Design and Evaluation of Self-Emulsifying Drug Delivery Systems (SEDDS) of Nimodipine

The ability of self-emulsifying drug delivery systems (SEDDS) to improve solubility, dissolution rate and bioavailability of a poorly water-soluble calcium channel blocker, nimodipine (NM) was evaluated in the present investigation. Solubility of NM in various oils, surfactants and cosurfactants was determined. The influence of the ratio of oil to surfactant + cosurfactant, pH of aqueous phase on mean globule size of resulting emulsions was studied by means of photon correlation spectroscopy. The NM loaded SEDDS selected for the in vitro and in vivo studies exhibited globule size less than 180 nm. In vitro dissolution studies indicated that NM loaded SEDDS could release complete amount of NM irrespective of the pH of the dissolution media. Pharmacokinetics of NM suspension, NM oily solution, NM micellar solution and NM SEDDS were evaluated and compared in rabbits. Relative bioavailability of NM in SEDDS was significantly higher than all the other formulations. NM loaded SEDDS were subjected to various conditions of storage as per ICH guidelines for 3 months. NM SEDDS successfully withstood the stability testing.     

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407

Aim of current research was to prepare ibuprofen-poloxamer 407 binary mixtures using fusion method and characterize them for their physicochemical and performance properties. Binary mixtures of ibuprofen and poloxamer were prepared in three different ratios (1:0.25, 1:0.5, and 1:0.75, respectively) using a water-jacketed high shear mixer. In vitro dissolution and saturation solubility studies were carried out for the drug, physical mixtures, and formulations for all ratios in de-ionized water, 0.1 N HCl (pH?=?1.2), and phosphate buffer (pH?=?7.2). Thermal and physical characterization of samples was done using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRD), and infrared spectroscopy (FTIR). Flow properties were evaluated using a powder rheometer. Maximum solubility enhancement was seen in acidic media for fused formulations where the ratio 1:0.75 had 18-fold increase. In vitro dissolution studies showed dissolution rate enhancement for physical mixtures and the formulations in all three media. The most pronounced effect was seen for formulation (1:0.75) in acidic media where the cumulative drug release was 58.27% while for drug, it was 3.67%. Model independent statistical methods and ANOVA based methods were used to check the significance of difference in the dissolution profiles. Thermograms from mDSC showed a characteristic peak for all formulations with T_peak of around 45°C which suggested formation of a eutectic mixture. XRD data displayed that crystalline nature of ibuprofen was intact in the formulations. This work shows the effect of eutectic formation and micellar solubilization between ibuprofen and poloxamer at the given ratios on its solubility and dissolution rate enhancement.     

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK _a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1–2591.4 μg/mL within the pH range 1.2–5.0) and low solubility at high pH (5.8–51.9 μg/mL within the pH range 6.5–7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8–98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2–5.0) and relatively low (15.9–86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5–7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.     

Design of a novel type IV lipid-based delivery system for improved delivery of drugs with low partition coefficient

Abstract

Context: The physicochemical properties of drugs such as partition coefficient play a major role in the development of lipid-based drug delivery systems. The major obstacle lies in encapsulation of a drug with low partition coefficient into these systems.

Objective: The objective of this study was to design and optimize a novel lipid-based delivery system with higher loading, improved pharmacokinetics consequently enhancing the oral bioavailability of drugs with low partition coefficient like valsartan.

Materials and methods: The optimized formulation consists of Capryol 90, Cremophor RH 40, and Transcutol HP. Pseudo ternary phase diagrams were used to optimize the components and their concentrations in the formulation. Dissolution studies of the selected formulations were compared with plain drug and marketed product at three pH conditions (pH 1.2, 4.5 and 6.8). Pharmacokinetic parameters of optimized formulations were determined in Wistar rats and compared with that of plain drug.

Results and discussion: The optimized formulation with a mean particle size of 50?nm showed significant improvement (p?<?0.05) in dissolution rate with pH independence compared to plain drug and marketed product. The in vivo studies in Wistar rats revealed about 2.30- and 1.68-fold increase in the oral bioavailability and C_max of valsartan from lipid-based formulation compared to plain drug.

