Encapsulation and modified-release of thymol from oral microparticles as adjuvant or substitute to current medications.

The aim of this study was to encapsulate, thymol, in natural polymers in order to obtain (i) taste masking effect and, then, enhancing its palatability and (ii) two formulations for systemic and local delivery of herbal drug as adjuvants or substitutes to current medications to prevent and treat several human and animal diseases. Microspheres based on methylcellulose or hydroxypropyl methylcellulose phthalate (HPMCP) were prepared by spray drying technique. Microparticles were in vitro characterized in terms of yield of production, drug content and encapsulation efficiency, particle size, morphology and drug release. Both formulations were in vivo orally administered and pharmacokinetic analysis was carried out. The polymers used affect the release and, then, the pharmacokinetic profile of thymol. Encapsulation into methylcellulose microspheres leads to short half/life but bioavailability remarkably increases compared to the free thymol. In contrast, enteric formulation based on HPMCP shows very limited systemic absorption. These formulations could be proposed as alternative or adjuvants for controlling pathogen infections in human or animal. In particular, methylcellulose microspheres can be used for thymol systemic administration at low doses and HPMCP particles for local treatment of intestinal infections.

Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies.

The nasal route is used both for local therapies and, more recently, for the systemic administration of drugs, as well as for the delivery of peptides and vaccines. In this study the nasal administration of Carbamazepine (CBZ) has been studied using microspheres constituted by chitosan hydrochloride (CH) or chitosan glutamate (CG). Blank microspheres were also prepared as a comparison. The microspheres were produced using a spray-drying technique and characterized in terms of morphology (scanning electron microscopy, SEM), drug content, particle size (laser diffraction method) and thermal behaviour (differential scanning calorimetry, DSC). In vitro drug release studies were performed in phosphate buffer (pH 7.0). In vivo tests were carried out in sheep using the microparticles containing chitosan glutamate, chosen on the basis of the results of in vitro studies. The results were compared to those obtained after the nasal administration of CBZ (raw material) alone. For the evaluation of in vivo data statistical analysis was carried out using the unpaired t-test. Spray-drying was a good technique of preparation of CBZ-loaded microspheres. The loading of the drug into the polymeric network always led to an increase in the dissolution rate compared to CBZ raw material. The microspheres obtained using chitosan glutamate had the best behaviour both in vitro and in vivo. They increased the drug concentration in the serum when compared to the nasal administration of the pure drug (Cmax 800 and 25 ng/ml for microspheres and pure drug, respectively). The results obtained indicate that the loading of CBZ in chitosan glutamate microspheres increases the amount of the drug absorbed through the nose.

Tabletted microspheres containing Cynara scolymus (var. Spinoso sardo) extract for the preparation of controlled release nutraceutical matrices.

Controlled release dosage forms based on tabletted microspheres containing fresh artichoke Cynara scolymus extract were performed for the oral administration of a nutritional supplement. Microspheres were prepared using a spray-drying technique; lactose or hypromellose have been chosen as excipients. Microspheres were characterized in terms of encapsulated extract content, size and morphology. Qualitative and quantitative composition of the extract before and after the spray process was determined. Compressed matrices (tablets) were prepared by direct compression of the spray-dried microspheres. In vitro release tests of microparticles and tablets prepared were carried out in both acidic and neutral media. Spray-drying is a good method to prepare microspheres containing the artichoke extract. The microspheres encapsulate an amount of extract close to the theoretical value. Particle size analyses indicate that the microparticles have dvs of approximately 6-7 microm. Electronic microscopy observations reveal that particles based on lactose have spherical shape and particles containing hypromellose are almost collapsed. The hydroalcoholic extract is stable to the microsphere production process: its polyphenolic composition (qualitative and quantitative) did not change after spraying. In vitro release studies show that microparticles characterized by a quick polyphenolic release both in acidic and neutral media due to the high water solubility of the carrier lactose. On the contrary, microspheres based hypromellose release only 20% of the loaded extract at pH 1.2 in 2 h and the total amount of polyphenols is released only after about further 6 h at pH 6.8. Matrices prepared tabletting lactose microspheres and hypromellose microparticles in the weight ratio 1:1 show a slow release rate, that lasts approximately 24 h. This one-a-day sustained release formulation containing Cynara scolymus extract could be proposed as a nutraceutical controlled release dosage form for oral administration.

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen.

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.

Emulsion spray-drying for the preparation of albumin-loaded PLGA microspheres.

