Thermoresponsive liquid crystalline formulation of Exemestane: Design and structural characterization.

Exemestane (EXE), a drug used for the treatment of breast cancer, has limited aqueous solubility of 0.08 mg/mL and log P∼ 4.22. The only available marketed formulation in form of tablets possess limitations of poor oral absorption (∼ 42 %), low solubility, extensive hepatic metabolism and numerous adverse effects due to its peripheral absorption. In order to address these issues, an alternative route of topical application is attempted through a lamellar liquid crystal based formulation. Pluronic® was used as stabilizer due to its higher surface activity and gelling properties. The solubility enhancement of EXE was achieved using liquid crystal formulation. We have investigated the effect of concentration of oil, Smix (surfactant - cosurfactant mixture) and EXE on lattice parameter, rheology and drug release for various combinations of the formulation. The small angle x-ray scattering (SAXS) measurement demonstrated an evidence of a lamellar structure with lattice parameter ∼15 nm, which increases with corresponding increase in oil and EXE due to increase in hydrophobic interactions leading to an expansion of lamella. The inter lamellar distance decreases at higher surfactant concentration, due to the distribution of the same amount of oil and drug within larger concentration of surfactant molecules. The rheology measurement exhibited gel like properties at low shear rate indicating soft gel formation, which converts to Newtonian type flowing liquid at higher shear rate. At constant Smix with increasing oil content, the viscosity decreases, which is attributed to the dilution of the lamellar structures with oil. The temperature sweep rheology reveals a change in the viscosity near physiological temperature, which may be attributed to the structural transition of lamellae. The formulation remains gel like at room temperature, which aids in proper application to skin and converts it to free flowing liquid above 37 °C. The invitro drug release of optimized formulation for 24 h was ∼ 38 % at 37 °C, which increased to 50 % at 42 °C. Accordingly, this formulation containing thermoresponsive lamellar liquid crystal gels of EXE represents a viable option for hyperthermia induced enhanced drug release. The characteristic and advantageous features offered by this formulation includes improved bioavailability of EXE due to enhanced solubility, permeability and absorption.

Multiple drug delivery from the drug-implants-laden silicone contact lens: Addressing the issue of burst drug release.

A fixed combination of bimatoprost/timolol eye drop solution is used to manage the elevated intra-ocular pressure in glaucoma patients, including individuals whose condition is poorly controlled by monotherapy. Eye drop solutions are generally given in high dose, due to poor ocular bioavailability. The high ocular dose of bimatoprost and timolol lead to hyperaemia and systemic cardiac side effects respectively. Here, we introduce multiple implant-laden contact lenses (IM) to passively deliver timolol, bimatoprost and hyaluronic acid at therapeutically relevant doses without high burst release. The drug-loaded implants were individually implanted in the outer periphery of the silicone contact lenses. Atomic force microscopy showed the smooth surface of the implant contact lens, as the implants were inside the contact lens matrix. The implant lens (IM) showed major loss of drugs [timolol = 60.60%, bimatoprost = 61.75% and HA = 46.03%] during the monomer extraction and wet sterilization, while the option of dry radiation sterilization (IM-R lens) and hydration for 24 h prior to use showed relatively lower loss of drugs [timolol = 16.87%, bimatoprost = 47.95% and HA = 24.41%]. The in-vitro drugs release data of IM-R lens, showed sustained release for 72 h, with low burst release in comparison to the soaked (SM) and direct drug-laden contact lenses (DL). The in vivo drug release data in the rabbit tear fluid showed sustained release using IM-R lens in comparison to the SM lens and eye drop therapy. The burst release with the IM-R lens was many folds reduced, which could bypass the side effects associated with multiple eye drop therapy. The in vivo pharmacodynamic study in the rabbit model showed peak and valley profile with multiple eye drop therapy, while IM-R lens showed prolong reduction in intra ocular pressure (IOP) for 120 h. The study demonstrates the application of implantation technology to deliver multiple drug through contact lenses to treat glaucoma.

Lidocaine tripotassium phosphate complex laden microemulsion for prolonged local anaesthesia: In vitro and in vivo studies.

