ay in hIntroduction
As a matter of fact, ophthalmic drug delivery have been considered one major area of pharmaceutical technology for many years. There are many reasons which have make scientists prefer using these delivery systems over any others.
Firstly, the bad bioavailability of drugs from ocular dosage forms is essentially because of the eye's intricate anatomical structure, the small spongy-like surface, lipophilicity of the cornea’s outermost region and drug bonding with proteins in tear fluid, in addition of, the defense mechanism of the eye, rapid turnover lacrimal fluid, eye blinking and extensive nasolacrimal drainage (Pahuja, et al., 2012 & Gaudana, et al., 2009).
Secondly, limited capacity of the upper and lower fornices (conjunctival sac) which is, about 30 µl, the mentioned defense methods cause short pre-corneal residence time, which limits effective transcorneal drug absorption.
The main function for the development of the ophthalmic dosage forms is to increase the bioavailability of ophthalmic drugs by prolonging the contact time between the preparation and corneal / conjunctival epithelium (Tangri and Khurana, 2011).
In recent years, it has been conducted on newer drug dosage forms which make it possible to use the exact amount of drug needed for eyeball tissues. These include multi-compartment carrier systems, insertions, collagen corneal shields, in situ-forming gels ,and contact lenses (Pahuja, et al., 2012). Using these drug dosage forms of controlled release is advantageous for many reasons; increase drug bioavailability by prolonging pre-corneal contact time, the probability of targeted therapy inhibiting the loss of drug to other tissues is increased, guaranteeing patient’s comfort on applying the drug form and during the complete therapy and increase the resistance to eye defense mechanisms, such as tearing (Rajasekaran, et al., 2010).
Eye anatomy
The eye is said to be shaped not similar a true sphere, in stead it is a fused two pieces unit. It is made up of two basic parts: the cornea which is like a dome representing the smaller frontal unit and the sclera which is connected to larger unit commonly known as the white. The radius of corneal segment is normally nearly 8 mm. The sclerotic chamber makes up the remaining five-sixths, with a radius about 12 mm. The cornea and sclera are linked by the limbus ring, which forms a border between the transparent cornea and opaque sclera. The reason that the iris which is the colored part of pupil and eye, its black center, are seen rather than the cornea, because of the cornea's transparency.
The eye ball consists of the following tissues;
1. Eye brows and eyelids.
2. The conjunctiva.
3. The outer most layer of the eye includes; cornea and sclera, known as the fibrous tunic.
4. The middle layer of the eye includes; choroid, ciliary body and iris, known as the vascular tunic or uvea.
5. The innermost layer of the eye includes; retina, optic nerves, chamber of the eyes and macula.
These layers are the aqueous humor, the vitreous humor and the elastic lens.
Fig. 1: Anatomical view of Human eye.
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The cornea
The cornea is the transparent external surface that covers both the pupil and the iris and has a diameter of about 11. 7 mm. It shapes the anterior one- sixth of the eyeball. Cornea conveys images to back of the eye and it is considered the main pathway for topical drugs permeation into the eye. The composition of the sclera and cornea is identical but, the clear appearance of cornea is because of the regular arrangement of the collagen fibers, while in the sclera, the fibers appear interwoven and extend in all directions. The cornea consists of five layers; epithelium, bowman’s membrane, stroma, descemet’s membrane and endothelium (Presland, 2007).
The corneal epithelium
It is lipoidal in nature, it should be noted that, the epithelium comprises 90 % of whole cells in cornea. Since the primary function of the epithelium is to block the passage of foreign material, it is very natural that it acts like a defensive barrier against the access of topically administered hydrophilic drugs. In addition, the fact that superficial corneal epithelial cell are linked together via desmosomes and enclosed by ribbon-like tight junctional complexes delays permeation of paracellular drug from the tear film into intercellular spaces of epithelium and the cornea inner layers. Consequently, the penetration rate of the drug is not sufficient enough to yield a desirable rapid healing effect.
