Formulation & Evalution of Atenolol Hcl Microemulsion for Ocular Administration

1. INTRODUCTION Objectives of the project (a) Develop a conceptualisation of atenolol HCL micro emulsion for optical application to decrement IOP in case of glaucoma. (b) better the quality of patients life suffering from glaucoma. (c) Reduce the bet of dosing per day. 1. 1 Eye If a physician per lineed a major feat on a seignior (a nobleman) with a bronze lancet and has salve the seigniors life, or he opened the snapper socket of a seignior with a bronze lancet and has saved the seigniors nucleus and soul, he shall receive ten net income of silver.But, if the physician in so doing has cause the seigniors death or has he finished the seigniors eye, they shall cut off his hand the forgoing excerpts atomic number 18 from 282 laws of King Hammurabis Code. The eye is unusual in its therapeutic challenges. An efficient clay, that of bust and tear drainage, which apace eliminates dose solutions which makes topical delivery to the eye somewhat diametric from close to other disciplines of the body. Preparations for the eye comprise a variety of different images of harvests they whitethorn be solutions (eye leave offs or eyewashes), suspensions, or ointments.Any modern text on dose product design and evaluation moldiness place into perspective the unique nature of the ophthalmic dosage form in general to a greater extent specifically. It must consider that the bodily organ which, probably better than whatever other, serves as a model structure for the evaluation of drug activity, the eye. In no other organ bear the practitioner, without surgical or mechanistic interaction, so well observe the activity of the drug being administered. most(prenominal) optic structures move be readily viewed from cornea to retina and in doing so any signs of ocular or systemic disease can be detected languish before sight-threatening or certain health threatening disease states produce intractable. Behind the proportional straightforward composition natu re of ophthalmic solutions and ointments, however, standardised many another(prenominal) physicochemical parameters which ask drug stability, safety and efficacy as they do most other products.Additionally, specialized dosage forms such as p arnteral type ophthalmic solutions for intraocular, subtenons, and retrobulbar use suspensions for insoluble substances such as hydrocortisone and impregnables for reconstitution such as ecothiophate iodide and tetracycline, all present the drug product designer with composition and manu accompanimenturing procedure challenges in the development of pharmaceuticals. Opthalmic products, handle most others in the medical armamentarium, are undergoing a process termed optimization.New modes of delivering a drug to the eye are being actively explored ranging from a solid hydrophobic device which is inserted into the ophthalmic cul-de-sac, to conventionally applied dosage forms which, callable to their formulation characteristics markedly incre ase the drug residence magazine in the orbit of the eye, thus providing drug for absorption for prolonged period of age and reducing the frequency with which a given drug product must be administered 1. Ocular diseases are mainly treated locally by application of drug solutions administered as eye drops.These conventional dosage forms musical score for 90% of the available ophthalmic formulations. This can be due to the repose and convenience of such dosage forms 2. It is often assumed that drugs administered topically to the eye are rapidly and totally absorbed and are available to the plummy site in the globe of the eye to exert their therapeutic doing. Indeed, this is loosely not the case. When a quantity of topical ophthalmic dosage form is applied to the eye, generally to the lower cul-de-sac, several factors immediately begin to partake the availability of the drug contained in that quantity of the dosage form.Upon application of 1 to 2 drops of a sterile ophthalmic solu tion, there are many factors, which unravel on participate in the removal of the applied drops from the lower cul-de-sac 5. The firstborn factor effecting drug availability is that the loss of the drug from the palpebral fling. This takes place by spillage of the drug from the eye and its removal via nasolachrymal apparatus. The normal heap of tears in human eye is estimated to be approximately 7 l, and if crashing(a) does not pass along the human eye can accommodate a volume of 30 III without spillage from palpebral fissure.With an estimated drop volume of l, 70% of the administered volume of 2 drops can be seen to expel from the eye by over campaign. If blinking occurs, the residual volume of lO l indicates that 90% of the administer volume of two drops provide be expelled. The second factor is the drainage of the administered drop via the nasolacrimal system into the gastrointestinal tract which begins immediately upon in gloss overation. This takes place when reflex veh ement causes the volume of the fluid in the palpebral fissure to exceed the normal lacrimal volume of 7 10 l.Fig (l) indicates the pathways for this drainage. A third weapon of drug loss from the lacrimal fluid is systemic absorption with the conjunctiva of the eye. The conjunctiva is a thin, vascularized membrane that lines the inner surface of the eyelids and covers the anterior