Hydrophilic Ointment Classification Essay

Although ointment bases can be classified in many ways, the simplest one based on composition is as follows:

A. Oleaginous bases.

B. Absorption bases.

C. Emulsion bases.

D. Water-soluble (hydrophilic) bases.

A. Oleaginous bases

Salient characteristics of these bases are:

i) they are anhydrous,

ii) they are hydrophobic (do not absorb water readily),

iii) they are insoluble in water, and

iv) they are not removable by water.

These are the earliest ointment bases which consisted of vegetable and animal fats as well as petroleum hydrocarbons. A list of commonly used materials has been given here although in practice still a larger number of materials are used.

Oleaginous bases are expected to provide a film, which resists soap and water yet readily removable by solutions of surfactants. This can possibly be achieved by emulsifying the silicones or other hydrophobic film formers so that when the protective ointment is properly applied, an invisible protective film is left on the skin. Film forming agents are exemplified by polyvinylpyrollidone, polyvinyl alcohol and the cellulose derivatives.

B. Absorption bases

The term absorption as applied here implies the hydrophilic or water absorbing properties of the base and not the absorption of medicaments from the bases. These bases are generally anhydrous but capable of absorbing several times their own weight of water ultimately forming w/o type of emulsions.

Absorption bases vary in their composition and are usually mixtures of animal sterols with petrolatum. Eucerin and Aquaphor are the commercial bases consisting of combination of cholesterol and/or other suitable lanolin fraction with white petrolatum. Anhydrous absorption bases can also be formulated by the addition of lipophilic surfactants to
petrolatum and anhydrous water-removable bases can be formed by the addition of hydrophilic surfactants to petrolatum. Some important formulae of absorption ointment bases are given below.

Absorption bases were primarily developed so as to have a product to which water or an aqueous solution of medicinal substances could be easily added. These bases are usually highly compatible with the majority of drugs used topically. The limited popularity of absorption bases however is attributed to their greasiness.

C. Emulsion bases

These may be either o/w or w/o type emulsions.

(a) Water-in-oil type emulsion (Hydrophobic ointment):

The w/o type emulsion bases such as lanolin and cold cream are used as emollients. The aqueous phase hydrates the skin and the oily phase forms an occlusive covering which prevents loss of water by evaporation. Emulsion bases also serve as vehicle for medicaments such as sulphur, ammoniated mercury, balsam of peru, zinc oxide etc. The main drawback of w/o emulsion bases is their greasy and sticky nature and therefore they are less popular than o/w type of bases.

Earlier cold creams consisted of oil (40 to 70%), wax or spermaceti (5 to 15%), and water (20 to 35%). Thus a large proportion of water was loosely held in the water- in-oil mixture. More stable creams were later formulated employing borax which formed the sodium soap by reacting with the fatty acids present in the beeswax.

Presently cold creams are also formulated by employing non-ionic surfactants alone or in combination with beeswax. When cold creams are applied, slow evaporation of the water causes a pleasant cooling sensation and hence these creams are given the name 'cold creams'. A simple formula for borax-beeswax cold cream is as follows.

(b) Oil-in-water ointment (Hydrophilic Ointment):

Oil in water type emulsion bases are used as vehicles for medicinal agents. Water being in the external phase they are easily removed with water alone from skin and linen. They are non-grease and non-sticky. Vanishing creams are often used as cosmetics.

The vanishing type of cream bases contain a large proportion of water which may be as high as 80% and this seems to account for the high release of medicaments from such bases. Vanishing creams essentially contain about 20% stearic acid (triple pressed) and a part of it is reacted with alkali to form soap in-situ. About 5 to 10% glycerin is also included in the formulation as humectant which can be substituted either partially or wholly by propylene glycol. The typical sheen of vanishing cream is due to stearic acid.

Truly speaking, vanishing cream should be regarded as dispersion and not an emulsion. Two simple formulae for vanishing cream are given below.

D. Water-soluble bases:

These bases are prepared from mixture of low and high molecular weight polyethylene glycols which range in their consistency from liquids to solids. Their water solubility is due to the presence of many polar groups and other linkages. They are non-volatile, unctuous, inert and possess the ability to form an emollient surface. They neither hydrolyse and deteriorate nor support mould growth.

