Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye

Accepted Manuscript Title: Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye Authors: Thorsteinn Loftsson, Einar Stef´ansson PII: DOI: Reference:

S0378-5173(17)30291-0 http://dx.doi.org/doi:10.1016/j.ijpharm.2017.04.010 IJP 16576

To appear in:

International Journal of Pharmaceutics

Received date: Revised date: Accepted date:

2-1-2017 4-4-2017 5-4-2017

Please cite this article as: Loftsson, Thorsteinn, Stef´ansson, Einar, Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye.International Journal of Pharmaceutics http://dx.doi.org/10.1016/j.ijpharm.2017.04.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cyclodextrins and topical drug delivery to the anterior and posterior segments of the eye

Thorsteinn Loftsson a,*, Einar Stefánsson b

a

Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107

Reykjavik, Iceland b

Department of Ophthalmology, Faculty of Medicine, National University Hospital,

Eiríksgata 37, IS-101 Reykjavík, Iceland *Corresponding author. Tel.: +354 525 4464; Fax: +354 525 4071 E-mail: [email protected]

Graphical abstract

Abstract It is generally believed that it is virtually impossible to obtain therapeutic drug concentrations in the posterior segment of the eye after topical application of aqueous, low viscosity eye drops. Thus, intravitreal drug injections and drug implants are currently used to treat diseases in the posterior segment such as macular edema. Here it is described how, through proper analysis of the drug permeation barriers and application of well-known pharmaceutical excipients, aqueous eye drops are designed that can deliver lipophilic drugs to the posterior segment as well as how such eye drops can maintain high drug concentrations in the anterior segment. Through stepwise optimization, eye drops containing solid drug/cyclodextrin complex microparticles with a

mean diameter of 2 to 4 µm, dissolved drug/cyclodextrin complex nanoparticles and dissolved drug molecules in an aqueous eye drop media of low viscosity were designed. After administration of the eye drops the microparticles slowly dissolved and maintained close to saturated drug concentrations in the aqueous tear fluid for several hours. Studies in rabbits and clinical evaluations in humans, using dorzolamide and dexamethasone as sample drugs, show that the eye drops deliver significant amounts of drugs to both the posterior segment and anterior segment of the eye. Clinical studies indicate that the eye drops can replace intravitreal injections and implants that are currently used to treat ophthalmic diseases and decrease frequency of drug administration, both of which can improve patient compliance.

Keywords Aggregates Cyclodextrin Eye drops Microparticles Nanoparticles Permeation

1. Introduction Drug permeation from the eye surface into the eye encounters multiple barriers resulting in topical bioavailability that is generally well below 5% with most of the drug

dose entering the general blood circulation. In spite of this very low topical bioavailability aqueous eye drops are the patient preferred dosage form, especially in treatment of diseases of the anterior eye tissues, accounting for over 90% of the market (Vadlapudi et al., 2015). For treatment of diseases of the posterior eye intravitreal injections and ocular implants are frequently preferred since it is generally believed that topically applied ophthalmic drugs are unable to give therapeutic drug concentrations in the posterior eye tissues. However, there are some reports on effective drug delivery from the eye surface to its posterior segment applying a matrix film in rabbits (Adelli et al., 2015), liposomes in rats (Davis et al., 2014), eye drops in rabbits (Lin et al., 2015), eye drops in rats (Ozaki et al., 2015) and nano-micelles in rabbits (Vaishya et al., 2014). Several general reviews on ophthalmic drug delivery have recently been published describing the eye’s physiology, the drug permeation barriers, and novel drug delivery techniques and devices under development (Achouri et al., 2013; Fangueiro et al., 2016; Vadlapudi et al., 2015). Here cyclodextrin-based formulations for topical drug delivery to the eye are reviewed.