part of the sclera. Due to the relative leakiness of the membrane, rich blood flow and stupendous surface area, conjunctival expenditure of a topically applied drug from the tear fluids is typically an show of magnitude greater than corneal uptake 3. Figure (1) The pathways for drainage of drug from the eye 2In competition with the three foregoing drug removal from the palpebral fissure is the transcorneal absorption of drug, the cornea is an avascular body and, with the percorneal tear film first refracting mechanism operant in the physiological process of sight. It is composed of lipophilic epithel ium, Bowmans membrane, deliquescent stroma, Descements membrane and lipophilic endothelium. Drugs penetrate across the corneal epithelium via the transcellular or paracellular pathway. Lipophilic drugs prefer the transcellular route.Hydrophilic drugs penetrate primarily by dint of the paracellular pathway which involves static or altered distribution through intercellular spaces, for most topically applied drugs, passive diffusion along their concentration gradient, either transcellularly or paracellularly, is the main permeation mechanism across the cornea 6. Physicochemical drug properties, such as lipophilicity, solubility, molecular size and shape and degree of ionization affect the route and rate of permeation in cornea 3. 1. 2 Microemulsions Oil and piss are immiscible. They sort into two manakins when mixed, each saturated with traces of the other dower 7.An attempt to combine the two physical bodys solicits expertness input to establish water- cover colour conta cts that would switch over the water-water and oil-oil contacts. The interfacial tension between bulk oil and water can be as high as 30- dynes/cm 8. To overcome this, wetting components can be used. Surfactants are surface-active molecules. They contain water-loving ( deliquescent) and oil-loving (lipophilic) moieties 9. Because of this characteristic, they tend to adsorb at the water-oil interface. If enough surfactant molecules are present, they align and create an interface between the water and the oil by decreasing the interfacial tension 8.An emulsion is make, when a small amount of an appropriate surfactant is mechanically provoke with the oil and water. This gives in a two-phase dispersion where one phase exists as droplets coated by surfactant that is dispersed throughout the unceasing, other phase. These emulsions are milky or turbid in appearing due to the fact that the droplet sizes range from 0. 1 to 1 micron in diameter 9. As a general rule, the type of surfac tant used in the system determines which phase is uninterrupted. If the surfactant is hydrophilic, accordinglyoil leave behind be emulsified in droplets throughout a continuous water phase.The opposite is true for more lipophilic surfactants. water will be emulsified in droplets that are dispersed throughout a continuous oil phase in this case 10. Emulsions are kinetically stable, that are ultimately thermodynamically unstable. Over time, they will begin to separate back into their two phases. The droplets will merge together, and the dispersed phase will sediment (cream) 9. At this point, they degrade back into bulk phases of pure oil and pure water with some of the surfactant dissolved in preferentially in one of the two 8. 1. 2. Characteristics of Microemulsions If a surfactant that possesses balanced hydrophilic and lipophilic properties is used in the right concentration, a different oil and water system will be produced. The system is still an emulsion, entirely salutes some characteristics that are different from the milky emulsions discussed previously. These new systems are called microemulsions. The interfacial tension between phases, amount of energy required for formation, droplet sizes and optical appearance are only a few of the differences seen when comparing emulsions to microemulsions.Microemulsions are in many respects small-scale emulsions. They are fragile systems in the sense datum that certain surfactants in specific concentrations are needed for microemulsion formation 11. In simplest form, they are a mixture of oil, water and a surfactant. The surfactant, in this case, generates an ultra-low fall by the wayside energy per unit of interfacial area between the two phases (103mN/m) which results from a precise balance between thehydrophilic and lipophilic nature of the surfactant and large oil-to-water interfacial areas.These ultra-low free energies allow thermodynamically stable equilibrium phases to exist, which require only gen tle mixing to form 12. This increased surface area would ultimately influence the transport properties of a drug 14. The free energy of the system is minimized by the compensation of surface energy by dispersion entropy. The flexible interfacial film results in droplet sizes that fall in a range of 10-100 nm in diameter for microemulsion systems. Although these systems are formed spontaneously, the driving forces are small and may possibly take time to reach equilibrium 14.This is a dynamic process. There is diffusion of molecules indoors the microstructures and there are fluctuations in the curvature of the surfactant film. These droplets diffuse through the continuous phase while kinetics of the collision, merging and separation of droplets occur 13, 10. With droplet sizes in the nanometer range, microemulsions