The purpose of this work was to study the encapsulation of bovine serum albumin (BSA) in polylactide-co-glycolide (PLGA) microspheres using an emulsion/ spray-drying method. Albumin was dissolved in an aqueous phase (w) in the presence of surfactant and emulsified in an organic phase containing the polymer (o). To stabilize the emulsion, different types of surfactant (Pluronic F68, Pluronic F127, sodium oleate, dioctylsulfosuccinate) were added to the aqueous phase. The w/o emulsion was spray-dried to obtain BSA-loaded PLGA microspheres. The effect of type of surfactant on microsphere characteristics was evaluated. The microspheres were characterized for their morphology by scanning electron microscopy (SEM) and granulometric analysis; drug content determination and in vitro dissolution tests were performed. Results showed that the emulsion/spray-drying method is suitable for obtaining small microparticles (2-5 micron) characterized by high drug payloads (70%-80% encapsulation efficiency). The type of surfactant affects the microsphere shape and BSA release

Preparation and analgesic activity of Eudragit RS100 microparticles containing diflunisal.

Two different techniques, the quasi-emulsion solvent diffusion method and spray drying that provide polar and nonpolar preparation environments, were used to prepare microspheres from Eudragit RS100 (RS) (acrylic/methacrylic copolymer) incorporating the nonsteroidal anti-inflammatory drug diflunisal. The effects of pH on the preparation medium and drug/polymer ratio on production yield and drug incorporation, as well as on the in vitro drug release at pH 1.2 and 6.8 from tabletted microparticles, were evaluated. The drug-polymer interactions and the effect of diflunisal incorporation in the polymer matrix on drug crystallinity have been evaluated by using differential scanning calorimetry, IR and ultraviolet spectroscopy, x-ray diffraction, and microscopy analysis. A preliminary biological assay confirmed that diflunisal maintains its analgesic activity after intraperitoneal administration to rats.

Spray-dried microspheres containing ketoprofen formulated into capsules and tablets.

In this study, microspheres were prepared by a spray-drying technique using solutions of ketoprofen and two polymers, cellulose acetate butyrate (CAB) and hydroypropylmethylcellulose phthalate (HPMCP), in different weight ratios. Different total concentrations were used in the feed solutions: 3, 6 and 9% w/v. The spray-dried microparticles were characterized in terms of shape (SEM), size (light scattering method), production yield and encapsulation efficiency. They were formulated into capsules; tablets were prepared by direct compression of the microparticles mixed with maltose and, in some cases, hydroypropylmethylcellulose (HPMC). In vitro release studies were performed both at acidic and neutral pHs. The spray-drying process of solutions of ketoprofen with polymeric blends of cellulose derivatives leads to microparticles which, depending on their final formulation (capsules or tablets), can give a rapid or prolonged drug release. The formulations here described can be proposed for the oral administration of NSAIDs.

Tabletted polylactide microspheres prepared by a w/o emulsion-spray drying method.

An emulsification-spray drying technique is used to prepare poly(D,L-lactic acid) (PDLLA) microparticles loaded with a water soluble, non-steroidal anti-inflammatory drug (NSAID), sodium naproxen (NaNPX). The method involves the preparation of a w/o emulsion in which the water soluble drug is dissolved in the aqueous dispersed phase, while the polymer is dissolved in the organic continuous phase. As a comparison, microparticles were prepared by spraying a suspension of the drug into an organic solution of the polymer. The spray-dried particles were characterized using SEM, DSC, XRD and in vitro release tests. The spray-dried product was then compressed (direct compression) to obtain controlled release matrix tablets. All microparticles release NaNPX within 30 min. The matrix tablets release the drug in 8-10 h; the matrix tablets characterized by the presence of surfactant (due to the emulsion used to obtain the microparticles) have the highest release rate.

A calorimetric study on diflunisal release from poly(lactide-co-glycolide) microspheres by monitoring the drug effect on dipalmitoylphosphatidylcholine liposomes: temperature and drug loading influence.

Diflunisal release from poly-Lactide-co-Glycolide (50:50, 34,000 MW) microspheres loaded with two different amounts of drug (2.5 +/- 0.5% and 10 +/- 0.5% w/w) was monitored by following the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine unilamellar vesicles at different temperatures. The effects of the drug released from the microspheres on the thermotropic behavior of lipid aqueous dispersion containing different molar ratios of drug was detected by differential scanning calorimetry and was compared with the effects exerted by the free Diflunisal. Diflunisal affects mainly the temperature (Tm) of the transition characteristic of phospholipid vesicles as model biomembrane, causing a shift toward lower values. This shift was modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Afterward, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and differently Diflunisal-loaded microspheres as well as free powdered Diflunisal after incubation for increasing times at three different temperatures (25, 37, and 50 degrees C). The Tm shifts of the lipid bilayer, caused by the drug released from polymeric system as well as by the free drug during incubation periods, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres as well as by the temperature acting on drug solubility and membrane disorder. This drug release model, monitored by the calorimetric technique shows that a) the poly-Lactide-co-Glycolide microspheres are a good delivery system able to sustain the drug release; b) the differential scanning calorimetry technique applied on the drug interaction with biomembranes constitutes a good tool to follow the drug release; 3) this model, representing an innovative alternative in vitro model, should be used to determine the different kinetics involved in the drug transfer from a drug delivery system to a membrane as uptake site.

