Giancarlo Ceschel

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.

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.

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.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.

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.

Solubility and Transdermal Permeation Properties of a Dehydroepiandrosterone Cyclodextrin Complex from Hydrophilic and Lipophilic Vehicles

The permeation ability of a compound is due principally to its concentration in the vehicle and to its aptitude to cross the stratum corneum of the skin. In this work ex-vivo permeation studies on newly developed formulations containing dehydroepiandrosterone (DHEA) were carried out to investigate vehicles that increase drug permeation through the skin. To enhance the solubility of DHEA, its complex form with α-cyclodextrin was used. In addition, the two forms (pure drug and complex form) were introduced in hydrophilic (water), lipophilic (paraffin oil), and microemulsion vehicles to evaluate the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation. From the results, DHEA solubility is notably conditioned by the type of the vehicle used: the highest solubilities (both for pure and complex drug forms) were obtained with microemulsion, followed by paraffin oil and water. Moreover, in all the studied vehicles, the c-DHEA was more soluble than DHEA. Permeation profile fluxes showed very interesting differences. That reflect the varying drug forms (pure drug and complex form), vehicles used, and drug concentrations in the vehicles. The major flux was obtained in complex of DHEA with α-cyclodextrins in the microemulsion vehicle. Therefore, this type of vehicle and drug form would be very useful in the development of a topical formulation containing DHEA.

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.

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.

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.

Bimodal release of olanzapine from lipid microspheres

Olanzapine was formulated as 10% (w/w) mixture with cutina to which stearic acid was added, ranging from 10% to 90% (w/w) of the total mass to control the drug release. The molten mixtures were processed by ultrasound-assisted spray-congealing technique, obtaining solid microspheres. The drug is stable under these conditions and only a partial miscibility in the solid state was observed by DSC between the two fatty materials with two separated melting endotherms in the thermograms: this can be due to the presence of two phases inside the solid dispersion. Olanzapine is distributed into the two phases according to its partition coefficient: two phases make the system less suitable to crystallization of the drug; the loading of the drug could reach saturation with difficulty and the rate of the olanzapine release is differentiated, since the drug is released from two different carriers. Dissolution profiles suggest occurrence of a bimodal release, where each portion of the release profile is linear and the slope increases with a higher content of stearic acid in the carrier mixture, that behaves as a release promoter. Tests were also carried out with palmitic and lauric acids for comparison and also for systems in the absence of ultrasound.

Design and in vitro-in vivo evaluation of a bi-layered tablet containing benzocaine for local buccal administration

Benzocaine is used in the stomatological field as regional anaesthetic for dental procedures and in the treatment of oral mucositis pain resulting from chemotherapy. In this study, double layered tablets containing benzocaine were specifically developed for local buccal administration. The tablets are made up of a mucoadhesive layer containing the drug and a protective layer covering the lower layer. The objective of the study was to create a tablet able to adhere to the buccal mucosa while giving local controlled release of the drug. A number of tablets were developed having different release rates and different protective layer thicknesses. In order to study the drug release from the mucoadhesive layer of the tablets, four different types of in vitro testing activities were performed. Initially, testing was carried out using a specific new apparatus developed to replicate the physiological conditions in the oral cavity. Testing was also carried out using the official release method by means of the USP 23/NF paddle apparatus. The third cycle of evaluation used a modified version of the paddle apparatus. While the last type of test was carried out in modified Franz diffusion cells allowing a contemporaneous study of the drug release rate from the tablets and of the drug permeation through the buccal mucosa. In vitro tests results were compared to in vivo release test results. In vitro and in vivo experiments pointed out that, of the tablets studied, the bi-layered tablets with the thickest protective layers were the most efficient in guaranteeing a controlled and prolonged release of the drug towards the mucosa. Of the in vitro release tests, the Franz diffusion cell test gave the release profile that most closely resembled the in vivo data.