Mucoadhesive tablets for buccal administration containing sodium nimesulide.

The possibility of improving the flux of nimesulide across the buccal mucosa using the drug in the form of a sodium salt was investigated in our study. The salt form may increase to flux across buccal membrane, starting from a suspension; its lower permeation coefficient is compensated by a higher concentration gradient. The salt was inserted into a mucoadhesive tablet for buccal administration. The tablets were designed to prevent the loss of the drug into the saliva by means of a protective layer and placed on the area not in contact with the mucosa. Ten volunteers were used. The in vitro release from mucoadhesive tablets was examined through a porcine buccal mucosa, using a standard Franz cell, modified for present purposes. The advantages of a higher concentration gradient for the flux, related to a higher solubility of the salt, and to a sufficiently high permeation coefficient of the drug, despite the ionized form, could not be completely exploited, because the composition of the formulation destroys the chemical form of the drug.

Degradation of components in drug formulations: a comparison between HPLC and DSC methods.

Information about the stability of drug components and drug formulations is needed to predict the shelf-life of the final products. The studies on the interaction between the drug and the excipients may be carried out by means of accelerated stability tests followed by analytical determination of the active principle (HPLC and other methods) and by means of the differential scanning calorimetry (DSC). This research has been focused to the acetyl salicylic acid (ASA) physical-chemical characterisation by using DSC method in order to evaluate its compatibility with some of the most used excipients. It was possible to show, with the DSC method, the incompatibility of magnesium stearate with ASA; the HPLC data confirm the reduction of ASA concentration in the presence of magnesium stearate. With the other excipients the characteristic endotherms of the drug were always present and no or little degradation was observed with the accelerated stability tests. Therefore, the results with the DSC method are comparable and in good agreement with the results obtained with other methods.

In vitro permeation through porcine buccal mucosa of caffeic acid phenetyl ester (CAPE) from a topical mucoadhesive gel containing propolis.

Recent studies have shown that propolis has on the oral cavity appreciable antibacterial, antifungal and antiviral actions, as well as anti-inflammatory, anaesthetic and cytostatic properties. In light of these studies, an assessment of the diffusion and permeation of caffeic acid phenetyl ester (CAPE) through porcine buccal mucosa was considered useful as a possible application in the stomatological field. To do so, a mucoadhesive topical gel was prepared to apply to the buccal mucosa. The gel was formulated in such a way as to improve the solubility of the propolis, conducting to an increase of the flux. The mucosal permeation of CAPE from the formulation was evaluated using Franz cells, with porcine buccal mucosa as septum between the formulation (donor compartment) and the receptor phase chamber. The diffusion through the membrane was determined by evaluating the amount of CAPE present in the receiving solution, the flux and the permeation coefficient (at the steady state) in the different formulations at set intervals. Qualitative and quantitative determinations were done by HPLC analysis. From the results, CAPE allowed a high permeability coefficient in comparison to the coefficient of other molecules, as expected from its physical-chemical structure. Moreover, the developed gel improved the CAPE flux approximately 35 times more with respect to an ethanol solution formulated at the same gel concentration. The developed gel was also tested in order to evaluate the mucoadhesive behaviour and comfort in vivo on 10 volunteers in a period of 8 h. The in vivo evaluation of mucoadhesive gel revealed adequate comfort and non-irritancy during the period of study and it was well accepted by the volunteers.

Correlation between the transdermal permeation of ketoprofen and its solubility in mixtures of a pH 6.5 phosphate buffer and various solvents.

The passage of a drug through the skin is directly proportional to the concentration of the drug in the donor phase and to the permeability coefficient constant Kp. Kp is determined essentially by two factors: the dissolution of the drug in the stratum corneum (measured by the partition coefficient P) and the diffusion in the same stratum (measured by the diffusion constant D). In our study, several saturated solutions of ketoprofen in mixtures of a pH 6.5 phosphate buffer and various co-solvents were studied to find correlations between the solubility of the ketoprofen in the mixtures and its permeation parameters in in vitro permeation studies with Franz cells. The results show that D does not change in the different mixtures; the diffusion of the drug into the stratum corneum is not influenced by the presence of the co-solvents, whereas the partition coefficient is strongly influenced. In particular, Kp and P were found to be inversely proportional to solubility, meaning that when the co-solvent increases the solubility, the partition of the drug and consequently Kp decrease. These findings were confirmed in some developed gels, and the developed gels were found to enhance the ketoprofen permeation with respect to the formulation in a commercial Fastum gel.

In vitro permeation screening of a new formulation of thiocolchicoside containing various enhancers.

