Cyclodextrins in Eye Drop Formulations

Ideally, eye drop formulations are aqueous solutions. Many drugs that are useful in topical application to the eye are not sufficiently water soluble to be dissolved in simple aqueous solutions. This problem is approached through hydrophilic prodrugs, suspensions, lipid based solutions and excipients such as cyclodextrins. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various ophthalmic drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine and cyclosporins. Their use in ophthalmology has already begun and it is likely to expand the selection of drugs available as eye drops. In this paper we review the use of cyclodextrins in eye drop formulations. The use of cyclodextrins to formulate dexamethasone eye drops is an example of their usefulness. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with concentration and ocular absorption, which in human and animal studies is many fold that seen with presently available formulations. Such formulations offer the possibility of once a day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation.     

Topical emulgel formulation containing inclusion complex of calcipotriol with cyclodextrin

Psoriasis is a relatively common, chronic, inflammatory disease that affects the skin, scalp, and joints. Calcipotriol is one of the most commonly used topical agents for the treatment of psoriasis. However, it is a water-insoluble active substance and frequently leads to skin irritation in patients. Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4-)-linked d-glucopyranose units. CD molecules have a hydrophilic outer surface and a lipophilic central cavity, and they are able to form inclusion complexes in aqueous solutions with many drugs. They can increase bioavailability, aqueous solubility, and stability and also reduce the side effects of the drugs. The aim of this study was to develop a new topical drug delivery system of calcipotriol in order to improve the solubility and dissolution characteristics of the drug and reduce the undesirable side effects. For this purpose, an inclusion complex of calcipotriol with Captisol^® was prepared, and complex formation was confirmed. The inclusion complex and pure drug were formulated separately in an emulgel base. Dissolution profiles of calcipotriol from emulgel formulations were compared with a commercial product of the drug. The drug release was significantly increased with the emulgel formulations compared to the commercial cream product.     

Studies on hydroquinone based maleate bolaamphiphile organogels and their drug formulations

Now a day’s there is an upsurge in topical gel formulations, they can be prepared by varying physico-chemical methods and provide better localized action. A maleate based symmetric bolaamphiphile was synthesized by using cost-effective starting materials under mild reaction condition. The gelation ability of bolaamphiphile in aqueous medium was examined for a series of organic solvents. In hexane, the gelator showed better gelation ability with relatively higher critical strain (54 Pa) values. Further, the microscopic images of the gel revealed flakes like morphology, both the XRD and DFT studies revealed the presence of non covalent interactions. These gels showed a high internal-phase mole ratio of the topical drugs in the order of curcumin < salicylic acid < Ibuprofen. Formation of aqueous and organic gel-phase formulation may facilitate the topical medications for various applications related to ophthalmic and skin infections.     

Development,Characterization, and Evaluation of Liposomes and Niosomes of Bacitracin Zinc

The skin permeation of bacitracin zinc in liposomes and niosomes after topical application were elucidated in the present study with the to increase its penetration capacity and, hence, efficiency. The formulations of bacitracin zinc were prepared by film hydration method and characterized for vesicle shape, size, entrapment efficiency, and drug permeation across rat skin and also evaluated for their stability. Formulation with niosomes demonstrated a better skin permeation potential, sustained release characteristic, and higher stability as compared to liposomes. The ability of liposomes and niosomes to modulate drug delivery makes the two vesicles useful to formulate topical bacitracin zinc.     