Conclusion: The engineered formulation strategy by type IV lipid-based formulations can be successfully exploited to improve the dissolution rate and oral deliverability of drugs like valsartan.     

Floating granules of ranitidine hydrochloride-gelucire 43/01: Formulation optimization using factorial design

The purpose of this research was to develop and optimize a controlled-release multiunit floating system of a highly water soluble drug, ranitidine HCl, using Compritol, Gelucire 50/13, and Gelucire 43/01 as lipid carriers. Ranitidine HCl-lipid granules were prepared by the melt granulation technique and evaluated for in vitro floating and drug release. ethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose were evaluated as release rate modifiers. A 3² full factorial design was used for optimization by taking the amounts of Gelucire 43/01 (X ₁) and ethyl cellulose (X ₂) as independent variables, and the percentage drug released in 1(Q₁), 5(Q₅), and 10 (Q₁₀) hours as dependent variables. The results revealed that the moderate amount of Gelucire 43/01 and ethyl cellulose provides desired release of ranitidine hydrochloride from a floating system. Batch F4 was considered optimum since it contained less Gelucire and was more similar to the theoretically predicted dissolution profile (f₂=62.43). The temperature sensitivity studies for the prepared formulations at 40°C/75% relative humidity for 3 months showed no significant change in in vitro drug release pattern. These studies indicate that the hydrophobic lipid Gelucire 43/01 can be considered an effective carrier for design of a multiunit floating drug delivery system for highly water soluble drugs such as ranitidine HCl. Published: April 13, 2007     

Artificial neural networks in the modeling and optimization of aspirin extended release tablets with eudragit L 100 as matrix substance

The purpose of the present study was to model the effects of the concentration of Eudragit L 100 and compression pressure as the most important process and formulation variables on the in vitro release profile of aspirin from matrix tables formulated with Eudragit L 100 as matrix substance and to optimize the formulation by artificial neural network. As model formulations, 10 kinds of aspirin matrix tablets were prepared. The amount of Eudragit L 100 and the compression pressure were selected as causal factors. In vitro dissolution time profiles at 4 different sampling times were chosen as responses. A set of release parameters and causal factors were used as tutorial data for the generalized regression neural, network (GRNN) and analyzed using a computer. Observed results of drug release studies indicate that drug release rates vary widely between investigated formulations, with a range of 5 hours to more than 10 hours to complete dissolution. The GRNN model was optimized. The root mean square value for the trained network was 1.12%, which indicated that the optimal GRNN model was reached. Applying the generalized distance function method, the optimal tablet formulation predicted by GRNN was with 5% of Eudragit L 100 and tablet hardness 60N. Calculated difference (f ₁ 2.465) and similarity (f ₂ 85.61) factors indicate that there is no difference between predicted and experimentally observed drug release profiles for the optimal formulation. This work illustrates the potential for an artificial neural network, GRNN, to assist in development of extended release dosage forms.     

Ocean acidification effects on calcification and dissolution in tropical reef macroalgae

Net calcification rates for coral reef and other calcifiers have been shown to decline as ocean acidification (OA) occurs. However, the role of calcium carbonate dissolution in lowering net calcification rates is unclear. The objective of this study was to distinguish OA effects on calcification and dissolution rates in dominant calcifying macroalgae of the Florida Reef Tract, including two rhodophytes (Neogoniolithon strictum, Jania adhaerens) and two chlorophytes (Halimeda scabra, Udotea luna). Two experiments were conducted: (1) to assess the difference in gross (⁴⁵Ca uptake) versus net (total alkalinity anomaly) calcification rates in the light/dark and (2) to determine dark dissolution (⁴⁵CaCO₃), using pH levels predicted for the year 2100 and ambient pH. At low pH in the light, all species maintained gross calcification rates and most sustained net calcification rates relative to controls. Net calcification rates in the dark were ~84% lower than in the light. In contrast to the light, all species had lower net calcification rates in the dark at low pH with chlorophytes exhibiting net dissolution. These data are supported by the relationship (R² = 0.82) between increasing total alkalinity and loss of ⁴⁵Ca from pre-labelled ⁴⁵CaCO₃ thalli at low pH in the dark. Dark dissolution of ⁴⁵CaCO₃-labelled thalli was ~18% higher in chlorophytes than rhodophytes at ambient pH, and ~ twofold higher at low pH. Only Udotea, which exhibited dissolution in the light, also had lower daily calcification rates integrated over 24 h. Thus, if tropical macroalgae can maintain high calcification rates in the light, lower net calcification rates in the dark from dissolution may not compromise daily calcification rates. However, if organismal dissolution in the dark is additive to sedimentary carbonate losses, reef dissolution may be amplified under OA and contribute to erosion of the Florida Reef Tract and other reefs that exhibit net dissolution.

