoof membranes poorly correlated with the amount of terbinafine remaining inside the hooves after 20 days, however, the ratio between rate of terbinafine partitioning into the hoof membrane and its rate of diffusion across the membrane was relatively constant within the same type of PSA. For influence of various vehicles in enhancing permeation of terbinafine across the hoof membrane, all vehicles except Labrasol(®) showed tendency to improve permeation rate. However, the enhancement ratio of a given vehicle differed from one adhesive to another with a moderate correlation between them. The infrared spectrum of the hoof treated with NMP, PPG 400 or PEG 200 indicated that the conformation of keratin changed from a non-helical to a helical structure.

Application of Carbopol/PVP interpolymer complex to prepare mucoadhesive floating granule.

Novel mucoadhesive floating granule was prepared using Carbopol/PVP interpolymer complex to deliver hydrophilic drugs in a controlled manner. Acetaminophen was used as a model drug. Maximum floatability of the granules was obtained at the ratio of 1/1, where 95 % of the granules floated for 12 h. As the concentration of sodium bicarbonate increased, both the floating duration and the release rate of the drug increased. The granules without sodium bicarbonate floated only for 2 h and floating onset time was 15 min. The release rate of drug gradually increased as the drug content in the granule increased. As the drug content in the granules increased, duration of adhesion decreased. However, the decrease in adhesion duration was minimal up to 40 % of drug content. The release rate from the granules prepared by dry granulation method was faster than that by wet granulation. The granules prepared by dry granulation method led to formation of highly porous structure; whereas, that by wet granulation method showed non-porous structure. The optimum size of the granules to retard the release of the model drug was within the range of 3-4 mm. Based on both mucoadhesive and buoyant properties, the floating granules are expected to reside in the upper part of the stomach for sufficient period of time and release the drug in a sustained manner.

Preparation and pharmacokinetic evaluation of curcumin solid dispersion using Solutol® HS15 as a carrier.

Solubility of curcumin at physiological pH was significantly increased by forming solid dispersion (SD) with Solutol® HS15. Since curcumin undergoes hydrolytic degradation, chemical stability study was conducted in pH 1.2, 6.8 and 7.4 buffer media. Solutol® HS15 exhibited superior stabilizing effect to Cremophor® RH40 and Kollidon® 30. The physical state of the dispersed curcumin in the polymer matrix was characterized by differential scanning calorimetry and X-ray diffraction studies. SD preparation transformed curcumin into amorphous form and facilitated micellar incorporation, thereby preventing hydrolysis in aqueous medium. In vitro drug release in pH 6.8 buffer revealed that SD (1:10) improved the dissolution of curcumin with approximately 90% release of the drug within 1h. Pharmacokinetic study of the solid dispersion formulation in rat showed that bioavailability of the drug was significantly improved as compared to pure curcumin. SD containing 1:10 ratio of drug and Solutol® HS15 resulted in approximately 5 fold higher AUC(0-12h). SD formulation was physically stable over the study period of 3 months.

Recent advances in transdermal drug delivery.

Transdermal delivery of pharmacologically active agents has been extensively studied for the past 40 years. Despite the strong efforts, currently, only about 40 products are in market on about 20 drug molecules, due to the requirements that the patch area should be small enough for the patients to feel comfortable, and to the barrier properties of the stratum corneum. Various approaches to overcome the barrier function of skin through physical and chemical means have been broadly studied. The development of an effective transdermal delivery system is dictated by the unique physicochemical property each drug molecule possesses. In this review, we have summarized various physical and chemical approaches for transdermal flux enhancement, including the application of electricity, ultrasound, microneedle and chemical enhancers. Pressure sensitive adhesive such as acrylics, rubbers and silicones are described together with recent developments. Factors affecting dosage form design, particularly for drug in adhesive system, like adhesion and crystallization are also discussed.

Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy.