The stroma
This is the thickest layer of the cornea. It lies between the epithelium and the inner endothelium. It is composed of organized collagen which maintain transparency. It is highly hydrated in nature, so, it resists the permeation of lipophilic drug.
The Endothelium
It is an extremely thin single layer of hexagonal-shaped cells and located in the inner surface of the cornea. To keep the cornea clear, this layer of cells drains water from the cornea, through a process of pumping. Because of its selective carrier-mediated transport and secretory job, it helps preserve the aqueous humor and corneal lucidity (Barar, et al., 2008). In addition, one characteristic of the corneal endothelial junctions is that they are permeable in such a way to let macromolecules passage among the aqueous stroma and humor happens in an easy way (Sunkara, 2003).
Hence, the main defense mechanisms for the ophthalmic drug delivery systems are corneal layers especially the epithelium and stroma. It is essential to understand that ocular dosage forms should be able to pass through particular permeable membranes those possess an amphipathic features to permeate across the layers (Barar, et al., 2008).
Fig. 2: Layers of cornea.
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The conjunctiva
Conjunctiva, (as shown in Figure 3), is a thin, transparent, moist mucous membrane, which patents at the junction of corneal scleral. Conjunctiva consists of, palpebral conjunctiva that forms the inner lining of the upper and the lower eyelids; bulbar conjunctiva covers the eye itself, except for cornea, and fornix, which is the area where the two conjunctivae meet. The conjunctiva epithelium is continuous with that of the cornea and the lachrymal drainage system. It is vascular and moistened by the tear film.
Fig. 3: Structure of conjunctiva.
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The sclera
It is outer opaque, fibrous, protective coat of the eye, and known as the "white". The sclera is continual with the clear cornea which starts from limbus and expands posteriorly through the rest of eye globe. It contains primarily of connective tissues (proteoglycans and collagen fibers) and has three layers (anterior to posterior): the episclera, the scleral stroma and the lamina fusca (Nanjawade, et al., 2007).
The permeability through sclera is also influenced by the charge on the drug molecule. Positively charged molecules causes low permeability seemingly because of their close connection to the negatively charged proteoglycan matrix of the sclera (Kim, et al., 2007).
Tear film
The tear film is highly specialized moist film that covers conjunctiva and cornea. A tear consists of three layers:
1. The outer oily layer that works as a sealant protecting tears from evaporating.
2. The middle aqueous layer that transports vitamins and minerals to the cornea.
3. The inner mucous layer that aids in moisturizing the eyes.
Tears contain water which forms about 98.2%. The other remaining 1.8% ingredients are solids such as salts, lipids, proteins, magnesium, potassium, sodium, calcium, chloride, bicarbonate, urea, ammonia, nitrogen, citric acid, ascorbic acid, and mucin. Tears have pH ranging between 6.5 and 7.6 and the quantity secreted per hour is between 30 and 120 ml. the tears are well-buffered system, because instilled solutions of different pH are quickly returned to physiological condition (Gipson and Argueso, 2003).
Nevertheless, this liquid layer exhibits a fast returning time ( 2-3 minutes), and majority of topically administered drops disappear within just 15–30 seconds after instillation. The average volume of the human tear is around 7 μl. The cul-de-sac is able to hold about 30 μl of the administered eye solution. Because of the short contact time of the dosage forms with the absorptive membranes, it is deliberated to be the main reason for less than 5% of the applied dosage forms getting into the intraocular tissues, taking into consideration all the precorneal factors (Ahmed, 2003).
Ophthalmic drug delivery
Three problems facing the pharmaceutical scientist in ophthalmic drug delivery; anatomy of the eye, eye physiology and the chemical and physicochemical processes that occur within the eye. These three problems make this very precious organ delicately sensitive to foreign interference.
The perfect ocular drug delivery system must capable to control the delivery of drugs of fluctuating physicochemical properties and offer constant therapeutic action on the eye. It should be non-irritating, sterile stable, and non-sensitizing, for allowing multiple dosages. The perfect ocular drug delivery system must be causes no foreign-body sensation or interference with vision, biodegradable, easily manufactured and with relatively low cost (Kaur & Kanwar, 2002).