2. Drug delivery to the eye 2.1 The eye anatomy and physiology The eye is an isolated organ with surface that is easily accessible for topical drug administration. It consists of an anterior segment that includes the cornea, aqueous humor, iris and lens, and a posterior segment that comprises the vitreous humor, retina, sclera and optic nerve (Fig. 1). The main routes of drug penetration into the eye are the corneal route (i.e., cornea → aqueous humor → intraocular tissues) and the scleral route (i.e., conjunctiva → sclera → choroid/retinal pigment epithelium) (Chastain et al., 2016;

Novack and Robin, 2016; Raghava et al., 2004; Vadlapudi et al., 2015). The cornea is a transparent five layer biomembrane. The outermost layer is the epithelium, followed by the Bowman’s membrane, stroma (which represents about 90% of the membrane thickness), Descement’s membrane and the inner most endothelium layer. The main barrier layer towards drug penetration through the cornea is the lipophilic epithelium, which contributes about 90% of the barrier towards hydrophilic drugs and about 10% of the barrier towards lipophilic drugs. The epithelium consists of three to six layers of tightly adherent epithelial cells. The epithelial surface is covered with microvilli. Drugs penetrate the epithelium either transcellularly (i.e. through the cells) or paracellularly (i.e. through pores between the cells). The transcellular route predominates for lipophilic drug molecules whereas the paracellular route predominates for hydrophilic molecules and small ions. The highly hydrophilic stroma forms a permeation barrier for some lipophilic drugs (Rabinovich-Guilatt et al., 2004).

The conjunctiva is a thin mucus

membrane that covers the inner surface of the eyelid and sclera. It is a moist and highly vascular epithelial tissue that secrets mucus.

The sclera is composed primarily of

collagen fibers embedded in a mucopolysaccharides matrix. The primary route for drug permeation through the sclera is passive diffusion through an aqueous pathway. The permeability of sclera does not display any apparent dependence on the drug lipophilicity but displays a strong dependence on the molecular weight of the drug, i.e. the hydrodynamic radius of the permeating drug molecule, the permeability coefficient decreasing with increasing molecular weight (Prausnitz and Noonan, 1998).

The

conjunctiva is approximately 15 to 25 times more permeable than cornea and sclera is approximately 10 times more permeable (Hämäläinen et al., 1997).

Although drug

transporters have been located in the eye epithelium it is believed that most drugs permeate from the eye surface into the eye via passive diffusion. The surface of the eye is covered with mucus, a gel-like fluid (mucus) containing mainly water (90–98%) and mucins (2–5%). Mucins are large, flexible glycoproteins having molecular weights ranging from 0.5 to 20 MDa (one megadalton [MDa] is one million Da). Mucins form hydrogen bonds with surrounding water molecules, leading to a significant increase in the thickness and viscosity of the tear fluid which forms an aqueous diffusion barrier to drug absorption into the eye. This aqueous diffusion layer is frequently referred to as the ‘unstirred water layer’ (UWL) (Loftsson et al., 2008). The aqueous tear film on the eye surface (including mucus) is about 8 μm thick.

2.2 Obstacles to topical drug delivery Passive drug diffusion into the eye is hampered by three major obstacles (Loftsson et al., 2008; Urtti, 2006). First is aqueous drug solubility. The tear fluid and mucus consist mainly of water and only dissolved drug molecules are able to permeate into the eye and, thus, drugs must possess sufficient aqueous solubility to diffuse into the eye. Increasing solubility of poorly water soluble drugs will increase their concentration gradient over the UWL and consequent passive diffusion into the eye. The second obstacle is the drug’s short contact time with the eye surface. When an eye drop (35 to 50 μl) is applied to the eye, the drop is mixed with the tear fluid and dispersed over the eye surface. The majority of the eye drop is then drained from the eye surface, thereby returning the solution volume to the normal resident tear volume of about 7 μl. While the pre-ocular solution volume remains constant, the drug concentration decreases due to dilution by tear turnover and corneal and non-corneal absorption. Normal tear turnover

is about 1.2 µl/min in humans (Sugrue, 1989). Thus, after the initial very rapid eye drop drainage, the pre-corneal half-life of topically applied drugs in solution is only between 1 and 3 minutes. The third major obstacle is the lipid membrane barriers, the cornea and conjunctiva/sclera.

