Somchai Sawatdee

Sildenafil citrate monohydrate-cyclodextrin nanosuspension complexes for use in metered-dose inhalers.

Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols.

Evaluation of sildenafil pressurized metered dose inhalers as a vasodilator in umbilical blood vessels of chicken egg embryos.

Sildenafil citrate is a selective phosphodiesterase-5 inhibitor used for the treatment for erectile dysfunction and pulmonary hypertension. The delivery of sildenafil directly to the lung could have several advantages over conventional treatments for pulmonary hypertension because of the local delivery, a more rapid onset of response, and reduced side effects. The major problem of sildenafil citrate is its limited solubility in water. Sildenafil citrate was complexed with cyclodextrins (CDs) to enhance its water solubility prior to development as an inhaled preparation. Four sildenafil citrate inhaled formulations were prepared with the aid of HP-β-CD (#1), α-CD (#2) and γ-CD (#3) and their effects were compared with the formulations without CDs (#4). The sildenafil citrate pressurized metered dose inhalers (pMDI) used ethanol as a solvent, PEG400 as a stabilizing agent, sorbitan monooleate as a surfactant and HFA-134a as a propellant. All formulations consisted of sildenafil citrate equivalent to a sildenafil content of 20μg/puff. These products were evaluated according to a standard guideline of inhalation products. Vasodilation testing was performed to investigate the efficacy of sildenafil pMDIs in relieving a vasoconstricted umbilical blood vessel of the chicken egg embryo. The sildenafil contents of the pMDI formulations #1-#3 were within the acceptance criteria (80-120%). The emitted doses (ED) were 102.3±11.5%, the fine particle fractions (FPF) were 60.5±5.6% and the mass median aerodynamic diameters (MMAD) were 2.3±0.3μm. The vasodilatory activity of those formulations reduced umbilical blood pressure by 67.1-73.7% after treatment by intravenous injection whereas only a 50.1-58.0% reduced blood pressure was obtained after direct spraying of the sildenafil pMDI containing CDs. With sildenafil formulations of a pMDI without CD the blood pressure was reduced by only 39.0% (P-value<0.05). The available sildenafil in the blood vessels of chicken egg embryos after spraying sildenafil-CDs pMDIs was within the range of 751-825ng/mL which was much higher than that of a sildenafil only pMDI.

Enhanced dissolution of sildenafil citrate as dry foam tablets

Abstract Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5 kg, friability test <1% with a disintegration time <5 min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.

Evaluation of the topical spray containing Centella asiatica extract and its efficacy on excision wounds in rats

Abstract Centella asiatica was extracted by methanol. The assay content of triterpenes in the extract was 0.12 % asiatic acid, 0.54 % madecassic acid, 0.25 % asiaticoside and 1.02 % madecassoside. The extract was complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD) and formulated with Eudragit E100, glycerol, PEG 400, copovidone, ethanol and purified water. A clear yellowish solution (F1-F8) was obtained. The formulations had a pH of 5.5–6.0 with viscosity in the range of 20–60 mPa s, surface tension 20.3–24.6 mN m–1 and contact angle less than 20°. The amount of PEG 400 and copovidone affected the film and spreadability. The content of triterpenes in the spray formulation was close to 100 % compared to triterpenes in the extract. The skin irritation study indicated that the formulation was non-irritating in a rat model. An in vivo excision wound healing model showed that wound excision was completely healed after 14 days.

Why sildenafil and sildenafil citrate monohydrate crystals are not stable

Sildenafil citrate was crystallized by various techniques aiming to determine the behavior and factors affecting the crystal growth. There are only 2 types of sildenafil obtaining from crystallization: sildenafil (1) and sildenafil citrate monohydrate (2). The used techniques were (i) crystallization from saturated solutions, (ii) addition of an antisolvent, (iii) reflux and (iv) slow solvent evaporation method. By pursuing these various methods, our work pointed that the best formation of crystal (1) was obtained from technique no. (i). Surprisingly, the obtained crystals (1) were perfected if the process was an acidic pH at a cold temperature then perfect crystals occurred within a day. Crystals of compound (2) grew easily using technique no. (ii) which are various polar solvents over a wide range of pH and temperature preparation processes. The infrared spectroscopy and nuclear magnetic resonance spectra fit well with these two X-ray crystal structures. The crystal structures of sildenafil free base and salt forms were different from their different growing conditions leading to stability difference.

Stabilization of luteinizing hormone-releasing hormone in a dry powder formulation and its bioactivity

Abstract Background: Luteinizing hormone-releasing hormone (LHRH) is a naturally occurring hormone that controls sex hormones in both men and women. In general, LHRH is poorly absorbed through the gastrointestinal tract due to its large molecular size, high polarity, and loss from enzymatic degradation. Objective: Prepare and develop LHRH in a dry power formulation with stability and biological activity. Methods: Mannitol (M) and glycine (G) were chosen as ingredients to stabilize and protect LHRH during the freeze drying processes and during storage. The physicochemical properties of LHRH dry powders were examined by capillary electrophoresis, fluorescence spectrophotometry, scanning electron microscopy, and photon correlation spectroscopy. The release of LHRH from the dry powder was carried out in dissolution apparatus. In addition, a rat model was employed to study the bioactivity of LHRH in the dry powder form. Results: The LHRH dry powder formulations using M and G in the ratios of 6:4 and 7:3 were more stable than other formulations. LHRH colloids containing M:G showed no aggregation after storage at 4°C for one month. The concentration of LHRH in the dry powder form was more stable than that of LHRH in solution form. All the LHRH dry powder formulations were instantly dissolved within 10 seconds in an aqueous medium. After the LHRH dry powder (13 mg) was reconstituted and administered intraperitoneally to male rats during a one-month period, the testosterone level in the plasma was significantly decreased compared with an untreated group (15.0±1.0 ng/mL, 15.0±1.0 ng/mL and 20.0±2.0 ng/mL for LHRH containing M:G; 6:4, 7:3, and 8:2, respectively, compared to the control of 35±2 ng/mL, p<0.05). Conclusion: The LHRH dry powder formulations had good physicochemical properties and bioactivity.