Medicaments like benzoic and salicylic acids, phenol, tannic acid, bacitracin etc. have a solubilizing effect on bases consisting of high molecular weight polyethylene glycols. Although the diffusion of medicaments through such bases occurs readily yet the percutaneous absorption is very little. Some formulae for water-washable ointments containing polyethylene glycols are given below.

Example

PEG 400 monostearate 26.0 PEG 4000 42.5

PEG 400 37.0 PEG 400 37.5

PEG 4000 37.0 1, 2, 5-Hexanetriol 20.0

Some of the water-soluble bases are also prepared by employing glyceryl monostearate (GMS), cellulose derivative, sodium alginate, bentonite, colloidal magnesium aluminium silicate, and Carbopol 934. Carbopol 934 and acid polymer disperses readily in water to yield an acid solution of low viscosity. It is physiologically inert, non- irritating and non-sensitizer. It exhibits excellent compatibility with materials frequently incorporated in ointment formulations. Some examples of ointment bases employing materials like GMS, hydrocolloids and Carbopol 934 etc. are given below.

Example 01

Calcium citrate 0.05 g

Sodium alginate 3.0 g

Methyl paraben 0.20g

Glycerin 45.0 g

Purified water to make 100 g

Example 02

Petrolatum 32.0 g

Bentonite 13.0 g

Sodium lauryl sulphate 0.5 g

Purified water

Methyl paraben 54 g

0.1 g

Example 03

Mineral oil 10

White petroleum 30

GMS 10

Cetyl alcohol 05

Glycerin 05

Purified water 40

Example 04

Methocel 90 HC 4000 1.0g

Carbopol 934 0.3g

Propylene glycol 20.0ml

Methyl paraben 0.15g

Purified water q.s

Sodium hydroxide q.s pH 7.0 100ml

Each ointment base type has different physical characteristics and therapeutic uses based upon the nature of its components. The following table summarizes the composition, properties, and common uses of each of the five types of bases.


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1. Introduction

Ophthalmic drug delivery presents major challenges for pharmaceutical and medicinal sciences. For several decades, progress has been achieved to improve the currently dosage forms. Ocular diseases are complicated to treat, and ocular forms need to be safe, non-allergic for the patient and sterile. Topical forms represent 90% of the marked formulation [1]. The tear fluid turnover, the nasolacrimal drainage, the corneal epithelium and the blood-ocular barriers are decreasing the local bioavailability of drugs and residence time on the ocular surface in topical application. Only 5%–10% of the drug crosses the corneal barriers. Anterior segment diseases as blepharitis, conjunctivitis, scleritis, keratitis and dry eye syndrome are resolved with topical or periocular administration. The delivery of drug to the posterior segment of the eye for glaucoma, endophthalmitis or uveitis and to the anterior segment has the same issue of poor bioavailability of the drug and barriers. However, intraocular administration might be preferred despite its risk of complication [2]. In addition, compared to the oral route, ocular drug delivery provided equivalent or better bioavailability in the eye [3]. Approaches have been made for the improvement of the bioavailability of the drug, the controlled release and the improvement of the therapeutic effect [4].

Antibiotics are group of medicines popularly used in ophthalmic delivery due to the multiples ocular diseases (microbial keratitis, conjunctivitis, Meibomian gland dysfunction and dry eye). Infectious disease is one of the most public health challenge [5]. Antibacterial therapies can be administrated in the eye by topical, subtenon, intraocular or subconjunctival administration. Tetracyclines, fluoroquinolones, aminoglycosides and penicillins are examples of antibiotics commonly used in the treatment of eye infections [6]. The antimicrobial resistance is the ability of bacteria to resist to the effect of an antibiotic administration. This limitation of efficacy is caused by the misuse of antibiotic, the overuse of this group of medicine and the adaptation of the bacteria to the effect. In fact, ophthalmic antibiotic delivery aims to decrease the frequency of administration and dosing by improving the current forms and developing new ones.

New ocular drug delivery forms are various; they included in situ gelling systems, liposomes, nanoparticles, niosomes, nanoemulsions and microemulsions. They are suitable for hydrophilic or lipophilic drugs, have the capacity of targeting a specific site and can be administrated in different routes. With the appropriate excipients, in situ gelling systems are able to increase the precorneal residence time and decrease the loss of drug due to the tear. Different polymers, methods of preparation and compositions allow the nanoparticles to respond to a need for mucoadhesion, topical, periocular or intraocular administration, and to obtain a stable, effective and non-irritating formulation for the patient.