Deformable liposomes containing alkylcarbonates of γ-cyclodextrins for dermal applications

Liposomes made with hydrogenated soya lecithin (HPC) mixed with dodecylcarbonate γ-cyclodextrin (C12CD) at 20:1, 10:1 and 5:1 w/w ratios were prepared by the solvent evaporation method. C12CD had emulsifying properties and the possibility of producing deformable liposomes, as topical delivery system of progesterone (PG), was evaluated. Liposome size, deformability and drug entrapment were determined and the interaction between C12CD and HPC was investigated using differential scanning calorimetry (DSC). The size and the amount of PG loaded in the liposomes depended on the lipid:C12CD ratio: the smallest liposomes were obtained using 20:1 ratio and the maximum drug entrapment at 5:1 ratio. DSC analysis suggested that C12CD interacted with liposomes disrupting and fluidizing the lipid bilayer. PG transepidermal permeation through intact pig skin and PG skin uptake from deformable liposomes were assessed and compared to the values obtained from aqueous suspension and conventional liposomes. The PG permeations were negligible for all systems, while skin uptake increased for liposomes containing C12CD. This was attributed to the deformability and to the increase in the drug entrapment efficiency of these liposomes. The use of C12CD in liposome formulations can improve PG topical therapy.     

Skin disposition of drugs after topical application in hairless rats.

Drug fraction transported from a topical formulation on skin to subcutaneous tissues or muscles is dependent on the physicochemical properties of the entrapped drug. Cutaneous disposition of model drugs, antipyrine (ANP), lidocaine (LC) and piroxicam (PXC) as well as flurbiprofen (FP) was thus evaluated in hairless rats in which an agar gel disc was subcutaneously inserted into the abdominal region as a drug receptor and a drug donor cell was placed above it. Time courses of plasma level and agar gel amount were measured after topical application of 50% ANP, 3% LC, 1% PXC and 1% FP in hydroxypropylcellulose gel. Percutaneous absorption clearance of unionized form, CLab* was proportional to true octanol/water distribution coefficient and the order of FP > PXC > LC > ANP, suggesting that skin permeation of the drug was determined mainly by its distribution from the formulation to the skin barrier. PXC, however, had a relatively low flux compared to the other three drugs, probably due to its high molecular weight and melting point. Migration clearance of unionized form from systemic circulation to the subcutaneous agar gel, CLg* was also influenced by the lipophilicity of drugs. On the other hand, fraction from the formulation to the systemic circulation was in the order of PXC > FP > ANP > LC. This fraction was much higher than the direct migration fraction from the formulation to the subcutaneous agar gel. Factors determining for these fractions are still unclear. A drug having a low lipophilicity and a low protein binding, however, had a tendency to have a great targeting ability to the subcutaneous agar gel. In addition, most of the drug in the agar gel was contributed by the direct flow from formulation, not from the systemic circulation. The present in situ experimental method is a useful tool to evaluate skin disposition of drugs. Detailed understanding of the skin disposition of drugs from several formulations will enable the findings of a good drug and formulation candidates.     

Topical application of Scutellaria baicalensis suppresses 2,4-dinitrochlorobenzene-induced contact dermatitis

Allergic contact dermatitis (ACD) is a prototypic T-cell-mediated cutaneous inflammatory response. In the present study we describe the anti-allergic effect of topically applied Scutellaria bacalensis aqueous extract (WSBE) in suppressing 2,4-dinitrochlorobenzene (DNCB)-induced ACD in BALB/c mice. Topically applied WSBE attenuated the epidermal thickness and mast cell infiltration into the skin in DNCB-induced contact dermatitis. Furthermore, WSBE suppressed DNCB-induced production of serum IgE as well as IL-4, IFN-γ, and TNF-α in the skin. Topical application of WSBE also ameliorated the significant decrease in dermal glutathione and superoxide dismutase levels. Moreover, present results demonstrated that the baicalin, bioactive compound of WSBE, was able to penetrate into the skin following topical application, which was confirmed by the HPLC analysis using rat model. Taken together, topical application of WSBE exerts beneficial effects in contact dermatitis model, suggesting that WSBE might be a candidate for the treatment of contact dermatitis.     