In the present study we developed doxorubicin-loaded solid lipid nanoparticles (SLN-Dox) using biocompatible compounds, assessed the in vitro hemolytic effect, and examined their in vivo effects on drug retention and apoptosis intensity in P-glycoprotein-overexpressing MCF-7/ADR cells, a representative Dox-resistant breast cancer cell line. Our SLNs did not show hemolytic activity in human erythrocytes. In comparison with Dox, SLN-Dox efficiently enhanced apoptotic cell death through the higher accumulation of Dox in MCF-7/ADR cells. Therefore, SLN-Dox have potential to serve as a useful therapeutic approach to overcome the chemoresistance of adriamycin-resistant breast cancer. FROM THE CLINICAL EDITOR: Doxorubicin loaded solid lipid nanoparticles (SLN-Dox) were studied in a cell line representative of doxorubicin resistant breast cancer. The nanoparticles did not show hemolytic activity; furthermore, they efficiently enhanced apoptotic cell death through higher accumulation of doxorubicin in cancer cells. This approach may be viable in overcoming the chemoresistance of adriamycin resistant breast cancer.

Preparation of Carbopol/chitosan interpolymer complex as a controlled release tablet matrix; effect of complex formation medium on drug release characteristics.

Chitosan/Carbopol971NF (poly acrylic acid) interpolymer complexes were prepared in pH 3.0, 4.0, and 5.0 medium to control the ratio of chitosan and Carbopol971NF in the interpolymer complex. FT-IR analysis confirmed that the mechanism of complexation involved an electrostatic interaction between the NH3+ of chitosan and COO(-) of Carbopol971NF. An increase in the pH of the preparation medium was accompanied by an increase in the ratio of chitosan in the chitosan/Carbopol971NF complex. The maximum yield of interpolymer complexes prepared at pH 3, 4, and 5 (IPC3, IPC4, IPC 5) were obtained at ratios of 1/10, 1/5, and 1/4 (chitosan/Carbopol971NF), respectively. At pH 1.2, the overall drug release from IPC tablets did not show significant differences. However, at pH 6.8, the rate of drug release from the IPC5 tablet was higher than that from the IPC4 tablet. The release rate from the IPC3 tablet was observed to increase with time. The release mechanism was increasingly dominated by the relaxational contribution in the order of IPC3, IPC5, and IPC4 at pH 6.8. The diffusional contribution was dominated only in the early stage of drug release and the relaxational contribution gradually increased with time.

Preparation of an extended-release matrix tablet using chitosan/Carbopol interpolymer complex.

A chitosan and Carbopol interpolymer complex (IPC) was formed using a precipitation method in an acidic solution. The chitosan and Carbopol IPC was characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and turbidity measurements. FT-IR demonstrated that the IPC formed a complex through an electrostatic interaction between the protonated amine (NH(3)(+)) group of chitosan and the carboxylate (COO(-)) group of Carbopol. DSC indicated the IPC to have different thermal characteristics from chitosan or Carbopol. The turbidity measurement revealed the complexation ratio of IPC between chitosan/Carbopol to be 1/4. A theophylline tablet was prepared using the IPC as a matrix material. The drug release profile from this tablet was similar to that from the HPMC tablet and showed a pH-independent release profile. The mechanisms for drug release from the IPC tablet were diffusional release at pH 6.8 and relaxational release at pH 1.2.

In vitro and in vivo study of poly(ethylene glycol) conjugated ketoprofen to extend the duration of action.

Ketoprofen-polyethylene glycol (PEG) conjugates (KPEG) were prepared and their potential as a prolonged release system was investigated. Three KPEG conjugates were synthesized from ketoprofen and methoxy PEG with three different molecular weights by esterification in the presence of DCC. The KPEG conjugates were characterized by FT-IR and (1)H NMR spectroscopy. The rate of hydrolysis profile showed a specific acid-base catalysis pattern with a minimum at pH 4-5. The pharmacokinetic study after the intravenous and intramuscular administration of KPEG750 showed that the plasma levels of KP increased slowly and reached a maximum concentration at later time. The AUC of KPEG750 was higher than that after administering an equivalent dose of ketoprofen except 40mg/kg dose of intramuscular administration. The tail-flick experiment and paw edema test after intramuscular administration showed that KPEG750 had extended analgesic and anti-inflammatory effects compared with ketoprofen. These results suggest that KPEG could be a promising NSAID prodrug with an extended pharmacological effect owing to delayed-release of parent drug.