The objective of this paper is to review the antibiotic formulations for an ophthalmic administration. First the ocular anatomy and physiology and the ocular barriers were described. Topical forms such as eye drops, ointments, hydrogels, contact lenses and ophthalmic inserts are developed in a second part to introduce the ocular administration and explain the currently marketed dosage form. Finally, recent advances on ocular antibiotic administration are reviewed. In vitro and in vivo studies explored the efficacy of antimicrobial formulations. Different compositions and forms are developed to improve the bioavailability of antibiotics, increase the residence time in the eye and the therapeutic response.

2. Anatomy and Physiology of the Eye for Ocular Drug Delivery

2.1. Anatomy and Physiology of the Eye

The eye has a spherical shape included in the orbital cavity and protected by lids. With a diameter of 24 mm and a volume of 6.5 cm3, it weighs about 7.5 g.

Several layers with specifics structures compose the eyeball and divide it in two segments [3,7]: the anterior segment (cornea, conjunctiva, aqueous humor, iris, ciliary body and lens) and the posterior segment (retina, choroid, sclera and vitreous humor) as illustrated in Figure 1.

2.1.1. Three Different Layers

The eye is surrounded by three different layers: the outer layer, the medium layer and the inner layer. The outer layer is composed by the cornea and the sclera. They are fibrous tissue and have a protective function for the eyeball. The sclera, continuous with the cornea, is an avascular, white, strong, and elastic tissue. It covers 80% of the eye’s tunic. The cornea, joining the sclera at the limbus, is a thin (0.5 mm) [8], avascular and transparent layer which allows the light penetration to the globe. The anterior and posterior segments of the eye are anatomically separated by the sclera and the cornea (Figure 1).

The middle layer is a vascular envelope also called uvea, formed by the iris, the choroid and the ciliary body. The iris is a contractile, circular membrane opened at its center by the pupil. It is the color part of the eye located to the posterior region of the cornea. At the posterior of the uvea, the choroid is a highly vascularized membrane. It supplies nutriments and oxygen to the iris and retinal photoreceptors. Between the sclera and the retina, the ciliary body secrets the aqueous humor with the ciliary processes and contains smooth muscles that control the shape of the lens.

The innermost tissue is the retina. It is the neuronal tissue responsible of the vision composed of two types of tissues. The retina as the choroid, cover the inside of the posterior segment from the optic nerve to the ora serrata. The neural tissue is composed by the photoreceptor (rods for the night and the peripheral vision and cones for the color and the details), the bipolar cells and the ganglion cells.

2.1.2. Inside the Globe

The inside of the eye is composed of three major compounds: the crystalline, the aqueous humor and the vitreous humor.

The crystalline is a biconvex, transparent lens located behind the iris and the pupil. It is an avascular, elastic organ connected to the optical layer by the ciliary body. The crystalline separates the aqueous humor from the vitreous humor. Its function is to allow the accommodation by concentrating the light on the retina with its contraction.

The aqueous humor is a clear optical fluid with low viscosity. Located in the anterior and the posterior chambers of the eye, the aqueous humor is continuously formed by the ciliary body (2.4 ± 0.6 µL/min in humans) [9]. The anterior chamber and the posterior chamber contain 0.250 mL and 0.060 mL of aqueous humor respectively. Composed by 99% of water the aqueous humor supplies nutriments to the iris, the crystalline and the cornea [10]. It also maintains the intraocular pressure of the eye and the convex form of the lens.

The vitreous body, also called vitreous humor, is located between the crystalline and the retina. It is a transparent and gelatinous liquid, which represents 90% of the volume of the eye (4.0 mL). Composed of 99% of water, it helps to maintain the structure of the eyeball and plays the role of a lens in the delivery of the light ray.

2.1.3. Ocular Annexes

Ocular annexes represent the external anatomic parts of the eye necessary for the proper functioning of the ocular apparatus as the muscles, the eyelids and the lacrimal apparatus.

The six extraocular muscles induce the movement of the eye in the orbit and the control of the superior eyelid movement. The eyelids are the first protection for the eye. They are movable folds of skin that covers the ocular surface, hydrate the cornea and clean the surface of the eye from debris. The superior eyelid regulates the light reaching the eye using extraocular muscles.

