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.