     

Use of hydrophilic natural gums in formulation of sustained-release matrix tablets of tramadol hydrochloride

The objective of this work was to develop matrix sustained-release tablets of highly water-soluble tramadol HCl using natural gums (xanthan [X gum] and guar [G gum]) as cost-effective, nontoxic, easily available, and suitable hydrophilic matrix systems compared with the extensively investigated hydrophilic matrices (ie, hydroxypropyl methylcellulose [HPMC]/carboxymethyl cellulose [CMC] with respect to in vitro drug release rate) and hydration rate of the polymers. Matrix tablets of tramadol (dose 100 mg) were produced by direct compression method. Different ratios, of 100∶0, 80∶20, 60∶40, 20∶80, 0∶100 of G gum (or X):HPMC, X gum:G gum, and triple mixture of these polymers (G gum, X gum, HPMC) were applied. After evaluation of physical characteristics of tablets, the dissolution test was, performed in the phosphate buffer media (pH 7.4) up to 8 hours. Tablets with only X had the highest mean dissolution time (MDT), the least dissolution efficiency (DE₈%), and released the drug following a zero-order model via swelling, diffusion, and erosion mechanisms. Guar gum alone could not efficiently control the drug release, while X and all combinations of natural gums with HPMC could retard tramadol HCl release. However, according to the similarity factor (f ₂), pure HPMC and H₈G₂ were the most similar formulations to Topalgic-LP as the reference standard. Published: March 17, 2006     

Statistical optimization of gastric floating system for oral controlled delivery of calcium

The development of an optimized gastric floating drug delivery system is described. Statistical experimental design and data analysis using response surface methodology is also illustrated. A central, composite Box-Wilson design for the controlled release of calcium was used with 3 formulation variables: X₁ (hydroxypropyl methylcellulose [HPMC] loading), X₂ (citric acid loading), and X₃ (magnesium stearate loading). Twenty formulations were prepared, and dissolution studies and floating kinetics were performed on these formulations. The dissolution data obtained were then fitted to the Power Law, and floating profiles were analyzed. Diffusion exponents obtained by Power Law were used as targeted response variables, and the constraints were placed on other response variables. All 3 formulation variables were found to be significant for the release properties (P<,05), while only HPMC loading was found to be significant for floating properties. Optimization of the formulations was achieved by applying the constrained optimization. The optimized formulation delivered calcium at the release rate of 40 mg/hr, with predicted n and T_50% values at 0.93 and 3.29 hours, respectively. Experimentally, calcium was observed to release from the optimized formulation with n and T_50% values of 0.89 (±0.10) and 3.20 (±0.21) hours, which showed an excellent agreement. The quadratic mathematical model developed could be used to further predict formulations with desirable release and floating properties.     