Located on the inside of the eyelid, the Meibomian glands are small, oily and sebaceous annexes secreting lipids and proteins to cover and protect the surface of the eye and reduce the evaporation of water contained in the tears.

The lacrimal apparatus is responsible of the tear secretion, which allows the evacuation of the debris from the ocular surface and the hydration of the eye. The lacrimal fluid is continuously formed (0.1 mL/hour) by the lacrimal glands and evacuated from the eye by the lacrimal canaliculus. At the end, all of the fluid and the debris are cleared out by the nasolacrimal duct. Human tears have a mean osmolarity of 310 mOsm/kg and a tonicity equivalent to that of 0.9% sodium chloride solution [8].

2.2. Blood-Ocular Barriers

The blood ocular barriers are composed of the blood-aqueous and the blood-retinal barriers. They are physical barriers between the blood and the eye that has a main function in the penetration, the elimination of ophthalmic route’s drugs and the maintenance of the homeostatic control [11].

The blood retinal barrier is a posterior segment barrier forming an inner barrier in the endothelial membrane of the retinal vessel and an outer barrier in the retinal pigment epithelium [11,12]. It prevents diffusion of the drugs in the posterior part of the eye and is responsible for the homeostasis of the neuroretina, composed of nonleaky tight junctions. These junctions have a high degree of control of solute and fluid permeability. The retinal pigment epithelium controls exchange of nutriments with colloidal vessels. Retinal capillary endothelial cells and retinal pigment epithelial cells are connected to one other with tight junctions.

The blood aqueous barrier is an anterior segment barrier. It is a nano-porous (104 Å) and isotonic membrane (Dernouchamps and Heremans 1975; Dernouchamps and Michiels 1977) composed by the ciliary epithelium and the capillaries of the iris. The blood aqueous barrier produces aqueous humor and prevents access of large plasma albumin molecules and many other molecules such antibiotics for example, into the aqueous humor. The aqueous humor is secreted by the non-pigmented epithelium from the ciliary body [13]. The permeability of the blood-aqueous barrier is controlled by the osmotic pressure due to the sodium, chlorine and bicarbonate transport and by the physical-chemical characteristics of the drugs. Passages from the aqueous humor to the blood of lipophilic molecules are passive and active for hydrophilic molecules. The blood-aqueous barrier is composed of an epithelial barrier and an endothelial barrier. The epithelial barrier is composed of tight junctions between the non-pigmented ciliary epithelial cells and forms a pathway for the free diffusion of molecules. Iris vessels contain proteins similar to the epithelial tight junctions and form the endothelial barrier.

These barriers restricted the entry of drugs from systemic circulation to the posterior eye segment and conversely. Acute inflammation caused by intraocular surgery, induced ocular hypotony, and the use of inflammatory mediators can occur the breakdown of blood-ocular barrier. The reversal of this situation is made by the self-limited action of the inductive drug, the administration of anti-inflammatory or anti-hypotensive drug.

The ocular surface is directly exposed to the environment and to pathogens or allergens. It is an epithelial barrier composed of corneal epithelium connected with intercellular. These junctions are tight junctions, desmosomes, adherent junctions and gap junctions. The tears film is the first line of the entire ocular barrier. It washes the surface of the eye from the debris and protects the eye from the desiccation. Ocular inflammation, intraocular surgery, trauma and vascular disease can alter the ocular barrier.

3. Ophthalmic Forms

Firstly, the choice of the drug administration route depends of the target tissue. Different routes are described for the ophthalmic administration: topical ocular and subconjunctival administration are used to target the anterior segment; intravitreal and systemic administration are used to reach the posterior segment.

Two types of drug permeation after topical administration can be described: the transcorneal permeation from the lachrymal fluid to the anterior chamber and the transconjonctival and transscleral permeation from the external ocular surface to the anterior uvea-ciliary body and iris. Lipophilic drugs permeability is higher via the transcorneal route than for hydrophilic drugs because of the lipidic composition of the corneal epithelium [14]. In contrast, the transconjonctival pathway is suited to hydrophilic drugs and large molecules. Topical administration is used for the treatment of anterior chamber pathologies as inflammation, allergy, keratoconjunctivitis, infection or corneal ulceration. The topical forms must satisfy the criteria of efficacy, sterility, stability and ocular tolerance.