Lidocaine is widely used as a local anaesthetic in the clinical practice to manage pre- and post-operative pain, skin burns, etc. However, the short duration of action (< 2 h) of marketed dosage forms limit their ability to meet clinical needs. Herein, we prepared a lidocaine-tPP(tri potassium phosphate)-complex loaded microemulsion to achieve greater penetration, followed by destabilization of microemulsion in the skin layer to precipitate oil-complex to produce a depot effect in the skin for prolonging the effects of anaesthesia. The lidocaine-tPP-complex-microemulsion was compared with lidocaine base loaded microemulsion, marketed ointment USP and lidocaine HCl. The pseudo ternary phase diagrams at three Smix ratios (1:2, 1:3 and 1:4; Pluronic F127: PEG 400) were constructed using Capmul MCM C8 EP as oil phase. The Smix at 1:4 ratio showed large microemulsion area in comparison to 1:2 and 1:6 ratio. The lidocaine base (LD-1:4-ME10O45SM and LD-1:4-ME20O45SM) and lidocaine-tPP-complex (LDC-1:4-ME10O45SM and LDC-1:4-ME20O45SM) loaded microemulsion batches (1:4 ratio) were thermodynamically stable. The ex vivo diffusion study showed sustained release up to 12 h with microemulsion batches, in comparison to lidocaine HCl (4 h) and ointment base (7 h). The selected LDC-1:4-ME20O45SM batch was non-irritating on the rabbit skin. In drug retention studies, LD-1:4-ME20O45SM and LDC-1:4-ME20O45SM batches showed 2.68- and 3.93-fold greater lidocaine retention in comparison to ointment USP. The radiant heat tail-flick test showed prolong local anaesthesia using LDC-1:4-ME20O45SM in comparison to ointment USP. The findings suggest that lidocaine-tPP-complex loaded microemulsion could be a potential strategy for providing prolong local anaesthesia.

Contact lenses with dual drug delivery for the treatment of bacterial conjunctivitis.

Currently, bacterial conjunctivitis is treated by frequent administration of antibiotic eye drop solutions, which is tedious and patient noncompliant. Contact lenses could be ideal medical devices to sustain the release of ophthalmic drugs, but the incorporation of the latter can alter the optical and physical properties of the lenses. In addition, many contact lens users have reported the pink eye syndrome, making them unsuitable as ocular medical devices. In the present study, we have designed a novel type of lenses containing semi-circular rings loaded with moxifloxacin HCl (a broad spectrum antibiotic) and hyaluronic acid (a comfort agent), respectively, in order to treat bacterial conjunctivitis without altering the critical lens properties. The drug loaded rings were implanted separately within the periphery of the contact lenses using the modified cast moulding technology. The atomic force microscopy report showed an average roughness of 22.27 nm for the implant lens, which was significantly lower in comparison to the marketed Freshlook® (116.27 nm) contact lens. The major amount of moxifloxacin HCl was leached (68.16-74.55%) during the monomer extraction and wet sterilization (autoclave) steps; hence the lenses were terminally sterilized by radiation and packaged under dry condition (dehydrated). The in vitro release data showed release for moxifloxacin HCl and hyaluronic acid up to 96 h. The in vivo drug release studies showed significant improvement [>MIC for Staphylococcus aureus] in the drug residence time in comparison to the eye drop therapy. The in vivo efficacy study in the staphylococcus aureus induced conjunctivitis showed equivalent healing effect with the single implant contact lens in comparison to the frequent high dose eye drop therapy. The study demonstrated the successful application of the implantation technology to co-deliver moxifloxacin HCl and hyaluronic acid from the contact lenses for the extended period of time to treat conjunctivitis.

Co-delivery of timolol and hyaluronic acid from semi-circular ring-implanted contact lenses for the treatment of glaucoma: in vitro and in vivo evaluation.

Glaucoma is a chronic disease, which is currently treated using frequent high dose applications of an eye drop solution; this method is tedious, and most of patients are non-compliant to it. Contact lenses are emerging as a convenient option to sustain the release of ophthalmic drugs. However, the incorporation of a drug/formulation changes the optical and physical properties of contact lenses. Contact lens users have also reported pink eye syndrome; this makes contact lenses unsuitable to be accepted as a medical device. The objective of the present study was to design novel timolol and hyaluronic acid (comfort agent)-loaded semi-circular ring-implanted contact lenses that could uphold the release at therapeutic rates without compromising the critical lens properties. The drug-loaded rings were individually implanted within the periphery of the contact lenses using modified cast-moulding technology. Atomic force microscopy showed an average roughness of 12.38 nm for the implanted lens that was significantly lower as compared to that of the Freshlook contact lenses (116.27 nm). A major amount of timolol was leached (from 46.47 to 58.79%) during the monomer extraction and moist sterilization (autoclave) steps; therefore, the lenses were sterilized by radiation and packaged under dry conditions (dehydrated). The in vitro release data showed sustained release of timolol and hyaluronic acid up to 96 h. The in vivo drug release study on rabbit eyes showed the presence of timolol in tear fluid up to 72 h. The in vivo pharmacodynamics studies showed a reduction in IOP till 144 h with a low drug loading (154 µg) as compared to the case of a single instillation eye drop solution (250 µg). This study has demonstrated the successful application of implantation technology to co-deliver timolol and hyaluronic acid from contact lenses for an extended period of time to treat glaucoma.

Extended release of hyaluronic acid from hydrogel contact lenses for dry eye syndrome.