Dissolution Testing of Sublingual Tablets: A Novel <Emphasis Type="Italic">In Vitro</Emphasis> Method

In the sublingual (SL) cavity, compared with the gastrointestinal tract, tablets are subjected to minimal physiological agitation, and a limited volume of saliva is available to facilitate disintegration and dissolution. None of the official compendial dissolution apparatuses and methods simulate these SL conditions. In this study, a custom-made dissolution apparatus was constructed, and a novel in vitro method that simulates SL conditions was evaluated. Several epinephrine 40 mg SL tablet formulations under development and two commercial SL tablets, isosorbide dinitrate 5 mg and nitroglycerin 0.6 mg, were studied. The dissolution medium was 2 mL of distilled water at 25°C. Dissolution was measured at 60 and 120 s. The novel in vitro method was validated for accuracy, reproducibility, and discrimination capability, and was compared with the official US Pharmacopeia (USP) dissolution method using apparatus 2 (Paddle). The data obtained following the novel in vitro method were accurate and reproducible. This method was capable of detecting minor changes in SL formulations that could not be detected using other in vitro tests. Results from the official USP dissolution method and our novel in vitro method were significantly different (p < 0.05). Results reflecting the dissolution of rapidly disintegrating tablets using simulated SL conditions were obtained using the novel in vitro dissolution method.     

Controlled Release Matrix Tablets of Zidovudine: Effect of Formulation Variables on the <Emphasis Type="BoldItalic">In Vitro</Emphasis> Drug Release Kinetics

The purpose of this research was to design oral controlled release (CR) matrix tablets of zidovudine (AZT) using hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC) and carbopol-971P (CP) and to study the effect of various formulation factors on in vitro drug release. Release studies were carried out using USP type 1 apparatus in 900 ml of dissolution media. Release kinetics were analyzed using zero-order, Higuchi’s square root and Ritger–Peppas’ empirical equations. Release rate decreased with increase in polymer proportion and compression force. The release rate was lesser in formulations prepared using CP (20%) as compared to HPMC (20%) as compared to EC (20%). No significant difference was observed in the effect of pH of dissolution media on drug release from formulations prepared using HPMC or EC, but significant difference was observed in CP based formulations. Decrease in agitation speed from 100 to 50 rpm decreased release rate from HPMC and CP formulations but no significant difference was observed in EC formulations. Mechanism of release was found to be dependent predominantly on diffusion of drug through the matrix than polymer relaxation incase of HPMC and EC formulations, while polymer relaxation had a dominating influence on drug release than diffusion incase of CP formulations. Designed CR tablets with pH independent drug release characteristics and an initial release of 17–25% in first hour and extending the release up to 16–20 h, can overcome the disadvantages associated with conventional tablets of AZT.     

Preparation and In Vitro Evaluation of Solid Dispersions of Total Flavones of Hippophae rhamnoides L.

The purpose of this study was to enhance the dissolution of total flavones of Hippophae rhamnoides L. (TFH) by solid dispersions consisting of the drug and a polymeric carrier, poloxamer 188 (PXM). The solvent evaporation method was used to prepare solid dispersions. A 3² full-factorial design approach was used for optimization wherein the amount of solvent (X ₁) and the drug-to-polymer ratio (X ₂) were selected as independent variables and the percentage of TFH dissolved in 10 min (Q ₁₀) was selected as the dependent variable. Multiple linear regression analysis revealed that a suitable level of X ₁ and X ₂ was required for obtaining higher dissolution of TFH from PXM solid dispersions. Solid dispersions were characterized by differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and dissolution tests. Characterization studies revealed that solid dispersion of TFH–PXM showed enhancement of TFH dissolution due to the conversion of TFH into a less crystalline and/or amorphous form. In conclusion, dissolution enhancement of TFH was obtained by preparing its solid dispersions in PXM using solvent method.     

Enantioselective analysis of N‐hydroxymexiletine glucuronide in human plasma for pharmacokinetic studies