Effects of application voltage and cathode and anode positions at electroporation on the in vitro permeation of benzoic acid through hairless rat skin

The enhancing effect of electroporation on the in vitro skin permeation of benzoate was evaluated. Needle and ring electrodes made of Ag/AgCl were connected to an electrical power source, which produced exponentially decaying pulses. The needle electrode was kept in contact with the skin surface, and the ring electrode was positioned either on or under the skin. The electrical pulse was applied to abdominal hairless rat skin at 150-600 V every minute from 4 to 6 h during the 10-h permeation experiment. Skin permeation of benzoate was promoted by electroporation and the effect was increased by application of a higher voltage. No immediate recovery to the control flux, however, was observed for high voltage groups after turning off the voltage application. When the cathode and anode were separated by the skin membrane by setting in the epidermal and dermal sides, respectively, an iontophoretic effect may also play a role in benzoate flux. These results indicated that the drug permeation by electroporation is the result of passive diffusion and an iontophoretic effect as well as the electroporation effect.     

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.     

Dose identification of triamcinolone acetonide for noninvasive pre-corneal administration in the treatment of posterior uveitis using a rapid,sensitive HPLC method with photodiode-array detector

Triamcinolone acetonide (TAA) is the drug of choice in the management of ocular inflammations due to its anti-inflammatory and immuno-suppressant activity. Available marketed formulations (Triesence, Trivaris, Kenalog) are in the suspension form recommended to be administered via intravitreal injection, which has many major complications. In the present study, we have designed and evaluated Hydroxypropyl-β-cyclodextrin (HP-β-CD),) based conventional formulations of TAA (aqueous suspensions) with different dose strengths to identify the dose strength required for achieving the effective concentrations in vitreous humor following pre-corneal administration of the formulations. Ocular pharmacokinetic studies of conventional formulations of triamcinolone acetonide (TAA) with different dose strengths (1 mg/30µL, 2 mg/30µL, 4 mg/30µL) were performed to identify the dose strength required to produce effective concentrations of TAA in the aqueous and vitreous humor. A rapid, sensitive, selective, accurate and precise bioanalytical method utilizing a small sampling volume (<45 µL) was developed and validated for quantification of TAA in the samples obtained from the ocular pharmacokinetic studies. Aqueous suspensions of TAA with 20% HP-β-CD produced time course profiles in the aqueous humor at all the dose strengths. However, measurable concentrations and time course of TAA in vitreous humor were achieved only with 4 mg/30µL dose strength.     

Skin permeability of water-soluble drugs

The permeabilities of several water-soluble drugs through excised hairless rat skin from their aqueous suspensions were investigated by using newly designed two-chamber diffusion cells. Disodium cromoglycate, diclofenac sodium, dopamine hydrochloride, isoproterenol hydrochloride, diltiazem hydrochloride and papaverine hydrochloride were selected as water-soluble drugs. Indomethacin, a lipophilic drug, and deuterium oxide (D2O) were used for comparison. The skin permeability coefficients of these water-soluble drugs were 100--1000 times lower than that of indomethacin. Since these drugs have high solubility in the donor solution (distilled water or lactate buffer), however, the skin permeation rates, which are in general proportional to the product of skin permeability coefficient and solubility of drugs in the drug-donor compartment, were comparable to or higher than that of indomethacin (1.7 micrograms/cm2/h): the skin permeation rate of dopamine hydrochloride (458 micrograms/cm2/h) was about 300 times higher than that of indomethacin. The water-soluble drugs with lower molecular weight and higher solubility in water showed higher skin permeation rates. These results suggest that some water-soluble drugs with low molecular weight and high solubility in water might be good candidates for transdermal drug delivery.     