The local ophthalmic therapy offers many advantages over that of systemic therapy used for the treatment of eye diseases and disorders. The local application is used in order to restrict the site of drug action to the eye, reduce the quantity of drug employed and the possibility of unwanted systemic effects (Diebold & Calonge, 2010).
Eye drops and ointment make up about 70% of ophthalmic drug delivery in the market. The problem with these medications is that once infused into the blind pouch known as cul-de-sac of the eye, they tend to be quickly drained away from the ocular cavity. This happens naturally as a result of the tear flow and nasolachrymal drainage. Accordingly, a very little amount of the medication remains. So the frequent dosing that is recommended by the ophthalmologist to produce the therapeutic effect. In the last three decades, therefore, newer pharmaceutical ophthalmic formulation such as in-situ gel, nanosuspension, liposomes, nanoparticles, microemulsions, intophoresis and ocular inserts have been developed to enhance the bioavailability of the drug. (Binstock and Domb, 2006).
Routes of drug application to eye
Routes of administration are commonly classified by the place at which the drug is applied. Common examples comprise oral and intravenous administration. Routes can also be classified according to site of action; topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract).
a- Topical administration
It is the application of drug preparations to the surface of the infected area of the body, in our case the eye. Some barriers within the eye pose a major challenge for delivery of the drug. Layers of cornea, sclera, and retina are called static barriers. Others such as dynamic barriers (choroid and conjunctival blood flow, tear dilution, and lymphatic clearance). It should be noted that after administration, these barriers are harmfully affect the topical formulations bioavailability (Ananthula, et al., 2009).
b- Parenteral administration
Unlike the topical administration in which the drug is applied directly on the area where its action is desired, or the enteral administration where the drug is given via the digestive tract, the parenteral or systemic administration occurs when drug is injected into the blood stream. The defense mechanism that the warts exchange of materials between the chambers of the eye and the blood known as the blood–aqueous barrier is the major barrier for anterior segment and blood–retinal barrier is posterior segment ocular drug delivery.
The tight junctions of the non-pigmented epithelium of the ciliary body, the junctions of the iris tissues, and iris blood vessels make up the blood-aqueous barrier. These layers stop the access of drugs into the intraocular environment (Gazayerly, et al., 1997).
The blood–ocular barrier that consists of cells attached tightly together to stop certain substances from entering the tissue of the retina is called the Blood–Retinal Barrier (BRB). It is made up of two kinds of cells known as the inner and the outer barriers.
The inner type is placed inside the retinal microvasculature, whereas the outer type refers to a monolayer of highly specialized cells which act as a barrier. It is formed at the Retinal Pigment Epithelial (RPE) cell layer between the neural retina and the choroid. RPE helps in biochemical process of selective transfer of molecules across photoreceptors and choriocapillaris. Additionally, RPE preserves the optical system via absorption and retinoid adaptation (Jain, et al., 2005).
On the other hand, tight junctions of the Retinal Pigment Epithelial RPE effectively limit intercellular permeation. Since the choroid, the middle layer of the eye located between the sclera and the retina, has a high vasculature when compared to retinal capillaries, so drugs can enter into it after oral or intravenous dosing. Nevertheless, Retinal Pigment Epithelial (RPE) barrier limits extra drugs access from the choroid leaking into the retina. What is needed, then, in order to transmit molecules from the choroid into the retina deeper layers is precise oral or intravenous targeting systems (Barar, et al., 2008).
Indeed, Gene delivery to the eye with intravenous path of administration has received some attention in the past few decades. Scientists observed a prolix expression of SV40/β galactosidase gene of mice inner retina, RPE, iris, along with conjunctival epithelium after intravenous administration of polyethylene glycol conjugated with immuno liposomes (Ghate and Edelhauser, 2006).
c- Periocular and intravitreal administration
These two routes are used to certain extent to avoid the ineffectiveness of topical and systemic dosing in therapeutic concentrations to the posterior segment of the eye. Furthermore, systemic administration can result in adverse effects that make it uncommon delivery route for elderly patients. Periocular route involves; peribulbar ,subconjunctival, sub-Tenons, and retrobulbar administration, it is reasonably less aggressive than intravitreal route.