Enzymatic hydrolysis with β‐glucuronidase/sulfatase was used for the enantioselective determination of N‐hydroxymexiletine glucuronide in plasma for pharmacokinetic studies. N‐Hydroxymexiletine glucuronide was determined as the quantity of mexiletine released by hydrolysis (difference between the enantiomeric concentrations of mexiletine obtained with and without hydrolysis). Plasma samples (100 μl) were treated at pH 5.0 with 10 mg of the enzyme (Limpet Acetone Powder type I) for 16 hr at 37°C and extracted at pH 10.4 with diisopropyl ether. Chiral mexiletine discrimination was obtained by reaction with o‐phthalaldehyde/N‐acetyl‐L ‐cysteine, separation of the resulting diastereomers on a C‐18 reversed‐phase column with a mobile phase of methanol–0.05 N acetate buffer, pH 5.5 (6.5:3.5, v/v), and fluorescence detection (λ_ex 350 nm, λ_em 455 nm). The performance characteristics for the enantioselective analysis of mexiletine preceded by enzymatic hydrolysis were recovery ∼90%, quantification limit 1 ng/ml, and linearity up to 1000 ng/ml plasma for both enantiomers. The coefficients of variation obtained in the study of intra‐ and inter‐day precision were respectively 5% and 7% for both enantiomers. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with the arrhythmic form of chronic Chagas' heart disease treated with 200 mg t.i.d. of racemic mexiletine hydrochloride. The high sensitivity of the method allows analysis of only 100 μl plasma. Chirality 11:85–90, 1999. © 1999 Wiley‐Liss, Inc.     

Preformulation Studies on Solid Self-Emulsifying Systems in Powder Form Containing Magnesium Aluminometasilicate as Porous Carrier

The influence of alkaline and the neutral grade of magnesium aluminometasilicate as a porous solid carrier for the liquid self-emulsifying formulation with ibuprofen is investigated. Ibuprofen is dissolved in Labrasol, then this solution is adsorbed on the silicates. The drug to the silicate ratio is 1:2, 1:4, and 1:6, respectively. The properties of formulations obtained are analyzed, using morphological, porosity, crystallinity, and dissolution studies. Three solid self-emulsifying (S-SE) formulations containing Neusilin SG2 and six consisting of Neusilin US2 are in the form of powder without agglomerates. The nitrogen adsorption method shows that the solid carriers are mesoporous but they differ in a specific surface area, pore area, and the volume of pores. The adsorption of liquid SE formulation on solid silicate particles results in a decrease in their porosity. If the neutral grade of magnesium aluminometasilicate is used, the smallest pores, below 10 nm, are completely filled with liquid formulation, but there is still a certain number of pores of 40–100 nm. Dissolution studies of liquid SEDDS carried out in pH = 1.2 show that Labrasol improves the dissolution of ibuprofen as compared to the pure drug. Ibuprofen dissolution from liquid SE formulations examined in pH of 7.2 is immediate. The adsorption of the liquid onto the particles of the silicate causes a decrease in the amount of the drug released. Finally, more ibuprofen is dissolved from S-SE that consist of the neutral grade of magnesium aluminometasilicate than from the formulations containing the alkaline silicate.KEY WORDS: dissolution, ibuprofen, labrasol, magnesium aluminometasilicate, self-emulsifying powder     

Naturally occurring apatite as a source of orthophosphate for growth of bacteria and algae

Several naturally occurring calcium-phosphate apatites which varied in crystalline structure and ionic composition were added as crystals of different particle size to P-free (<1g/liter total P) nutrient media. Sufficient ortho-PO ₄ ^3– was released by the partial dissolution of apatite crystals at limnetic pH levels (pH 7.8) to support growth of several unialgal-mixed bacterial cultures. The biomass produced by mixed populations increased as the amount of available apatite was increased and as the pH of the media and the particle size of the apatite crystals were decreased. These findings suggest that although apatite characteristically displays reduced solubility under alkaline conditions, the tons of apatite which are continuously entering aquatic environments as erosion material may be contributing to the P loading of those ecosystems.     

Formulation Development of Morphine Sulfate Sustained-Release Tablets and Its Bioequivalence Study in Healthy Thai Volunteers

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C _max and AUC_s were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C _max and AUC_s between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC_last and AUC_inf between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4–102.6% and 87.7–139.4%, respectively. However, the C _max of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0–93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.     