Polylactide microspheres for the modified release of corticosteroids.

A steroidal drug, prednisolone 21-acetate, has been incorporated into polylactide (PDLLA) microspheres using a single emulsion/evaporation technique. This paper describes the method used and the characterization of the microspheres obtained: morphology, particle size distribution, drug content, yield of production and in vitro drug release behaviour.

Enhancement of ursodeoxycholic acid bioavailability by cross-linked sodium carboxymethyl cellulose.

The bioavailability of ursodeoxycholic acid from a new formulation based on drug-loaded cross-linked sodium carboxymethyl cellulose was studied in man. The plasma levels of ursodeoxycholic acid were determined by gas chromatography-mass spectrometry after derivatization and sample purification by solid-phase extraction. Capsules containing the drug/polymer system were prepared and compared with conventional commercial ursodeoxycholic acid capsules after single oral administration using a randomized crossover experimental design. Although the drug/polymer system improved the in-vitro dissolution rate of ursodeoxycholic acid in simulated intestinal fluid, statistical evaluation of the area under the plasma concentration curves indicated no significant difference in the extent of bioavailability between the two formulations (14.93+/-4.43 vs 14.95+/-5.79 microM h; P > 0.2). However, following the administration of the ursodeoxycholic acid/cross-linked sodium carboxymethyl cellulose system with an enteric-coated capsule, the mean area under the plasma concentration curve (27.60+/-10.11 microM h) was significantly higher than that obtained after treatment with the commercially available ursodeoxycholic acid capsule (16.24+/-8-38 microM h; P < 0.05). We concluded that improved intestinal absorption of the drug was obtained with enteric-coated capsules filled with the ursodeoxycholic acid/polymer system. Moreover, the simplicity of the preparation and the non-toxicity of the polymer used as the carrier represented additional advantages of this dosage form.

Evaluation of alginate compressed matrices as prolonged drug delivery systems.

This research investigated the use of sodium alginate for the preparation of hydrophylic matrix tablets intended for prolonged drug release using ketoprofen as a model drug. The matrix tablets were prepared by direct compression using sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC) in different combinations and ratios. In vitro release tests and erosion studies of the matrix tablets were carried out in USP phosphate buffer (pH 7.4). Matrices consisting of sodium alginate alone or in combination with 10% and 20% of HPMC give a prolonged drug release at a fairly constant rate. Incorporation of different ratios of calcium gluconate leads to an enhancement of the release rate from the matrices and to the loss of the constant release rate of the drug. Only the matrices containing the highest quantity of HPMC (20%) maintained their capacity to release ketoprofen for a prolonged time.

Pectin microspheres as ophthalmic carriers for piroxicam: evaluation in vitro and in vivo in albino rabbits.

Microparticulate polymeric delivery systems have been suggested as a possible approach to improve the low bioavailability characteristics shown by standard ophthalmic vehicles (collyria). Purpose of this study was the evaluation of pectin microspheres as delivery system for piroxicam (Px). The microspheres were prepared by a spray-drying technique; their morphological characteristics were investigated by scanning electron microscopy (SEM), and their in vitro release behavior was evaluated in pH 7.0 USP buffer using a flow-through apparatus. Px loaded in the pectin microspheres showed a faster in vitro dissolution rate with respect to solid micronized drug. The precorneal retention of fluorescein-loaded microspheres was evaluated in vivo in albino rabbits: an aqueous dispersion of fluorescent microspheres showed a significantly increased residence time in the eye (2.5 vs. 0.5 h) when compared with a fluorescein solution. In vivo tests in rabbits of dispersions of Px-loaded microspheres also indicated a significant improvement of Px bioavailability in the aqueous humour (2.5-fold) when compared with commercial Px eyedrops. The potential advantages and limitations of this delivery system are discussed.

In vitro degradation study of polyester microspheres by a new HPLC method for monomer release determination.

Biodegradable polyesters have increasing importance as materials used for the preparation of microspheres. The knowledge of their degradation process is important to prepare microparticulate delivery systems with suitable drug release rates. In this work an in vitro degradation study of empty and drug loaded microspheres is described. Three different polyesters were used: two poly-d, l-lactides of different molecular weight and a poly-d, l-lactide-co-glycolide (50:50). Diazepam has been chosen as the model drug. Solvent evaporation and spray-drying were used as preparation methods. To study the polymer degradation process, a new HPLC method is proposed for the direct and (in the case of the copolymer) simultaneous determination of the monomer(s): lactic acid (LA) and glycolic acid (GA). SEM and particle size analysis highlight the different characteristics of the particles, depending on their preparation method: spray-dried spheres result to be always smaller with respect to particles obtained by solvent evaporation. The results obtained indicate in particular that: the preparation methods play an important role in determining the degradation behaviour of microspheres, as unloaded spray-dried particles are characterized by a higher monomer release rate with respect to microspheres obtained by solvent evaporation; PLGA spheres degrade faster than PDLLA microparticles, according to the higher hydrophilicity of the copolymer; the two monomers are released at a different rate in the case of PLGA (faster for GA, slower for LA); the presence of diazepam increases the polymer degradation rate, with respect to empty particles.