Three various ways can be used to enable drugs administered by periocular injections and reach to the posterior segment:
1. Trans-scleral pathway.
2. Systemic circulation through the choroid.
3. The anterior pathway through the tear film, cornea, aqueous humor, and the vitreous humor (Ghate and Edelhauser, 2006).
Since the sclera occupies two thirds of the eye surface, it is a tempting route for ocular drug delivery taking into consideration that drugs delivered by trans-scleral pathway can reach both anterior and posterior segments of the eye. If the permeability of both sclera and cornea is compared, it is soon discovered that, the sclera is very permeable through numerous molecular weight of compounds, than cornea. Moreover, when aiming at the choroid and retina, the sclera has a shorter diffusional path way than that of the cornea (Hosseini, et al., 2008 & Kim, et al., 2009).
The most direct means of delivering drug to the vitreous humor and retina is by intravitreal injection, while this method of administration has been connected to dangerous side effects (e.g.,endophthalitis, retinal detachment ,cataract, and hemorrhage)(Geroski and Edelhauser, 2000), intravitreal injection remains the best choice for a cut intraocular treatment. This route has become the standard of care for providing treatment of several chronic ocular disease, such as associated retinal edema. In addition, after an intravitreal injection, the vitreous body serves as a defense mechanism for retinal gene delivery. It should be noted that the vitreous body has a high ratio of hyaluronic acid which has negatively charged with glycosaminoglycan. This hyaluronic acid can interact with cationic lipid, polymeric, and liposomal DNA complexes (Pitkanen, et al., 2003). The problem of this reaction is that, it can cause serious accumulation and entire DNA/ cationic liposome complexes immobilization.
In the same way, two factors determine the nanoparticles mobility in the vitreous body; the structure and the charge of surface. The reason that produce the polystyrene nanospheres is that they stick to collagen fibrillar structures (Peeters, et al., 2005).
The boundary between the vitreous body and the retina is called the inner limiting membrane that forms a barrier for retinal delivery after intravitreal administration of gene-therapy. For instance, when the adeno-associated virus penetrates the retina coming from the vitreous body, the inner limiting membrane represents a formidable defense barrier. Notably, mild digestion of the inner limiting membrane with a nonspecific protease activated considerably enriched multiple retinal cell types transduction from the vitreous. This is a good indicator of the vitreous' high barrier property (Dalkara, et al., 2009). In addition, because of the existence of Retinal Pigment Epithelial (RPE), drug transfer between vitreous and external segments of retina and choroid is more complicated.
d- Subconjunctival application
In addition to being loss invasive compared with intravitreal injection, subconjunctival injection can be well suited to drug depots for prolonging the duration of drug therapy. Furthermore, this type may avoid of the toxicity come across systemic administration, with concentrations of drug in eye normally higher and systemic administration (Ghate, et al., 2007).
Types of ophthalmic dosage forms
Various types of ophthalmic dosage forms are commonly used such as; (Lang, et al., 2006).
1. Liquid dosage forms; Eye drop, microemulsions, in-situ gel systems and suspensions.
2. Semisolid dosage forms; Gels and ointments.
3- Non-biodegradable Ophthalmic inserts; Ocular inserts and contact lenses.
4- Degradable ophthalmic inserts.
5- Minidiscs/OTS (Ocular Therapeutic System).
6- Collagen shield.
7- New ophthalmic delivery system (NODS).
8- Ophthalmic minitablets.
9- Vesicular drug delivery systems.
