Ketoprofen (1) an analgesic, antipyretic and anti-inflammatory agent, is practically insoluble in water. An increase in the aqueous solubility of 1 was attempted by various cosolvents. The solubility increased up to 8556 times (maximum) in case of ethanol while it was 33 times (minimum) in case of glycerol. Using selected cosolvents and hydrotropes, aqueous injections of 1 were formulated.
"Utilization of this method in the formulation of dosage forms made of water insoluble drugs can also reduce the concentration of individual hydrotropic agents, in order to minimize the side effects (in place of using a large concentration of one hydrotrope, a blend of several hydrotropes can be employed in much smaller concentrations, reducing their individual toxicities). Hydrotropic solubilization technique for the formulation development of aqueous injection of various poorly water-soluble drugs has also been demonstrated (23-27). "
[Show abstract][Hide abstract] ABSTRACT: Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID) that exhibits analgesic, antipyretic and anti-inflammatory activities. It is practically insoluble in water. The effect of hydrotropes such as urea and sodium citrate and blends (urea + sodium citrate) on the solubility of aceclofenac was investigated. The enhancement in the solubility of aceclofenac was more than 5 and 25 folds in 30% sodium citrate solution and 30% urea solution, respectively, as compared to its solubility in distilled water. The enhancement in the solubility of aceclofenac in a mixed hydrotropic solution containing ≥ 20% urea and 10% sodium citrate solution was more than 250 folds (compared to its solubility in distilled water). This proved a synergistic enhancement in solubility of a poorly water- soluble drug due to mixed hydrotropy. Synergistic combination of hydrotropic agents can minimize the amount of hydrotropic agents employed, minimizing the chances of their toxicities. Aqueous injection of aceclofenac, using the mixed hydrotropic solubilization technique, was developed and by using the lyophilization method, the problem of inadequate stability of aceclofenac in aqueous solution was overcome. The developed formulation was studied for physical and chemical stability.
Iranian journal of pharmaceutical research (IJPR) 03/2010; 9(3):233-42. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quaternary amine prodrugs resulting from N-phosphonooxymethyl derivatization of the tertiary amine functionality of drugs represents a novel approach for improving their water solubility. Separate reports have demonstrated the synthetic feasibility and rapid and quantitative prodrug to parent drug conversion in rats and dogs. This work is a preliminary evaluation of the physicochemical and in vitro enzymatic reversion properties of selected prodrugs. The loxapine prodrug had over a 15 000-fold increase in aqueous solubility relative to loxapine free base at pH 7.4. The loxapine prodrug was also shown to be quite stable at neutral pH values. The time for degradation product (parent drug) precipitation from an aqueous prodrug formulation would be expected to dictate the shelf life. Using this assumption, together with solubility and elevated temperature chemical stability studies, the shelf life of a parenteral formulation of the loxapine prodrug was projected to be close to 2 years at pH 7.4 and 25 degrees C. In addition, the prodrugs of cinnarizine and loxapine have been shown to be substrates for alkaline phosphatase, an enzyme found throughout the human body, and revert to the parent compound in its presence. The results from these evaluations demonstrate that the derivatives examined have many of the ideal properties required for potential clinical application.
[Show abstract][Hide abstract] ABSTRACT: This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.
Journal of Drug Targeting 02/2004; 12(9-10):575-83. DOI:10.1080/10611860400010655 · 2.74 Impact Factor
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