Thiocolchicoside, a muscle relaxant agent with anti-inflammatory and analgesic actions, also is used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. In this study, thiocolchicoside was formulated to use as foam to avoid contact with the afflicted area during the spreading phase. To enhance drug penetration, various enhancers were added to the base formulation. The tested enhancers were ethoxyethylendiglycol (Transcutol), highly purified phosphatidylcholine (Lipoid S20), capsaicin, propylene glycol dipelargonate (DPPG), and glycolysed ethoxylated glycerides (Labrafil M1944 CS). The transdermal absorption of the tested formulations containing enhancers, in comparison with base formulation, was evaluated in vitro through rat skin using standard Franz diffusion cells. Base formulation was found to have a higher permeation profile than the simple aqueous and hydroalcoholic solutions of the drug, meaning that the base formulation by itself enhances the drug permeation. Among the tested formulations, only the formulation containing DPPG/ethanol was found to be statistically different, showing an enhancement factor of 3.58. In the same experimental session, Muscoril ointment, the commercially available pharmaceutical product containing the same thiocolchicoside concentration (0.25%), also was tested. The formulation containing DPPG/ethanol showed a 4.86 times increase of permeability constant in comparison with Muscoril ointment. The formulation containing DPPG/ethanol as an enhancer could be a good candidate for a new topical foam, considering its good characteristics of permeability and compliance.

Development of a mucoadhesive dosage form for vaginal administration.

The antimycotic imidazole derivative clotrimazole is employed locally for the treatment of genitourinary tract mycotic infections and is formulated as creams, foams, tablets, gels, irrigations, or pessaries. In this study, a new dosage form was developed by including bioadhesive polymers (polycarbophyl, hydroxypropylmethylcellulose, and hyaluronic sodium salt) into pessaries made of semisynthetic solid triglycerides. These polymers hold the delivery systems in the vaginal tract for a few days without any toxic effects or important physiological modifications, prolonging the permanence of the drug on the vaginal mucosa. Technological controls (compatibility with differential scanning calorimetry [DSC] studies, particle size analysis, and liquefaction time test) and biopharmaceutics studies for the evaluation of the release of the drug from the dosage form and of the bioadhesive properties were carried out. Moreover, a new test for the evaluation of the permanence of the drug in a simulated application site was developed from a modification of the Satnikar and Fantelli method for the evaluation of the liquefaction time of rectal suppositories. This test simulates the physiological vaginal condition and verifies the efficiency of the polymers in prolonging the permanence of the dosage form in the location where it is applied. The technological controls demonstrated that the presence of the polymers did not have an influence on the characteristics of the pessaries. On the other hand, there was an improvement in adhesivity of the pessaries in the in vitro adhesion test and prolonging of the liquefaction time in the liquefaction time test in the presence of mucoadhesive polymers, which increased with increasing polymer concentration. The presence of the mucoadhesive had a large influence on the permanence of the drug in the simulated application site because it modified the distribution of the drug along the simulated application site. In conclusion, the developed new formulations showed good technological and adhesion properties and the capacity of hold the dosage form in the target site. Among the employed bioadhesive polymers, the best behavior in the performed test was by polycarbophyl at its maximum concentration.

Design and evaluation of buccal adhesive hydrocortisone acetate (HCA) tablets.

Many studies have shown that topical buccal therapy with steroid anti-inflammatory drugs is useful in controlling ulcerative and inflammatory mucosal diseases. This local treatment is based on the concept that a high activity of steroids can be produced at the site of administration and, at the same time, the degree of systemic side effects can be minimized or avoided. In this study we developed a new formulation consisting of a mucoadhesive tablet formulation for buccal administration of hydrocortisone acetate (HCA). Three types of tablet were developed containing three mucoadhesive components: hydroxypropylmethyl cellulose (Methocel K4M), carboxyvinyl polymer (Carbopol 974P), and polycarbophyl (Noveon AA1); the first polymer is a cellulose derivative, the others are both polyacrylic acid derivatives. For each of those, three tablet batches were produced changing the quantity of the mucoadhesive component (10, 20, and 30%), resulting in 9 different formulations. The compatibility of HCA with all excipients using Differential Scanning Calorimetry (DSC) was assessed. Tablets were manufactured by wet granulation followed by compression. Technological controls on granulates (Hausner index, Carr index, granulometry and Karl-Fischer percentage humidity) and tablets (thickness, diameter, friability, hardness, uniformity of content, weigh uniformity and dissolution kinetic) were carried out. Mucoadhesion properties, ex vivo permeability through porcine buccal mucosa, in vivo behavior and compliance were evaluated. Technological controls have demonstrated that the increase in the (percentage) of mucoadhesive causes an increase in granulometry followed by a reduction in the granulate flowability, however all the tablets have given satisfactory technological results and conformed to the 3rd Ed. European Pharmacopoeia specifications. Mucoadhesion, ex vivo permeability and in vivo behavior results notably differed among tablets, depending on the quality and quantity of the mucoadhesive component. An overall comparison of results showed the tablets containing Carbopol 20% resulted to be the best formulation among those developed.

Analysis of all-in-one parenteral nutrition admixtures by liquid chromatography and laser diffraction: study of stability.