1- Liquid dosage forms
A) Eye Drops
Eye drops are still the main method of using topical ocular route. This is may be due to, easiness of manufacturing and managing, does not cause unclear vision and relatively cheap . The medicament in eye drops was instilled into the eye for its anesthetic, antibacterial, anti-inflammatory, miotic, mydriatic or other specific effects. Eye drops should instilled with special care because the mucous membranes of the eye are very sensitive. Thus, eye drops must fulfill certain requirments like; clarity, pH and buffering capacity, tonicity, stability, viscosity, the proper choice of preservative and sterilization (Ding, et al., 2006).
B) Microemulsions
Microemulsion can be defined as a clear, thermodynamically stable homogenous dispersion of two immiscible liquids containing appropriate amounts of surfactants and cosurfactant. It is characterized by the small particle size of its dispersed phase (Fialho & Silva- Cunha, 2004). The presence of surfactant and cosurfactant is highly advantageous, because they increase membrane permeability to the drug uptake so the system acts as penetration enhancer to facilitate corneal drug delivery (Lawrence and Rees, 2000).
C) In-situ gel systems
A disadvantage of solutions is their moderately short seat time in the eye, which can be avoided via the development of solutions that are liquid in container and this can be instilled as eye drop but transformed to gel on contact with the tear fluid. Thus, it increase contact time with the possibility of improve drug absorption and increase duration of therapeutic effect.
In general, the gelation of a polymeric solution can be triggered by a number of factors (Hatefi and Amsden, 2002), such as change in temperature, as for poloxamers (Cho, et al., 2003) and cellulose derivatives. Change in PH, as for cellulose acetophthalate and carbopol (Srividya, et al., 2001), or the presence of cations, as for alginates and gelrite. Some drugs as ciprofloxacin hydrochloride, ganciclovir, pilocarpine ,and timolol maleate are prepared in the form of gel forming solutions (Gaudana, et al., 2009, Tangri and Khurana, 2011 & Rathore and Nema, 2009).
D) Suspension
Ophthalmic suspensions are aqueous preparations ,which include solid particles. The size of the particle should be the smallest to avoid irritation of the eye. It is suggested that particles must not excced10 µm in to diminish the eye irritation. This range of size is considered to satisfy this necessity. A second condition is the existence of tendency of the solid undissolved particles to adhere to conjunctiva. When drug is absorbed, these solid particles will dissolve to replenish the absorbed drug. This reservoir influence rises the contact time and duration of action of a suspension on comparing with a solution preparation.
2- Semisolid dosage forms
A) Eye Ointments
Eye ointments are a sterile semisolid preparation of drug involving solid or semisolid hydrocarbon base with a melting or softening point near to the body temperature. They are applied outside the edges of eyelid to the conjunctiva and the cornea to produce a local effect directly on the eye. One major advantage of eye ointment is that, after applications, it decays into small drops that remain for a longer time in conjunctival sac, that means increasing medication contact time. However, there are some disadvantages when using eye ointments, such as; blurred vision and tear film instability following its application. In addition, the use of ophthalmic ointments will not work effectively with contact lens use (Rathore and Nema, 2009).
B) Eye Gels
Gels are another form of ophthalmic preparations which appear to offer several advantages over ophthalmic solutions and ointments, either in terms of improved ocular bioavailability or enhanced therapeutic effects. The polymers used to prepare the pharmaceutical gels include; natural gum, tragacanth, pectin, agar and alginic acid and synthetic and semisynthetic materials such as methylcellulose, hydroxypropyl methylcellulose, carboxyl methylcellulose, polyvinyl pyrrilidon and carbomer. The drug release mechanism from gel includes binding of drug diffusion within the gel and the gel surface ersion (dissolution) (Missel, et al., 2009).
3- Non-biodegradable Ophthalmic inserts
A) Contact Lenses.
Scientists stated that they have created a contact lens coated with certain drugs that can deliver a high concentration of that drug at a steady rate for more than 30 days. In the past, cross-linked poly (2-hydroxyethyl methacrylate) in little quantity of ethylene glycol dimethylacrylate was the most broadly polymer used in the lenses production. Recently, many studies have been carried out on using silicon-based lenses (Jung, et al., 2013 & Peng and Chauhan, 2011). Ciprofloxacin (Hui, et al., 2008), dexamethasone (Boone, et al., 2009), and cyclosporine (Peng and Chauhan, 2011) are examples of drugs that coated with contact lenses.