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations

This study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by thef ₂ metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean C_max and AUC_inf for the small batch of propranolol were 79.0 μ g/L and 536 μ g/L/hr and for the large batch they were 83.5 μ g/L and 575 μ g/L/hr. C_max and AUC_inf for the small batch of metoprolol were found to be 95.5 μ g/L and 507 μ g/L/hr and for the large batch, 95.1 μ g/L and 495 μ g/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for InC_max, and InAUC_inf for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.     

Bio-Dis and the Paddle Dissolution Apparatuses Applied to the Release Characterization of Ketoprofen from Hypromellose Matrices

The purposes of this work were: (1) to comparatively evaluate the effects of hypromellose viscosity grade and content on ketoprofen release from matrix tablets, using Bio-Dis and the paddle apparatuses, (2) to investigate the influence of the pH of the dissolution medium on drug release. Furthermore, since direct compression had not shown to be appropriate to obtain the matrices under study, it was also an objective (3) to evaluate the impact of granulation on drug release process. Six formulations of ketoprofen matrix tablets were obtained by compression, with or without previous granulation, varying the content and viscosity grade of hypromellose. Dissolution tests were carried out at a fixed pH, in each experiment, with the paddle method (pH 4.5, 6.0, 6.8, or 7.2), while a pH gradient was used in Bio-Dis (pH 1.2 to 7.2). The higher the hypromellose viscosity grade and content were, the lower the amount of ketoprofen released was in both apparatuses, the content effect being more expressive. Drug dissolution enhanced with the increase of the pH of the medium due to its pH-dependent solubility. Granulation caused an increase in drug dissolution and modified the mechanism of the release process.Key words: apparatus 3, Bio-Dis, dissolution, hypromellose matrix, ketoprofen     

A highly sensitive photometric method for proton release or uptake: Difference protometry

A highly sensitive quantitative method was developed to detect protons released or taken up upon ligand binding. A small change in pH due to proton release or uptake was detected by measuring the difference in the absorbance of a pH indicator upon ligand addition. Owing to the difference detection of protons, the uncertainty of pH due to CO₂ dissolution and unknown buffering capacities of sample solutes could be compensated with easy manipulations. Precise calibration of the absolute amount of protons could also be made very easily. The amount of protons measurable by the method is as small as 0.5 nmol that is 10 to 30 times more sensitive than the pH-stat method. We measured the Mg²⁺ ion-induced proton releases of ADP to confirm the accuracy and reliability of the method and of Escherichia coli ribosomes to show the improvement in sensitivity. The method is useful for protometric studies of biomolecules that are difficult to obtain in large amount.     

Permeation and Distribution of Ferulic Acid and Its α-Cyclodextrin Complex from Different Formulations in Hairless Rat Skin

Ferulic acid (FA) is a natural product that occurs in seeds of many plants where it is generally located in the bran. This compound is a multifunctional ingredient endowed with antioxidative, radical scavenging, sunscreening and antibacterial actions. The aim of this study was to analyse the ferulic acid cutaneous permeation and distribution, through and into the skin layers, from different cosmetic vehicles, an O/W emulsion (pH 6.0) and two gel-type formulations at different pH levels (6.0 and 7.4), containing FA alone or an inclusion complex with α-cyclodextrin (CD-FA). In vitro permeation studies were performed in vertical diffusion cells using hairless rat excised skin. At appropriate intervals of time, the amount of permeated sunscreen/radical scavenger was evaluated by high-performance liquid chromatography (HPLC). At the end of experiments, treated skin samples were sectioned with a cryomicrotome and the FA content of the individual slices was analysed by HPLC. FA-containing formulations, O/W emulsion, gels A and B, originated FA fluxes of 8.48 ± 2.31, 8.38 ± 0.89 and 5.72 ± 0.50 μg/cm² h, respectively, thus suggesting the pH influence on FA percutaneous permeation. The use of the inclusion complex, CD-FA, determined in all cases a decrease of FA transdermal permeation while no influence of pH was observed. Gel-type formulations containing FA ensured higher sunscreen storage in the superficial layers if compared with O/W emulsion. When FA was included in α-cyclodextrin, FA amount retained into skin layers decreased markedly.