All-in-one parenteral nutrition admixtures are complex lipid emulsions (oil/water) which require absolute sterility, stability and no precipitates. Particle diameter must be in the range 0.4--1 microm in order to mime the size of chylomicra. Added vitamins must not degrade during infusion time (24 h). In this study, the physicochemical stability of parenteral nutrition admixtures was tested in the course of time at different storage temperatures. Two liquid chromatographic methods, based on solid phase extraction (SPE), were developed for fat-soluble vitamin determination. Stability studies were carried out on three industrial lipid emulsions and on six compounded all-in-one admixtures. They were stored at three different temperatures: 4 degrees C (storage), 25 degrees C (compounding) and 37 degrees C (infusion); then they were analyzed at starting time and at 24, 48 and 72 h after compounding. Particle diameter was determined by means of Laser Particle Sizer Analysette 22, which uses laser diffraction technique (light scattering -- reverse Fourier optics). Fat-soluble vitamins (retinol palmitate and alpha-, delta-, gamma-tocopherol) were determined in admixtures with a branded vitamin compound called Idroplurivit Liofilizzato. Samples were extracted by SPE on C(18) cartridges, then they were separated by reversed-phase liquid chromatography (LC) and detected by ultraviolet detection (retinol palmitate) and electrochemical detection (tocopherols). Laser diffraction analysis pointed out that particle size did not change in the course of time at the tested temperatures. LC analysis showed that vitamins interact each other and degrade after compounding at different times and storage temperatures; only retinol palmitate is stable at 37 degrees C. Retinol palmitate recovery was 98%, coefficient of variation (CV) 5.4%, detection limit 25 microg/l, limit of quantitation 75 microg/l and there were not interfering substances. Tocopherols average recovery was 99%, CV 3.5%, detection limit 15 ng/l and limit of quantitation 50 ng/l. In conclusion, all-in-one parenteral admixtures were proved to be physically stable under analysis conditions, but degradation of retinol palmitate and tocopherols requires admixtures with vitamins to be infused within 24 h after compounding.

In vitro permeation through porcine buccal mucosa of Salvia desoleana Atzei & Picci essential oil from topical formulations.

In the light of recent studies, which have shown that the essential oil derived from some Lamiaceae species has appreciable anti-inflammatory activity, moderate anti-microbial action and the ability to inhibit induced hyperalgesia, an assessment of the diffusion and permeation of Salvia desoleana Atzei & Picci (S. desoleana) essential oil through porcine buccal mucosa was considered useful for a possible application in the stomatological field. Topical formulations (microemulsions, hydrogels and microemulsion-hydrogels) were prepared for application to the buccal mucosa. The mucosa permeation of the oil from the formulations was evaluated using Franz cells, with porcine buccal mucosa as septum between the formulations (donor compartment) and the receptor phase chambers. The study also aimed at optimising the permeability of the S. desoleana essential oil by means of an enhancer, the diethylene glycol monoethyl ether Transcutol. The diffusion of the oil through the membrane was determined by evaluating the amount of essential oil components present in the receiving solution, the flux and the permeation coefficient (at the steady state) in the different formulations at set intervals. Qualitative and quantitative determinations were done by gas chromatographic analysis. All the formulations allow a high permeability coefficient in comparison with the pure essential oil. In particular, the components with a terpenic structure (beta-pinene, cineole, alpha-terpineol and linalool) have the highest capacity to pass through the porcine buccal mucosa when compared to the other components (linalyl acetate and alpha-terpinil acetate). Moreover, the enhancer, diethylene glycol monoethyl ether largely increases the permeation of the essential oil components in relation to the concentration.

Optimization of a tablet containing chlorthalidone.

In pharmaceutical technological research, optimization studies generally deal with the search for the formulation that is as effective and as functional as possible. The effect of a formulation parameter (the amount of lactose in the composition of the tablets) and of a technological parameter (compression pressure) on four physical characteristics (tablet thickness, friability, hardness, and drug dissolution rate) of tablets containing the antihypertensive drug chlorthalidone were studied. The results obtained indicate that, in the development of a tablet formulation, it is possible to identify the most suitable formulation by applying a simple optimization method. The effect of the microclimatic stress (temperature and humidity) was also evaluated, and it was found that the optimized tablets were no longer within limits that had been established for them. This may indicate that it is opportune to keep the storage conditions of the excipients under control before their use.

Design and evaluation of a new transdermal formulation containing chlorpheniramine maleate.

The antihistamine chlorpheniramine maleate (CPM) is used for symptomatic relief of hypersensitive reactions and in pruritic skin disorders. The objective of the present study was to develop a topical formulation that contained CPM to increase patient compliance. Compliance was increased by exploiting foams that, given their application methods, avoid direct contact with the afflicted area. The study also aimed to optimize the permeability of the CPM by discerning an adequate carrier, as well as choosing the correct enhancer. The foams were formulated using aqueous solutions. In vitro studies were carried out using Franz cells with the formulations, as well as with the available pharmaceutical product Polarmin Crema, which contains CPM. These studies showed that the permeability of the CPM in the solutions is increased more then 100 times with respect to the water-in-oil emulsion Polarmin Crema. In particular, the highest permeability was obtained using limonene as an enhancer.