Determination of Quinine Sulfate in Extemporaneous Suspension by Stability Indicating High Performance Liquid Chromatography

Malaria is a public health problem worldwide, especially in tropical countries. Quinine is a cinchona alkaloid used as an alternative treatment of this infection. However, the drug is only available in tablet dosage form in Thailand. Extemporaneous suspension is always prepared for pediatric use in the hospital. The aim of this study was to develop and validate a high performance liquid chromatographic (HPLC) system, according to ASEAN guideline for validation of the analytical procedure, for determination of quinine sulfate in an extemporaneous suspension. The method used a C18 column with mobile phase of 0.1 M ammonium acetate pH 7.0, acetronitrile and methanol (40:25:35 v/v) at a flow rate of 1.0 mL/min. Injection volume was 50 µL, and UV detection was measured at 330 nm. The result showed that the retention time of quinine was about 7.73 min, and the method was specific to quinine while other excipients in the preparation did not interfere the drug. A linear correlation was obtained over the concentration range of 0.08-600.00 µg/mL (R2 = 0.9999). The method was accurate (99.83±0.92%) and precise (<1.09 % RSD). The limit of detection (LOD) and limit of quantification (LOQ) were 4.32 and 13.09 µg/mL, respectively. Forced degradation showed that the method would serve as a stability-indicating procedure that applied for analysis of the drug in the stability studies. It concluded that the validated method was accurate and reliable to determine quinine sulfate in the extemporaneous suspension.

Host-guest interactions between sildenafil and cyclodextrins: Spectrofluorometric study and molecular dynamic modeling

Sildenafil (SF) was included in cyclodextrins (CD) to enhance its solubility. Spectrofluorometry was used to confirm the complexation constant (stability constant). The orientations of SF inside the β-CDs and γ-CDs were fully illustrated. Molecular dynamics simulations were performed on two inclusion complexes (β-CD/SF and γ-CD/SF) in the aqueous system. The polar methylpiperazine group was found to locate inside the β-CD cavity, both in the wide and narrow side and was positioned 2°A from the center. In contrast, the methylpiperazine group did not fit well within the γ-CD cavity. Moreover, these results also confirmed hydrogen bonding that the highest number of bonding formed between the polar methylpiperazine sulfonyl structure and the hydroxyl group of β-CD. The simulated binding free energy of the methylpiperazine-β-CD inclusion complex (-6.01kcal/mol), featured a large contribution from electrostatic and van der Waals forces, which was the most stable complex. The association constant of β-CD/SF (12.3) was higher than γ-CD/SF (3.3) and confirmed with in silico measurements of binding free energy. In summary, SF forms a stable complex with β-CD.

Quantitative analysis of povidone-iodine thin films by X-ray photoelectron spectroscopy and their physicochemical properties

Abstract In this study, povidone-iodine (PVP-I) has been formulated as a topical spray to produce a thin film for the controlled release of I2. By means of experimental design, 27 formulations containing glycerol, ethanol, PEG 400, copovidone and HFA 134a as a propellant were prepared. The pH values of all formulations were in the range of 6-7. The viscosity was within the range of 11.9-85.9 mPa s. The surface tensions were 20.3 to 24.6 mN m-1 and the contact angles were between 19.3 and 38.7°. The assays for the iodine contents were within acceptable range (80-120 %). X-ray photoelectron spectroscopy analysis revealed the ionized form of iodine was much higher than the unionized form. The MIC and MBC values of the PVP-I sprays against Staphylococcus aureus, S. epidermidis and Pseudomonas aeruginosa were higher than that of commercial PVP-I solution. The cytotoxicity study confirmed that the PVP-I spray had lower toxic effects on keratinocytes and fibroblasts compared to the commercial PVP-I solution. The formulation containing 59 % ethanol, 18 % copovidone and 12 % PEG 400 showed good antibacterial activity.

Physicochemical and Microbiological Stability of Extemporaneous Sildenafil Citrate Oral Suspension

Sildenafil is a potent and selective phosphodiesterase-5 inhibitor that is effectively used in the treatment of pulmonary arterial hypertension. In several countries, hospital pharmacists prepare the drug in an extemporaneous liquid preparation as there are no liquid formulations available for pediatric and adult uses. The purpose of this study was to evaluate the stability of an extemporaneous sildenafil citrate oral suspension for 90 days, according to the ASEAN guideline on stability studies of drug products. The results showed that the preparation was a white suspension with a sweet taste. It was a viscous and weakly acidic mixture with pseudoplastic behavior. The drug content was in the range between 99.23% and 102.23%, and the microbial examination met the general requirements throughout the study period. Therefore, the extemporaneously compounded sildenafil suspensions were physically, chemically, and microbiologically stable for at least 90 days when stored at 30° and 40°C. Furthermore, the in-use stability study showed that the preparations had acceptable attributes at least 14 days after the first-time use. This might provide an alternative option when the commercial suspension is unavailable.