Current dry eye treatment includes delivering comfort enhancing agents to the eye via eye drops, but low residence time of eye drops leads to low bioavailability. Frequent administration leads to incompliance in patients, so there is a great need for medical device such as contact lenses to treat dry eye. Studies in the past have demonstrated the efficacy of hyaluronic acid (HA) in the treatment of dry eyes using eye drops. In this paper, we present two methods to load HA in hydrogel contact lenses, soaking method and direct entrapment. The contact lenses were characterized by studying their optical and physical properties to determine their suitability as extended wear contact lenses. HA-laden hydrogel contact lenses prepared by soaking method showed release up to 48 h with acceptable physical and optical properties. Hydrogel contact lenses prepared by direct entrapment method showed significant sustained release in comparison to soaking method. HA entrapped in hydrogels resulted in reduction in % transmittance, sodium ion permeability and surface contact angle, while increase in % swelling. The impact on each of these properties was proportional to HA loading. The batch with 200-µg HA loading showed all acceptable values (parameters) for contact lens use. Results of cytotoxicity study indicated the safety of hydrogel contact lenses. In vivo pharmacokinetics studies in rabbit tear fluid showed dramatic increase in HA mean residence time and area under the curve with lenses in comparison to eye drop treatment. The study demonstrates the promising potential of delivering HA through contact lenses for the treatment of dry eye syndrome.

Effect of chain length on binding of fatty acids to Pluronics in microemulsions.

We investigated the effect of fatty acid chain length on the binding capacity of drug and fatty acid to Pluronic F127-based microemulsions. This was accomplished by using turbidity experiments. Pluronic-based oil-in-water microemulsions of various compositions were synthesized and titrated to turbidity with concentrated Amitriptyline, an antidepressant drug. Sodium salts of C(8), C(10), or C(12) fatty acid were used in preparation of the microemulsion and the corresponding binding capacities were observed. It has been previously determined that, for microemulsions prepared with sodium caprylate (C(8) fatty acid soap), a maximum of 11 fatty acid molecules bind to the microemulsion per 1 molecule of Pluronic F127 and a maximum of 12 molecules of Amitriptyline bind per molecule of F127. We have found that with increasing the chain length of the fatty acid salt component of the microemulsion, the binding capacity of both the fatty acid and the Amitriptyline to the microemulsion decreases. For sodium salts of C(8), C(10) and C(12) fatty acids, respectively, a maximum of approximately 11, 8.4 and 8.3 molecules of fatty acid molecules bind to 1 Pluronic F127 molecule. We propose that this is due to the decreasing number of free monomers with increasing chain length. As chain length increases, the critical micelle concentration (cmc) decreases, thus leading to fewer monomers. Pluronics are symmetric tri-block copolymers consisting of propylene oxide (PO) and ethylene oxide (EO). The polypropylene oxide block, PPO is sandwiched between two polyethylene oxide (PEO) blocks. The PEO blocks are hydrophilic while PPO is hydrophobic portion in the Pluronic molecule. Due to this structure, we propose that the fatty acid molecules that are in monomeric form most effectively diffuse between the PEO "tails" and bind to the hydrophobic PPO groups.

Effect of long-chain alcohols on SDS partitioning to the oil/water interface of emulsions and on droplet size.

The effect of long-chain alcohols (C(n)OH for n=8, 10, 12, 14, 16, 18) on the partitioning of sodium dodecyl sulfate (SDS) to the oil/water interface in oil-in-water macroemulsions was investigated and related to emulsion droplet size and total interfacial area (TIA) contributed by SDS. Alcohols were solubilized in hexadecane and emulsified in SDS solutions. Ultrafiltration was carried out in centrifuge tubes having nanoporous filters with a 30,000 molecular weight cutoff (MWCO), so that emulsion droplets would not pass through, and only SDS that is in the bulk water phase as monomers or micelles (i.e., not at the interface) could pass through. The results showed a chain-length compatibility effect; the maximum amount of SDS partitioned to the interface when dodecanol (C(12)OH) was added to the oil. The results also showed that partitioning of SDS is affected only when dodecanol is added. All other alcohols had no significant influence on SDS partitioning to the oil/water interface. Droplet size measurements revealed a minimum in droplet size for emulsions with added C(12)OH. In order to explain the results, it was proposed that the penetration of alcohol molecules into the interfacial film occur at the interface, resulting in more cohesive molecular packing at the interface, and the minimum droplet size and maximum partitioning of SDS at the oil/water interface for C(12)OH/SDS emulsion system. The TIA provided by the SDS molecules, as determined from our ultrafiltration method, was two orders of magnitude greater than that calculated from the droplet size measured by light scattering. Possible explanations for this disparity are discussed.

A novel method to quantify the amount of surfactant at the oil/water interface and to determine total interfacial area of emulsions.