Preparation of floating microspheres for fish farming.

The aim of this study was to develop floating microspheres with practical applications to fish farming. Each microsphere with a central hollow cavity was prepared using a solvent diffusion and evaporation method with Eudragit E100. Various manufacturing parameters were investigated by single factor method. The macrolide antibiotic josamycin was selected as a model drug. The loading efficiency of the drug in the microspheres was 64.7%. In the release study, virtually none of the drug was released into the fresh water whereas the entire drug was released from the josamycin-loaded microspheres into the simulated gastric fluid of rainbow trout (pH 2.7). The buoyancy was excellent with approximately 90% of the microspheres still floating after 24h.

Preparation of a solid dispersion of felodipine using a solvent wetting method.

A straightforward solvent wetting method was used to prepare felodipine solid dispersions in the presence of various carriers. Dichloromethane is not needed when HPMC solid dispersions were produced using the solvent wetting method. The amount of ethanol used to prepare solid dispersions did not have a significant effect on the dissolution rate of felodipine. The results of X-ray diffraction and thermal analysis indicated that the drug was in the amorphous state when PVP, HPMC, and poloxamer were used as carriers. The dissolution rates of felodipine in PVP, HPMC, or poloxamer solid dispersions were much faster than those for the corresponding physical mixtures. However, dissolution profiles were found to depend on the carrier used; the dissolution rate of felodipine increased slowly for solid dispersions prepared using HPMC, whereas rapid initial dissolution rates were observed for solid dispersions prepared using PVP or poloxamer. Increases in dissolution rates were partly dependent on the ratios of felodipine to carrier. No significant changes in crystal form were observed by X-ray diffraction or thermal analysis, and no significant changes in dissolution rate were observed when sorbitol and mannitol were used as carriers.

Preparation of mucoadhesive microspheres containing antimicrobial agents for eradication of H. pylori.

Mucoadhesive microspheres containing either amoxicillin or clarithromycin were prepared via the interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and solvent diffusion method. The complexation between the PAA and PVP in an ethanol/water mixture was confirmed by the change in the transmittance of the solution as a function of repeating PAA and PVP unit ratio. The loading efficiency of clarithromycin in the complex microspheres was higher than that of amoxicillin due to the stronger interaction of clarithromycin with the PAA. The microspheres had a spherical shape with a smooth surface and the inside of the microspheres was completely filled. The dissolution rate of the complex microspheres was significantly slower than that of the PVP microspheres, particularly at pH 2.0. Amoxicillin and clarithromycin degraded significantly during the release study at pH 2.0. Therefore, their release rates were corrected using first order degradation rate constants. The amoxicillin release rates were similar regardless of the pH of the medium, while those of clarithromycin differed depending on the pH. The release mechanism of amoxicillin was mainly by a diffusion process and that of clarithromycin was via a dissolution process. The drug release rate from the complex microspheres was significantly lower than that from the PVP microspheres.

Mucoadhesive microspheres prepared by interpolymer complexation and solvent diffusion method.

