Co-crystallization of Amoxicillin Trihydrate and Potassium Clavulanate Provides a Promising Approach for Preparation of Sustained-Release Microspheres.

This work aimed to prepare sustained-release microspheres for amoxicillin trihydrate and potassium clavulanate. Co-crystals of amoxicillin trihydrate and potassium clavulanate were prepared using three different techniques, including supercritical fluid technology. Full characterization was performed for the prepared co-crystals, including molecular dynamic simulation. Next, the co-crystals were microencapsulated with ethylcellulose using the emulsion solvent evaporation method in spherical microspheres. Physicochemical characterizations for the prepared co-crystal were performed using FTIR, DSC, and PXRD. Finally, scanning electron microscopy was used to assess the morphology of the prepared microspheres. Physicochemical studies showed the solid-state interaction between amoxicillin trihydrate and potassium clavulanate in the prepared co-crystals. The total energy suggested differences between the three methods of co-crystal preparations suggesting some structural changes have occurred with better stabilization at supercritical fluid technology. Encapsulation of the co-crystals was successfully performed using ethylcellulose polymer. The in vitro release studies revealed sustained-release profiles for the co-crystal microspheres. Potassium clavulanate was released at a lower rate from the crystal microspheres prepared using co-crystals than the release in microspheres of potassium clavulanate alone. The empirical Higuchi model best fitted the in vitro release profile for amoxicillin trihydrate-potassium clavulanate co-crystal microspheres.

Preparation and characterization of ethylcellulose microspheres for sustained-release of pregabalin.

BACKGROUND AND PURPOSE: Pregabalin is used in the treatment of epilepsy, chronic pain, and other psychological disorders. Preparation of pregabalin in the sustained-release formulation will enhance patient compliance and reduce the incidence of side effects. The aim of this study was to prepare sustained-release microspheres for pregabalin utilizing ethylcellulose and evaluate the processing factors that influence the fabrication and the performance of the prepared microspheres. EXPERIMENTAL APPROACH: The microspheres were prepared using the water-oil-oil double emulsion solvent evaporation method. Microspheres were characterized for particle size, encapsulation efficiency, and in vitro drug release. The influence of the processing variables on the characteristics of the prepared microspheres was studied. Microspheres solid-state characterization performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and scanning electron microscopy. FINDINGS/RESULTS: The results described in the context of the current work illustrated the suitability of the water-oil-oil system in the preparation of sustained-release microspheres for pregabalin. The optimum formulation was prepared at a drug to polymer ratio of 1:3 w/w, stirring speed of 600 rpm, surfactant concentration of 1.5%, and external phase volume of 150 mL. This formula produced microspheres particle size in the range 600-1000 µm, with 87.6% yield, and 80.14 ± 0.53% encapsulation efficiency. Drug release from the microspheres was found to be diffusion controlled, with a pH-independent behavior. CONCLUSION AND IMPLICATION: The current work presented a successful attempt to fabricate a sustained-release microsphere comprising pregabalin. This will help overcome the frequent dosing problems with conventional pregabalin dosage forms and improve product performance.

Vitamin D Pretreatment Attenuates Ciprofloxacin-Induced Antibacterial Activity.

BACKGROUND: Ciprofloxacin is an antimicrobial that is commonly used to treat several types of infections. It exerts its antimicrobial activity through interfering with bacterial DNA replication and transcription, leading to increase oxidative stress and eventually bacterial death. Vitamin D, on the other hand, has been found to have DNA protective and antioxidant effects. In the current study, the possible interactive effect of vitamin D on ciprofloxacin-induced cytotoxicity was investigated in various standard bacterial strains. METHODS: The bacterial strains that were used include Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Acinetobacter baumannii, Proteus mirabilis, and Klebsiella pneumoniae. The antibacterial effect of ciprofloxacin with and without vitamin D treatment of the bacteria was assessed using disc diffusion method and by measuring the minimum inhibitory concentration (MIC) and zones of inhibition of bacterial growth. Moreover, reactive oxygen species (ROS) generation after pretreatment of E. Coli cells with ciprofloxacin and/or vitamin D was measured as a function of as a function of hydrogen peroxide generation. RESULTS: Ciprofloxacin demonstrated a potent antibacterial effect against the tested strains of bacteria. Moreover, pretreatment with vitamin D resulted in protecting the bacteria from the cytotoxicity of ciprofloxacin, this was indicated by the significantly smaller zones of inhibition and higher MIC values compared to ciprofloxacin alone as well as reduced ciprofloxacin-induced ROS generation after treatment with vitamin D. CONCLUSION: Results revealed the possible reduction in the activity of ciprofloxacin when used in combination with vitamin D. This could be explained by the ability of vitamin D to reduce oxidative stress in the bacterial cells.

Delivery of Peptidic Gonadotropin Releasing Hormone Antagonists.