Polyorganophosphazene microspheres for drug release: polymer synthesis, microsphere preparation, in vitro and in vivo naproxen release.

Microsphere preparation for naproxen slow release was investigated using two newly prepared biodegradable polyorganophosphazenes, derivatized at the phosphorus atoms with phenylalanine ethyl ester and imidazole at molar ratios of 71/29 and 80/20. The polymers were prepared by substitution of the chloride atoms of polydichlorophosphazene with a phenylalanine ethyl ester-imidazole mixture followed, after 7 or 48 h reaction, by the addition of excess imidazole. Three methods of microsphere preparation have been considered: spray-drying, emulsion/solvent evaporation and emulsion/solvent evaporation-extraction. Microparticles obtained by spray-drying were found to possess a narrow distribution size with a mean diameter of 2-5 microm. Their internal structure consisted of a porous or empty core depending upon the solvent used for the preparation. Furthermore the microspheres prepared with this technique rapidly released the entrapped naproxen independently of the used polymer, the drug loading or the preparation process. On the other hand microspheres prepared by solvent evaporation or solvent evaporation-extraction showed a distribution size ranging between 10 and 100 microm. By the appropriate choice of pH and solvent composition of the external phase, naproxen could be entrapped, in these microspheres, with a yield higher of 80%. The polymer composition dictates the in vitro release rate of naproxen from the particles, which was faster when the microspheres were prepared with the polymer at higher imidazole content. In vivo experiments, carried out by subcutaneous implantation in rats of microspheres prepared by solvent evaporation, demonstrated that a constant level of naproxen in plasma could be maintained up to 400 h at a suitable concentration for antinflammatory activity.

Formulation and characterization of calcium alginate beads containing ampicillin.

The purpose of this work was the preparation and characterization of calcium alginate beads containing ampicillin. Aqueous solutions of drug and sodium alginate (three viscosity grades) were added drop by drop to aqueous solutions of calcium chloride; the droplets instantaneously formed gel beads, which were then dried. Morphological studies and drug contents, in vitro release, and erosion tests were carried out for the characterization of the prepared beads. The dried particles were characterized by irregular shape and a smooth or rough surface, depending on the viscosity grade of the alginate used. The control of the drug for different time intervals depended on the molecular weight of the polymer used; however, the pH-change test showed that this capacity was much lower in the case of acid-treated particles. The results obtained show that the ampicillin beads prepared are suitable for intramammary therapy.

Preparation and characterization of ampicillin loaded methylpyrrolidinone chitosan and chitosan microspheres.

Ampicillin was embedded in microparticles made of a new derivative of chitosan: methylpyrrolidinone chitosan. They were prepared using different drug-to-polymer weight ratios and by a spray-drying technique. Spray-dried drug-loaded chitosan microspheres were prepared for comparison. The microparticles were characterized by scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry (DSC) and in vitro drug release. Microbiological assay was performed using different bacterial strains. Spray-dried microspheres of almost spherical shape, smooth surface and narrow size distribution were always obtained. Ampicillin loaded into both polymer matrices showed amorphous behaviour as determined by DSC. Drug-loaded microspheres resulted to control the drug release in a 30-120 min range, depending on chitosan type. Thermal denaturation of the microspheres does not modify drug release rate. The results of the microbiological assay show that the loading of ampicillin into chitosans is able to maintain or improve the anti-bacterial activity of the drug.

PDLLA microspheres containing steroids: spray-drying, o/w and w/o/w emulsifications as preparation methods.

Hydrocortisone and its more soluble ester, hydrocortisone 21-acetate, have been incorporated into poly(D,L-lactic) acid (PDLLA) microspheres using single, double emulsion/solvent evaporation and by spray-drying techniques. This paper describes the characterization of the microparticles obtained (morphology, particle size distribution, drug content, yield of production, in vitro drug release behaviour) and a comparison of the results (drug loading, drug release, size of the microspheres) obtained from the different techniques used. These results demonstrate that by using a relatively more soluble ester of an insoluble steroid, hydrocortisone, the drug content within the microspheres can be increased, together with a high efficiency of loading, irrespective of the technique employed. In the case of hydrocortisone, spray-drying produces the highest loading and encapsulation efficiency compared to both single and double emulsion methods for microspheres of similar size (about 2-4 microns) and suitable for lung delivery, but with lower yields (about 55% versus about 33%).