3.1. Eye Drops

Eye drops are sterile and mainly isotonic solution containing drugs or only lubricating or tears replacing solution. This conventional dosage form for ocular administration represents 90% of the marketed formulations due to its simplicity of development and production. Eye drops are cheaper than the other forms and have a good acceptance by patient [2]. Unfortunately, 95% of the drugs are eliminated with the lachrymal apparatus and the different barriers in 15 to 30 s after the instillation [14]. Moreover, a secondary eye infection may be caused by a microbiological contamination with multidoses packaging. The pH must be ideally around 7.4 which the pH of the tears [15] and the osmolarity around 310 mOsm/kg. Despite a little burning sensation after administration, responsible for lacrimation and cell desquamation, eye drops, single or multidose, are the most common dosage forms for the eyes.

However, the ocular bioavailability can be improved by increasing drug permeation through the cornea and the eye drop residence time at the eye surface. For this purpose, excipients as permeation enhancers, viscosifiant agents and cyclodextrins are used to improve the efficiency formulations [15]. Permeation enhancer modifies the corneal integrity and decreases barrier resistance [3]. Examples of permeation enhancers include polyoxyethylene glycol ester and ethylenediaminetetra acetic acid sodium salt [15]. Benzalkonium chloride is popularly used as preservative but could also plays the role of penetration enhancer due to its surfactant properties [16,17]. Viscosity enhancers by increasing the viscosity of solution allow the improvement of the residence time on the eye and the local bioavailability of the drug. To increase residence time of eye drops viscosifiant are used such as polyvinylalcohol (PVA) [18], hydroxylmethylcellulose, hydroxylethylcellulose [15]. Cyclodextrins (CD) are polysaccharides with a hydrophobic internal cavity and a hydrophilic external surface [19]. Sigurdsson et al. used CD to form inclusion complex with lipophilic molecules such as steroids or cyclosporine [20]. CD also allow the stabilization of drugs in aqueous solutions, the decrease of a local irritation after administration and the increase of the permeation of the drug through the ophthalmic barrier [21].

3.2. Ointments

Ophthalmic ointments are sterile, semi-solid, homogeneous preparations intended for application to the eye (conjunctiva or eyelid). Non-aqueous excipients are mainly used for this preparation and it must be non-irritating for the eye. Four types of ointment are described: oleaginous base, absorption base, water-removable base and water soluble base [22]. The oleaginous base is a lipophilic ointment, immiscible with water avoiding moisture evaporation. Composed of petrolatum and white ointment in a large amount, it can remain on skin or mucus for long period without drying out (Sterdex® , Thea, Clermont-Ferrand, France ). The adsorption base may be used as emollient and contains lanolin, fatty alcohol and petrolatum (Maxidrol®, Norvatis, Bazel, Swizerland ). It can adsorb a quantity of water and is difficult to wash. A water-soluble base is composed only of water soluble excipients as macrogol with high molecular weight. This hydrophilic ointment is easy to wash but its use is limited due to the possible discomfort from the osmotic effect. Water removable base is an oil in water emulsion, easy to wash and easily miscible with water. It facilitates the contact between the skin and the drug but of the presence of hydrophilic surfactant (such as lauryl sulfate) in formulation can be irritating for the eye.

Unlike eye drops, this form slows down the elimination of the drug by the tears flow and increases the corneal residence time by prolonging surface time residence. Ointment application is responsible for blurred vision and its administration is advised in the evening. The packaging can be single dose or multidose and the content is limited to 5 g of preparation.

3.3. Hydrogels

In ocular administration, hydrogels are used to increase residence time of drugs on the eye. Hydrogels are three-dimensional water-swollen structure, composed of a viscosity agent dispersed in water or hydrophilic liquid. Hydrogels are retained in the eye and well better tolerated than ointment by patient by decreasing the side effects induced by the systemic absorption. There are two types of hydrogel, the preformed gels and the in situ gels. Gels are usually composed of hydrophilic polymers. Research focus on the development of new materials and hydrogel has many potential applications in ocular drug delivery. Applications of hydrogels were recently described in a review [23]. The main disadvantage of this form can be the quantity and the homogeneity of the drug loading in the hydrogel which can be limited, specifically in the case of hydrophobic drug. Moreover, the viscosity of gels must be stable over time to maintain the physical properties and the efficacy of the product.

The preformed gels are simple viscous solution administered on the eye. This type of polymeric gels is commonly used as bioadhesive hydrogel to improve residence time on the eye and reduce dosing frequency [2

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