Biodegradable,implantable sustained release systems based on glutamic acid copolymers

Polymer pellets that contain drugs and may be implanted under the skin offer effective means for providing sustained, controlled drug therapy to humans and animals. Among the most useful drug delivery systems are those based on biodegradable polymers that ultimately are absorbed by the body — eliminating the need for their surgical removal. Copolymers of L-glutamic acid and γ-ethyl L-glutamate biodegrade to L-glutamic acid and ethanol, at rates that are determined by the initial copolymer composition. The materials are permeable to a wide range of drugs, including steroids, narcotic antagonists, peptide hormones, antimalarials, and anticancer agents. When fabricated into matrix rods or capsules, the copolymers have been used to release drugs in animals at constant rates for prolonged periods of time. p]In this study, rods composed of a blend of drug and copolymer were found to be useful for the long-term release (i.e., 6 to 24 months) of drugs having low aqueous solubility, such as progesterone and levonorgestrel. Capsules, composed of a copolymer sheath surrounding the drug, were better suited for shorter durations of release (i.e., up to 6 months) of drugs having higher aqueous solubility, such as luteinizing hormone-releasing hormone and naltrexone. The physical dimensions and copolymer compositions of either dosage form were readily varied to meet specific delivery rate and duration objectives while satisfying equally important degradation requirements.     

Submicron Size Formulation of Linseed Oil Containing Omega-3 Fatty Acid for Topical Delivery

The aim of the present study was to design and develop topical submicron size gel formulation of linseed oil with enhanced permeation through the skin for the management of psoriasis. Linseed oil contains significant amount of α-linolenic acid (ALA) an omega-3 fatty acid, which is responsible for its pharmacological actions. In order to enhance permeation through skin, microemulsion based gel formulation was prepared and characterized. Microemulsions were prepared by aqueous phase titration method, using linseed oil, Unitop 100, PEG 400, and distilled water as the oil phase, surfactant, cosurfactant and aqueous phase, respectively. Selected formulations were subjected to physical stability studies and consequently in vitro skin permeation studies. Surface morphology studies of optimized formulation were done by transmission electron microscopy (TEM). The droplet size of microemulsions ranged from 70 to 500 nm with average particle size 186 nm. The optimized microemulsion was converted into hydrogel using carbopol 971 which had a viscosity of 498 ± 0.04 cps. During in vitro permeation study the flux of microemulsion formulation and gel was found to be 19.05 and 10.2 µg/cm²/hr, respectively, which indicated better penetration of linseed oil through the skin. These result indicated that the developed ME formulation may be a good approach for topical therapy for the management of psoriasis.     

Stability‐indicating analytical method of quantifying spironolactone and canrenone in dermatological formulations and iontophoretic skin permeation experiments

A simple, stability‐indicating, chromatographic method of quantifying spironolactone (SPI) and its metabolite, canrenone (CAN), in the presence of excipients typical in dermatological formulations and skin matrices in studies of passive and iontophoretic permeation was proposed and validated here. SPI and CAN were separated using a reversed‐phase column with a mobile phase of methanol–water (60:40, v/v) at a flow rate of 1.0 mL/min. Data were collected with a UV detector at 238 and 280 nm, with retention times of 6.2 and 7.9 min for SPI and CAN, respectively. The method was precise, accurate and linear (r² > 0.99) in a concentration range of 1–30 μg/mL, and recovery rates of SPI and CAN from the different skin layers exceeded 85%. The method was not only sensitive (LOD of 0.05 and 0.375 μg/mL and LOQ of 0.157 and 1.139 μg/mL for SPI and CAN, respectively) but also selective against skin matrices and highly representative components of topical formulations. The method moreover demonstrated SPI's degradation in iontophoresis by applying Pt–AgCl electrodes and its continued drug stability using Ag–AgCl electrodes. Altogether, the method proved valuable for quantifying SPI and CAN and may be applied in developing and controlling the quality of dermatological products.     

Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis.     

Influence of isosorbide dinitrate concentration on its skin permeability from adhesive matrix devices.