B) Ocular inserts
These are sterile, thin, multilayered, drug-impregnated, and solid devices placed into the cul-de-sac or conjunctival sac, whose size and shape are particularly intended for ophthalmic application (Aburahma and Mahmoud, 2011). They are made up of a polymeric support that contain a drug. They provide numerous advantages as prolonged ocular residence time and continual release of medication into the eye and so increase bioavailability. The release of drug from the inserts depends upon the diffusion, osmosis, and bioerosion of the drug. (Rathore and Nema, 2009 & Aburahma and Mahmoud, 2011). Several materials are developed for these delivery systems by means of polymer technology.
Polymeric materials most frequently used in the development of inserts as; methylcellulose (Goudanavar, et al., 2012), and its derivatives, that is, hydroxypropyl methylcellulose (HPMC) (Kumar and Sharma, 2013), and ethylcellulose. Polyvinylpyrrolidone (PVP K-90) (Patil, et al., 2012), polyvinyl alcohol (Kumar, and Sharma, 2013), chitosan (Aburahma and Mahmoud, 2011), and its derivatives, like carboxymethyl Chitosan (Goudanavar, et al., 2012), gelatin (Mundada, et al., 2006) and different mixtures of the above mentioned polymers can be used to develop the inserts. There are two types of ocular inserts:
1) Degradable ocular inserts
They are prepared with water-soluble polymers absorb the tear fluid and slowly dissolved and erode, then releasing their content of drug. They have potential benefits: increasing retention time and thus elongate therapeutic effect , biodegradable, and drug bioavailability (Missel, et al., 2009).
2) Non degradable ocular inserts
They have also been developed with polymers related to soft contact lenses and ethylene vinyl alcohol copolymers. The matrix requires topical safety during application and removal from the eye after use (Missel, et al., 2009). A famous ocusert is (Alza Corporation), which is prepared from copolymer of ethylene and vinyl acetate. It is an instance of insoluble insert that consist of an active ingredient pilocarpine (Venkata Ratnam, et al., 2011).
Inappropriately, these insert delivery systems are refused by patients owing to discomfort, interference with vision and the feeling of foreign (Aburahma and Mahmoud, 2011 and Venkata Ratnam, et al., 2011).
4- Degradable Ophthalmic Inserts
Composed of copolymers of acrylamide, poly-vinylpyrrolidone, and ethyl acrylate, impregnated with a drug. They are soluble eye ocular inserts in shape of small oval crackers. They are wetted with tear fluid, thus they soften and adhere to eyeball surface after they are applied to conjunctival sac. Drug diffuses from SODI in a pulsational, uncontrolled manner, and so increase the effectiveness of the drugs. The soluble ophthalmic inserts are effective in retaining many drugs (e.g., neomycin, kanamycin, atropine, pilocarpine, dexamethasone, tetracaine and sulfapyridine) (Shivhare, et al., 2012).
5- Minidiscs / OTS (Ocular Therapeutic System)
It is a contoured disc, convex outside, concave in contact with eye ball, it's dosage is similar to a contact lens with 4-5 mm diameter. Core copolymers from which minidiscs are made are –bis (4-methacryloxy)-butyl poly (dimethylsiloxane) and poly (hydroxyethyl methacrylate). This dosage form may be either hydrophilic or hydrophobic that permits prolonged time period of release of water-soluble and poorly water-soluble drugs. Sulfisoxazole and gentamicin sulfate are the active ingredients employed in research on minidiscs (Nisha, et al., 2012 & Rajasekaran, et al., 2010).
6- Collagen Shield
Succinylateed collagen was used to fabricated erodible inserts for placement in the fornix for long-term delivery of some drugs into the eye.