GnRH antagonists have several clinical applications in prostate cancer, regulation of ovulation induction in females, breast cancer, male contraception and others. Antagonists differ from natural GnRH decapeptide in having five or more amino acid substitutions, whereas most of the antagonists are available as subcutaneous (SC) formula for injection some are formulated as a depot formulation for sustained release (e.g., Cetrorelix, Degarelix). Systemic delivery of cetrorelix acetate by intratracheal route can be achieved using dry powder for inhalation of the adhesive mixture when the powder deposition reaches stage four. The oral route for systemic delivery of peptide without its degradation can be achieved using gastrointestinal permeation enhancement technology GIPET® provided by acyline.

Preparation and characterization of microemulsion formulations of nicotinic acid and its prodrugs for transdermal delivery.

At pharmacological doses, nicotinic acid has a lipid-regulating effect and is in use clinically for that purpose. However, despite of all features, its utility is strongly limited by several disadvantages such as, extensive hepatic metabolism and flushing. Transdermal delivery of nicotinic acid may, therefore, be the solution to reducing side effects associated with oral administration, and to maintaining constant therapeutic blood levels for longer duration. The aim of this investigation was to develop a suitable formulation or select a suitable vehicle for the transdermal delivery of highly lipophilic prodrugs of nicotinic acid (dodecyl and myristyl nicotinate) designed to deliver nicotinic acid through skin without causing vasodilatation and flushing and optimizing its delivery to the blood stream. A microemulsion system and penetration enhancers have been attempted in this study. The microemulsion system was composed of isopropyl myristate (IPM), water and a 4:1 (w/w) mixture of Labrasol and Peceol where a pseudoternary phase diagram was constructed. Furthermore, the microemulsion formulations with different component ratios were characterized by determination of conductivity, pH, particle size, viscosity and refractive index. According to the particle size analysis, conductivity and viscosity measurements, the microemulsion formulations that formed were of oil-in-water type. The transdermal permeability of nicotinic acid and its prodrugs was evaluated in vitro using Franz diffusion cells fitted with mice skin and nicotinic acid concentration was analyzed by high performance liquid chromatography. A theoretical design of percutaneous penetration optimization in which prodrugs derivation and enhancer application are combined based on the skin diffusion model was experimentally verified. The selected formulations seemed promising for developing a transdermal drug delivery system of nicotinic acid from dodecyl nicotinate that would offer advantages like possible controlled drug release, reduced flushing, increased drug stability and ease of large-scale production.

Release behaviour of diclofenac sodium dispersed in Gelucire and encapsulated with alginate beads.

Sustained release polymeric particles containing diclofenac sodium dispersed in Gelucire matrix and encapsulated in calcium alginate shell were prepared with different drug-to-polymer ratios and also with different concentrations of sodium alginate for a fixed drug-to-polymer ratio in an aqueous environment. Spherical particles were formed by dropping an emulsion of diclofenac sodium in Gelucire matrix, emulsified with sodium alginate, into calcium chloride solution. The gelled beads formed by ionotropic gelation of alginate with calcium ions showed sustained release of the water soluble drug in in-vitro release study. Drug release was a function of square-root of time, suggesting a matrix diffusion release pattern. The rate of release was significantly suppressed with increasing proportions of Gelucire in the mixture. Sustained and complete release was achieved with Gelucire of low melting point and low HLB value. No significant drug release occurred in a dissolution medium of pH 1.5, whereas complete release was observed at pH 6.8, consistent with considerable swelling of the alginate gel at this pH.

Synthesis of piperazinylalkyl ester prodrugs of ketorolac and their in vitro evaluation for transdermal delivery.

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37 degrees C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t(1/2) = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t(1/2) in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P(app) was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.

Effect of microenvironment pH of swellable and erodable buffered matrices on the release characteristics of diclofenac sodium.

The aim of this work is to design pH-dependent swellable and erodable-buffered matrices and to study the effect of the microenvironment pH on the release pattern of diclofenac sodium. Buffered matrix tablets containing diclofenac sodium, physically mixed with hydrophilic polymer (hydroxypropyl methylcellulose [HPMC]) and pH-dependent solubility polymer (Eudragit L100-55) were prepared with different microenvironment pHs. The release of diclofenac sodium from the buffer matrices was studied in phosphate buffer solutions of pH 5.9 and 7.4. The swelling and erosion matrices containing only HPMC and Eudragit L100-55 were studied in phosphate buffer solution of pH similar to the microenvironment pHs of the matrices. Drug release from matrices was found to be linear as a function of time. Amount of drug released was found to be higher in the medium of pH 7.4 than that of pH 5.9. The rate of drug release increased with the increase of the microenvironment pH of the matrices as determined from the slope. The pattern of drug release did not change with the change of microenvironment pH. The swelling and erosion occurred simultaneously from matrices made up of HPMC and Eudragit L100-55. Both extent of swelling and erosion increased with increase of the medium pH. It was concluded from this study that changing the pH within the matrix influenced the rate of release of the drug without affecting the release pattern.