Adhesive matrix devices containing a model drug, isosorbide dinitrate (ISDN), were prepared with three different types of pressure sensitive adhesives (PSAs). ISDN permeation through excised hairless rat skin from the different devices was measured in vitro. For each PSA type, the steady state permeation rate of ISDN increased proportionally with an increase of ISDN concentration in the PSA and reached a maximum level at a certain concentration. Although the concentrations reaching the maximum skin permeation level varied among PSA types, the maximum rate for each PSA type was largely similar to that for ISDN aqueous suspension. The release rate of ISDN from devices was too fast to influence the skin permeation rate for all devices. In the PSA of devices showing maximum skin permeability, ISDN crystalline was observed by polarizing microscopy and differential scanning calorimetry. These results suggest that the skin permeation of ISDN from adhesive matrix devices was controlled by the thermodynamic activity of the drug in the PSAs.     

Phenothiazine Drug Poly(vinyl chloride) Matrix Membrane Electrodes and Their Use in Pharmaceutical Analysis

The construction and performance characteristics of ion-selective membrane electrodes for phenothiazine drugs based on their ion-pair complexes with tetraphenylborate and dinonylnaphthalenesulfonate in a poly(vinyl chloride) matrix are described. The electrodes show a near-Nernstian response over various ranges depending on the nature of the phenothiazine drug. The selectivity of these electrodes to a number of amino acids, alkaloids, neurotransmitters, quaternary ammonium compounds, and other drugs or pharmaceutical excipients is reported. The standard additions method and potentiometric titrations are used to determine the phenothiazine drugs in pharmaceutical preparations with satisfactory results.     

The thermal and photostability of solid pharmaceuticals

Drugs degrade to different extents on separate exposure to heat, moisture, oxidation and light. Combination of these stresses causes very complex behaviour. Many studies have been reported of the thermal behaviour of drugs in the solid-state, but most of the information available on the photodegradation of drugs refers to reactions in solution, (usually aqueous) and photoreactions in the solid-state are even more complex. In drug formulations, the presence of excipients adds further complications because the excipients may increase, have no effect on, or decrease the inherent stabilities of the drug. The literature has been explored to review the thermal and photostabilities of solid pharmaceuticals. This revised version was published online in August 2006 with corrections to the Cover Date.     

Membrane permeation-controlled transdermal delivery system design. Influence of controlling membrane and adhesive on skin permeation of isosorbide dinitrate

A membrane permeation-controlled transdermal delivery system (MC-TDS) of isosorbide dinitrate (ISDN), a model drug, was prepared from polyvinyl alcohol aqueous gel containing the drug, a membrane consisting of ethylene-vinyl acetate copolymer membrane and acrylic adhesive (EV-a). The permeability of ISDN through the EV-a membrane was 2.5 times higher than that through excised hairless rat skin. The ratio of plasma concentration of ISDN after application of MC-TDS on stripped (damaged) skin relative to intact skin was lower than that after application of Frandol tape-S, a marketed ISDN TDS, which suggests that the EV-a membrane might work as a control membrane for overall delivery rate of ISDN to the body. When MC-TDS stored at 30 degrees C for 13.5-48h was applied to the damaged skin, however, the initial plasma concentration of ISDN was very much higher than the expected therapeutic level and was not controlled by the EV-a membrane. The initial high plasma concentration of ISDN after application of the stored MC-TDS on the damaged skin was due to migration of ISDN from the reservoir to the adhesive during storage at 30 degrees C. The migration of drugs into the adhesive might be an important problem in developing efficient MC-TDS.     

Plastic membrane electrodes responsive to beta-blocker drugs

The construction and performance characteristics of ion-selective PVC membrane electrodes for metoprolol, propranolol and timolol are described. The electrodes, based on ion-pair complexes with dinonylnaphthalenesulphonate or with tetra(2-chlorophenyl)borate show near-Nernstian responses down to 10(-5)M drug concentration. Their selectivity relative to various inorganic and organic cations is reported. Direct potentiometry is used to determine beta-blocker drugs both in aqueous solutions and pharmaceutical preparations, with good results.