Sometimes collagen shields are manufactured from porcine scleral tissue, which bears a collagen composition similar to that of the human cornea (Willoughby, et al., 2002). The shields are kept in dry conditions and hydrated earlier introducing to the eye. Drug is loaded into collagen shield easily via soaking in the drug liquid. The collagen matrix: performs as a stock, which increasing the contact time between drug and cornea, reversibly combines drug molecules which are successively released in a slowly and decrease the systemic toxicity, particularly if dose reduced is probable.
7- New Ophthalmic Delivery System (NODS)
New Ophthalmic Delivery System is a dosage form established by Smith and Nephew Pharmaceuticals Ltd, the system consists of solidified paper handle and a polyvinyl alcohol flag, containing the active ingredient, fixed to the handle with a soluble membrane. A film-containing drug splits from the handle at the point of introduction to conjunctival sac and liquefies in the tear liquid, discharging the active ingredient. This system guarantees delivery of specified drug dose to the eyeball and improved bioavailability of active ingredient (up to eight fold in the case of pilocarpine) on comparing to traditional eye drops. New Ophthalmic Delivery System is free of preservatives and is sterilized by rays of gamma (Baranowski, et al., 2014).
8- Ophthalmic Mini-tablets
They are biodegradable and solid dosage formulas that change into gels, after use to conjunctival sac. It is used to prolong contact time between the drugs and the eyeball surface, so increase the bioavailability (Weyenberg, et al., 2005). It is suggested that Mini-tablets have the advantages : easiness of usage, resistance to defense mechanisms like tearing or drainage via nasolacrimal duct, long contact time with the cornea because of the existence of muco-adhesive polymers and slow releasing of active ingredient from the formulation on site of application because of the outer carrier layers swelling (Moosa, et al., 2013 & Abd El-Gawad, et al., 2012).
The choice of the polymer to function as drug carrier in minitablets is an important factor to consider because it contributes to the manner in which the delivery system operates and to how the drug is release. Specifically, polymers should be biocompatible, bviodegradable, non-toxic and readily available (Thakur and Kashiv, 2011). Common polymers used in mini-tablets include; cellulose derivatives, such as hydroxypropyl methylcellulose, ethyl cellulose ,hydroxyethyl cellulose, and sodium carboxymethyl cellulose, (Ghadjahani, et al., 2012 and Mortazavi, et al., 2010), acrylates (Moosa, et al., 2013), that is, polyacrylic acid and its cross-linked forms, carbopol or carbomer (Weyenberg, et al., 2005), chitosan (Moosa, et al., 2013), starch as; drum-dried waxy maize starch (Weyenberg, et al., 2005).
Minitablets are manufactured by direct compression technique or indirect method. The advantage of indirect technique is the dry granulation phase that improves flow properties of powders frequently inclosing bio-adhesive polymers, which facilitates minitablets manufacturing (Weyenberg, et al., 2005).
Minitablets are effective in retaining various drugs as; piroxicam (Abd El-Gawad, et al., 2012), timolol (Moosa, et al., 2013, Ghadjahani, et al., 2012), ciprofloxacin (Weyenberg, et al., 2005, Moosa, et al., 2013, and Mortazavi, et al., 2010), gentamicin, and acyclovir (Moosa, et al., 2013).
9- Vesicular Drug Delivery Systems
a) Nanoparticles and Microparticles
Hopeful dosage formulas are considered to be polymeric, solid, multi-compartment drug delivery systems. Two types of polymeric vesicles can be distinguished according to particle size into; nanoparticles and microparticles. They are colloidal particles 10-1000 nm or 0.01-1 µm in size for nanoparticles and microparticles, respectively, in which drug able to be distributed, compressed or absorped.