are optically transparent and are considered to be solutions. They are homogeneous on a macroscopic scale, still are heterogeneous on a molecular scale 7. Microemulsions usually exhibit low viscosities and Newtonian flow characteristics.Their flow will remain eternal when subjected to a variety of shear rates. Bicontinuous formulations may show some non-Newtonian flow and plasticity 16. Microemulsion viscosity is close to that of water, even at high droplet concentrations. The microstructure is ceaselessly changing, making these very dynamic systems with reversible droplet coalescence 15. To study the different properties of microemulsions, a variety of techniques are usually employed. Light scattering, x-ray dif ingredient, ultracentrifugation, electric conductivity, and viscosity measurements have been widely used 20.These are only a few of themany techniques used to characterize microemulsions. Instrumentation and their application to microemulsions will be discussed in a later chapter. 1. 2. 2 Types of Microemulsions Microemulsions are thermodynamically stable, provided are only found under carefully defined conditions 3. superstar way to ch aracterize these systems is by whether the domains are in droplets or continuous 22. Characterizing the systems in this way results in three types of microemulsions oil-in-water (o/w), water-in-oil (w/o), and bicontinuous.Generally, one would assume that whichever phase was a larger volume would be the continuous phase, but this is not always the case. Figure (2) Possible nanostructures present within microemulsions a) o/w b) o/w, and c) Bicontinuous 22 Oil-in-water microemulsions are droplets of oil adjoin by a surfactant (and possibly co-surfactant) film that forms the indispensable phase distributed in water, which is the continuous phase. This type of microemulsion generally has a larger interaction volume than the w/o microemulsions 23.The monolayer of surfactant forms the interfacial film that is oriented in a arbitrary curve, where the polar head-groups face the continuous water phase and the lipophilic go after face into the oil droplets 17. The o/w systems are interesti ng because they enable a hydrophobic drug to be more soluble in an sedimentary based system, by solubilizing it in the internal oil droplets. Most drugs tend to favor small/medium molecular volume oils as irrelevant to hydrocarbon oils due to the polarity of the poorly water-soluble drugs. An o/w drug delivery tends to be straightforward when compared to w/o microemulsions.This is the result of the droplet structure of o/w microemulsions being retained on dilution with the biologic aqueous phase 23. Water-in-oil microemulsions are made up of droplets of water surrounded by an oil continuous phase. These are generally known as reverse-micelles, where the polar headgroups of the surfactant are facing into the droplets of water with the fatty harsh tails facing into the oil phase. This type of droplet is usually seen when the volume fraction of water is low, although the type of surfactant impacts this as well.A w/o microemulsion used orally or parenterally may be destabilized by th e aqueous biological system. The biological system increases the phase volume of the internal phase, at long last leading to a percolation phenomenon where phase separation or phase inversion occurs 23. Oral peptide delivery in w/o microemulsions is still used, however, The hydrophilic peptides can be easily incarnate into the water internal phase and are more protected from enzymatic proteolysis by the continuous oil phase than other oral dosage forms 17, 18.A w/o microemulsion is best employed, though, in situations where dilution by the aqueous phase is un same(p)ly, such as intramuscular injection or transdermal delivery 17, 19. When the amount of water and oil present are similar, a bicontinuousmicroemulsion system may result. In this case, both water and oil exist as a continuous phase. Irregular channels of oil and water are intertwined, resulting in what looks like a sponge-phase 20, 21. Transitions from o/w to w/o microemulsions may pass through this bicontinuous state.B icontinuousmicroemulsions, as mentioned before, may show non-Newtonian flow and plasticity. These properties make them curiously useful for topical delivery of drugs or for intravenous administration, where upon dilution with aqueous biological fluids form an o/w microemulsion 25. 1. 2. 3 Preparation of Microemulsion The preparation of microemulsions requires the decision of the existence range of microemulsions, which can be determined by visual reflexion of unhomogeneous mixtures of surfactant, co-surfactant, oily phase, and aqueous phase reported in a phase diagram.Two techniques are presented in the literature, each of them resulting in microemulsions (1) demand process by autoemulsification (2) process based on supply of energy. 1. 2. 3. 1 Autoemulsification Due to the spontaneous formation of the microemulsions, they can be prepared in one tempo by mixing the constituents with magnetic stirrer. The order of the accession of the constituents is not considered a critical fa ctor for the preparation of micro emulsions, but it can influence the time required to obligate equilibrium.This time will increase if the co-surfactant is added to the organic phase, because its greater solubility in this phase will prevent the diffusion in the aqueous phase. This method is easier and much simpler then supply of energy method 25. 