We present a methodology to quantitatively determine the fraction of sodium dodecyl sulfate (SDS) that partitions to the oil/water interface in oil-in-water macroemulsions and calculate the total interfacial area (TIA) through the novel use of filtration through nanoporous membranes. Ultrafiltration was carried out in centrifuge tubes having nanoporous filters with a 30,000 molecular weight cutoff (MWCO), so that emulsion droplets would not pass through, and only SDS (as monomers and micelles) that is in the bulk water phase (i.e., not at the interface) could pass through. The concentration of SDS in the filtrate was determined and used to calculate the TIA for each system. The mean droplet diameter of the emulsions was measured by light scattering. We analyzed the effects of total SDS concentration and oil chain length on the amount of SDS that partitions to the interface, the TIA, and the droplet diameter. The results showed that partitioning of SDS to the oil/water interface increases with increasing total SDS concentration in emulsion systems (i.e., the more SDS we add to the bulk solution, the more SDS partitions to the oil/water interface). However, the surface-to-bulk partition coefficient (i.e., the SDS concentration at the interface divided by the SDS concentration in the aqueous phase) remains the same over the entire concentration range (8-200 mM). The results showed a chain-length compatibility effect in that the minimum amount of SDS partitioned to the interface for C(12) oil. The droplet size measurements revealed a maximum size of droplets for C(12) oil. Penetration of oil molecules into SDS film at the interface has been proposed to account for the maximum droplet size and minimum partitioning of SDS at the oil/water interface for C(12) oil+SDS emulsion system. The TIA, as determined from our ultrafiltration method, was consistently two orders of magnitude greater than that calculated from the droplet size measured by light scattering. Possible explanations for this disparity are discussed.

Combination HCV core antigen and antibody assay on a fully automated chemiluminescence analyzer.

BACKGROUND: HCV exposure among blood donors is serologically determined by detection of antibodies to HCV (anti-HCV); however, the recent development of an assay for the detection of HCV core antigen identifies infection before anti-HCV development. Simultaneous detection of HCV core antigen and anti-HCV would shorten the window period before seroconversion over conventional HCV antibody screening assays. STUDY DESIGN AND METHODS: A prototype chemiluminescent immunoassay was developed for simultaneous detection of HCV core antigen and anti-HCV in human sera and plasma. The assay was performed on a single-channel instrument representing an automated serologic analyzer (PRISM, Abbott Laboratories) system. Sensitivity and specificity were evaluated by testing 23 HCV seroconversion panels and plasma or sera from volunteer blood donors. RESULTS: The prototype HCV core antigen and antibody combination assay detected 80 of 89 (89.9% ) HCV RNA-positive and antibody-negative specimens from 23 panels, thereby reducing the seroconversion window period by an average of 34.3 days compared to PRISM HCV antibody detection. All PRISM HCV antibody-positive specimens were detected by the combination assay for a relative sensitivity of 100 percent. The repeatedly reactive rate was 0.20 percent based on testing of 3017 screened anti-HCV-negative sera and plasma. CONCLUSIONS: The prototype combination assay was shown to detect HCV core antigen and anti-HCV simultaneously and significantly closed the time gap between the initial detection of HCV RNA and the first appearance of detectable antibodies to HCV.

Kinetics of the Formation of Nano-Sized Platinum Particles in Water-in-Oil Microemulsions.

The effect of surfactant type and temperature on the kinetics of the formation of platinum nanoparticles in water-in-oil microemulsions by chemical reduction of PtCl(6)(2-) were examined with time-resolved UV-vis absorption spectroscopy. The surfactants used were poly(ethylene glycol)monododecyl ethers (C(12)E(4), C(12)E(5), C(12)E(6)), sodium bis(2-ethylhexyl)sulphosuccinate (AOT), and mixtures of the alcohol ethoxylates and AOT. The oil domain was n-heptane. The microemulsion droplet size was measured by a dynamic light scattering technique (photon correlation spectroscopy) and the final platinum particle size was determined by transmission electron microscopy. The reaction rate for platinum particle formation was approximately the same in microemulsions based on either of the alcohol ethoxylates but considerably lower for microemulsions based on AOT. In microemulsions based on mixtures of an alcohol ethoxylate and AOT the reaction rate was similar to that obtained when alcohol ethoxylate was the sole surfactant. The reaction was observed to be particularly rapid in microemulsions based on combinations of AOT and C(12)E(5) or C(12)E(6), and the rate was relatively independent of the ratio of the nonionic and anionic surfactants. The reaction was found to be of first order for platinum nanoparticles formed in alcohol ethoxylate-, AOT-C(12)E(5)-, and AOT-C(12)E(6)-based microemulsions, whereas in microemulsions with AOT and AOT-C(12)E(4) the reaction rate seemed to be of higher reaction order. The platinum particles were found to be less than 5 nm in average diameter, which was consistent with the microemulsion droplet size. Copyright 2001 Academic Press.