Mucoadhesive microspheres were prepared to increase gastric residence time using an interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and a solvent diffusion method. The complexation between poly(acrylic acid) and poly(vinyl pyrrolidone) as a result of hydrogen bonding was confirmed by the shift in the carbonyl absorption bands of poly(acrylic acid) using FT-IR. A mixture of ethanol/water was used as the internal phase, corn oil was used as the external phase of emulsion, and span 80 was used as the surfactant. Spherical microspheres were prepared and the inside of the microspheres was completely filled. The optimum solvent ratio of the internal phase (ethanol/water) was 8/2 and 7/3, and the particle size increased as the content of water was increased. The mean particle size increased with the increase in polymer concentration. The adhesive force of microspheres was equivalent to that of Carbopol. The release rate of acetaminophen from the complex microspheres was slower than the PVP microspheres at pH 2.0 and 6.8.

Preparation and characterization of enrofloxacin/carbopol complex in aqueous solution.

Since the bitter taste of enrofloxacin apparently limit the patient compliance in the oral formulations of the antibacterial agent, the masking of the taste is essential for the improvement of the therapeutic effectiveness. Therefore, this study was carried out to examine the feasibility of taste masking of enrofloxacin by the retardation of its dissolution rate using the formation of complex between the drug and Carbopol. The complexation between Carbopol and enrofloxacin was confirmed by turbidity, UV spectrophotometry, wide angle X-ray diffraction, and differential scanning calorimetry. The enrofloxacin content in the complexes was 34% (Carbo-enrofloxacin complex I) and 57% (Carbo-enrofloxacin complex II) depending on the preparation method. The dissolution rate of enrofloxacin from the complex increased as the pH was reduced. The dissolution rate of enrofloxacin from the Carbo-enrofloxacin complex I was significantly lower than that of the enrofloxacin powder. Therefore, these observations suggest that Carbo-enrofloxacin complex I can be used to mask the taste of enrofloxacin.

Preparation of buccal patch composed of carbopol, poloxamer and hydroxypropyl methylcellulose.

A polymeric film composed of Carbopol, Poloxamer and hydroxypropyl methylcellulose was prepared to develop a buccal patch and the effects of composition of the film on adhesion time, swelling ratio, and dissolution of the film were studied. The effects of plasticizers or penetration enhancers on the release of triamcinolone acetonide (TAA) were also studied. The hydrogen bonding between Carbopol and Poloxamer played important role in reducing swelling ratio and dissolution rate of polymer film and increasing adhesion time. The swelling ratio of the composite film was significantly reduced and the adhesion time was increased when compared with Carbopol film. As the ratio of Poloxamer to hydroxypropyl methylcellulose increased from 0/66 to 33/33, the release rate of TAA decreased. However, no further significant decrease of release rate was observed beyond the ratio of 33/33. The release rate of TAA in the polymeric film containing polyethylene glycol 400, a plasticizer, showed the highest release rate followed by triethyl citrate, and castor oil. The release rate of TAA from the polymeric film containing permeation enhancers was slower than that from the control without enhancers. Therefore, these observations indicated that a preparation of a buccal patch is feasible with the polymeric film composed of Cabopol, Poloxamer and hydropropyl methylcellulose.

Mucoadhesive drug carrier based on interpolymer complex of poly(vinyl pyrrolidone) and poly(acrylic acid) prepared by template polymerization.

To develop a new mucoadhesive drug carrier, poly(vinyl pyrrolidone) (PVP)/poly(acrylic acid) (PAA) interpolymer complexes were prepared by the template polymerization of acrylic acid using PVP as a template polymer. Fourier transform infrared results showed that the interpolymer complexes were formed by hydrogen bonds between the carboxyl groups of PAA and the carbonyl groups of PVP. The adhesive forces of the PVP/PAA interpolymer complexes were higher than that of commercial Carbopol 971. Moreover, the adhesive force and the release rate can be controlled by changing the mole ratios of PVP and PAA. The release rates of ketoprofen from the PVP/PAA interpolymer complexes showed pH-dependency, and were slower at lower pH. The release rate of ketoprofen from the complex seemed to be mainly controlled by the dissolution rate of the complex above a pK(a) of PAA (4.75) and by the diffusion rate below the pK(a). The prepared complex appears to be an adequate carrier for the mucoadhesive drug delivery system.