1. 2. 3. 2 Process based on supply of energy In this case, microemulsions are not obtained spontaneously. A decrease of the quantity of surfactants results in the use of high- crush homogenizers in order to obtain the desired size of droplets that constitute the internal phase as opposed to the former technique 23.Benita and Levy 18 have studied the efficacy of various equipment for obtaining particles of different sizes. Two steps are required the first step produces a coarse emulsion (0. 65 mm) by using a high-speed mixer. The second step consists of using a high pressure homogenizer. The dispersion of the oily phase in the aqueous phas e is in addition facilitated by heating the phases before mixing them, the choice of the temperature depending on the aesthesia of the drug to heat.Cooling the preparation is required before its introduction in the trenchant homogenizer, which can raise the temperature. A blue opalescent micro emulsion is obtained. 1. 2. 4 Review of literature The microemulsion dosage form provided a delay pharmacologic action compared to the pharmacological action of regular eye drops. This observation led to the conclusion that the micro emulsion eye drops have a real advantage compared to regular eye drops which must be administered 4 times a day due to the short duration of the pharmacological action.harmonize to Naveh et al. , it appeared that the retention of pilocarpine content in the internal oil phase, and the oil-water interface of the emulsion are sufficient to concomitantly enhance the ocular absorption of the drug through the cornea, and also increasing the corneal concentration of pilocarpine. After comparing the diffusion profiles of two microemulsions preparations and an aqueous solution of pilocarpine, Hasse and Keipert 29 studied their pharmacological effect in vivo by using six rabbits for each group.The obtained results were different from those observed in vitro. The two microemulsions provided a delayed release compared to the release of the drug incorporated in the aqueous solution. No experimental study has been conducted with microemulsions prepared by autoemulsification. However, several trials were conducted with microemulsions prepared by supply of energy. Melamed et al. 27 prepared micro emulsions containing adaprolol maleate. According to these authors, no ocular irritation was noticed in the group of xl healthy volunteers as opposed to regular eye droplets.The depressor effect was delayed the intra-ocular pressure was still high 6 and 12 h after the instillation of the micro emulsion. A iodine instillation of microemulsion or corresponding placebo, namely microemulsion without any drug, was administered to twenty healthy volunteers. The determined parameters were the pupillary diameter and variation of intra-ocular pressure. The effect of the micro emulsion which contains pilocarpine is obvious as compared to the placebo and was noticed within 1 h from instillation. The return to the initial value was noticed within 12 h 28,29. Lv et al. 32 investigated micro emulsion systems composed of Span20/80, Tween20/80, n-butanol, H20, isopropyl palmitate (IPP)/isopropy lmyristate (IPM) as model systems of drug carriers for eye drops. The results showed that the stability of the chloramphenicol in the micro emulsion formulations was increased remarkably. Study of the effect of a single dose of atenolol 4% eye drops on 21 patients with primary open-angle glaucoma during a double-blind clinical trial. Monitoring of intraocular pressure (IOP), blood pressure, and quiver rate. At three and six h after medication, the average dec rement of IOP was 7. and 4. 1 mm Hg respectively compared to the baseline readings without medication. The reduction of IOP at four h after medication was 6. 3 mm Hg compared to the pretreatment value. This corresponds to an average change from the pretreatment value of 22 percent. Blood pressure and twinkling rate did not change significantly. We observed no subjective or objective ocular side effects. The duration of the effect of a single dose of atenolol 4% eye drops is approximately six h. atenolol 4% eye drops may become a useful agent in the medical treatment of glaucoma if a long-term effect and no ocular side effects 30. . 3 Atenolol Atenolol is a selective ? 1 receptorantagonist, a drug belonging to the group of genus Beta blockers (sometimes written ? -blockers), a class of drugs used primarily in cardiovascular diseases. Introduced in 1976, atenolol was developed as a replacement for propranolol in the treatment of hypertension. The chemical works by slowing down the he art and reducing its workload. Unlike propranolol, atenolol does not pass through the blood-brain obstacle thus avoiding various central nervous system side effects. 25 Atenolol is one of the most widely used ? -blockers in the United body politic and was once the first-line treatment for hypertension. The role for ? -blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line, as they perform less appropriately or effectively than newer drugs, particularly in the elderly. Some evidence suggests that even in normal doses the most frequently used ? -blockers carry an unacceptable risk of exposure of provoking type 2 diabetes. Figure (3) Chemical structure of Atenolol 26