Nanoparticles are polymeric carriers, built from biodegradable, biocompatible, natural, or synthetic polymers with often mucoadhesive properties (Nagarwal, et al., 2009 & Sahoo, et al., 2008), such as poly (alkylcyanoacrylate), polylacticacid, poly(epsilon-caprolactone), gelatin , poly(lactic-co-glycolicacid), chitosan, (Bucolo, and Salomone, 2012 & Mudgil, et al., 2012), sodium alginate (Sahoo, et al., 2008 and Mudgil, et al., 2012), and albumin (Mudgil, et al., 2012). These forms can be classified into nanospheres and nanocapsules. Nanospheres are solid, monolithic spheres made of dense polymer matrix, wherein the active ingredient is dispersed, while nano-capsules creating reservoirs, made of polymer membrane contiguous the drug in solid or liquid form (Bucolo and Salomone, 2012). The drug absorption mechanism from nano-spheres or nano-capsules after their application to conjunctival sac includes dispersion of the drug and degradation of the polymer (Rathore, and Nema, 2009). The benefits of nano-particles are, as an ophthalmic dosage form, they increase the penetration of corneal and huge the dissolution area, which enhances of the drug bioavailability on comparing with traditional eye drops (Bucolo, and Salomone, 2012).
b) Liposomes
They are phospholipid drug carriers commonly involve phosphatidyl choline, stearyl amine, and different quantities of cholesterol or lecithin and α-L-dipalmitoyl-phosphatidylcholine (Sahoo, et al., 2008, Kaur, et al., 2004 and Budai, et al., 2007). The advantages of liposomes are; biocompatibile, biodegradabile, amphiphilic properties, and relative in toxicity (Tangri and Khurana, 2011 & Sahoo, et al., 2008). Liposomes are a potentially beneficial ocular drug delivery system, but have drawbacks of instability because of the hydrolysis of phospholipids commonly utilized in their manufacturing, low drug loading capacity and technological problems to gain a sterile preparation of liposomal (Sahoo, et al., 2008 & Rathore and Nema, 2009).
Their use in ophthalmic drug formulae can enhancement the bio-availability of the drug and protect the drug from enzymes existing on the surface of corneal epithelium (Sahoo, et al., 2008). It must be stressed that efficacy in the active ingredient delivery from liposomes depebdes on many factors, that are, size , charge , stability of liposomes in conjunctival sac, resemblance to corneal surface, and encapsulation effectiveness, (Sahoo, et al., 2008 & Kaur, et al., 2004).
Liposomes with Positive charges are more efficient than those with negatively charged or neutral or liposomes in improving the corneal absorption of certain ocular drug. This may be due to the corneal epithelium is finely coated with negatively charged mucin to which the positive surface charged of the liposomes may be adsorbed more powerfully (Sahoo, et al., 2008). Introducing liposome suspensions to muco-adhesive gels has been proposed for maximizing adhesion of liposomes carry negative and no charges to corneal or conjunctival surface (Rajasekaran, et al., 2010), and so increase contact time between liposome suspensions and eye. Acyclovir, pilocarpine, acetazolamide, chloramphenicol and ciprofloxacin were developed as liposomal ophthalmic drug delivery system have (Kaur, et al., 2004 & Budai, et al., 2007).
c) Niosomes
They are stable, made of nonionic surfactants, two layered carriers utilized for both hydrophilic and hydrophobic molecules, aiming to avoiding disadvantages of liposomes (instability, oxidative decaying of phospholipids, and high cost of natural phospholipids) (Nisha, et al., 2012 and Shivhare, et al., 2012). Furthermore, they are bio-degradable, biocompatible, and non-immunogenic carriers, prolong the contact time between drug and cornea that in turn improves drug’s bioavailability (Sahoo, et al., 2008).
d) Dendrimers
They are spherical, branched, mono-disperse and three dimensional polymer configurations of particular shape, size, and molecular mass (Malik, et al., 2012 & Vandamme and Brobeck, 2005). Dendrimers can be employed as carriers, which encapsulate the drug into the polymer configuration or, electrostatic or covalence bonds between drug and their active groups (carboxyl, hydroxyl and amine groups) (Mishra, 2011 & Vandamme and Brobeck, 2005). It is revealed that poly-amidoamine dendrimers, employed as carriers for ophthalmic drugs to expand the duration of drug efficacy and rise the bioavailability (Vandamme and Brobeck, 2005).
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