The permeation rate through the lipophilic corneal epithelium is

affected by a drug’s lipophilicity (i.e. the ability of the drug molecule to partition from the aqueous exterior into the lipophilic membrane). Passive transport of a drug through the cornea is proportional to the drug concentration gradient within the membrane. The octanol/water partition coefficient (Ko/w) is commonly used to express the lipophilicity of a drug.

For example, it has been shown that the optimum LogKo/w value for drug

permeation through the cornea is between approximately 2 and 3 (Shirasaki, 2008). In addition to lipophilicity, the permeation rate of a drug through the corneal epithelium is affected by whether or not the drug is charged. Various formulation and molecular designs have been tested in an effort to improve topical bioavailability of ophthalmic drugs (Achouri et al., 2013; Fangueiro et al., 2016; Vadlapudi et al., 2015).

For example, solubilizing systems such as cyclodextrins,

liposomes and microemulsions that enhance drug solubility in the aqueous tear fluid, prodrugs that increase lipophilicity of hydrophilic drugs and enhance their partition from the aqueous tear film into the lipophilic membrane barrier, mucoadhesive polymers and nanogels that increase drug residence time on the eye surface, and nanoparticles that are thought to enhance drug permeation into the mucus. However, for effective topical drug delivery into the eye a delivery system is needed that addresses all three obstacles, that is increases drug solubility in the aqueous tear film, increases the contact time of the drug with the eye surface and increases drug partition into and then drug permeation through the lipophilic membrane barriers (i.e. cornea and conjunctiva).

3. Cyclodextrins and cyclodextrin aggregates Cyclodextrins (CDs) are natural cyclic oligosaccharides that are formed by bacterial digestion of starch (Frömming and Szejtli, 1994; Jansook et al., 2010a; Loftsson and Duchene, 2007; Schönberger et al., 1988). The most common natural CDs consist of 6 (αCD), 7 (βCD) and 8 (γCD) 1,4-linked α-D-glucopyranoside units. Although they are very hydrophilic the natural CDs have somewhat limited solubility in water and, thus, more water-soluble CD derivatives are frequently used in pharmaceutical products (Table 1). CD molecules are cone-shaped with a hydrophilic outer surface and a somewhat lipophilic central cavity.

CDs can form hydrophilic

inclusion complexes, guest/host complexes where lipophilic drug molecules are the guests and the CD molecules are the hosts.

The complexes are kept together by

relatively weak forces such as electrostatic interactions, van der Waals contributions and hydrogen bonding, release of conformational strain and charge-transfer interactions (Liu and Guo, 2002). In aqueous solutions the complexes are in a dynamic equilibrium with free guest and host molecules where the inclusion complexes are constantly being formed and dissociated with a half-life of few milliseconds or less (Stella et al., 1999). Thus, with only few exceptions guest molecules such as drugs are instantly released from the CD hosts up on, for example, media dilution (Kurkov et al., 2012; Stella et al., 1999). In aqueous solutions the natural CDs have tendency to self-assemble to form aggregates while the more water-soluble CD derivatives have less tendency to form aggregates (Bonini et al., 2006; He et al., 2008; Jansook et al., 2010a; Messner et al., 2010; Wu et al., 2006).

The natural γCD has especially high tendency to form

aggregates in aqueous media (Szente et al., 1998). Formation of inclusion complexes frequently increases the CD aggregation (Messner et al., 2011a) while addition of organic solvents or heating of the media decreases the aggregation (Messner et al., 2011b).

The aggregation is concentration dependent; increases with increasing CD

concentration and decreases upon media dilution. In aqueous solutions CD aggregates are in dynamic equilibrium with free CD molecules and their inclusion complexes (Fig. 2). The first article on CDs was published by Villiers in 1891 (Villiers, 1891) and the foundation of the cyclodextrin chemistry was laid by Schardinger at the very beginning of last century (Schardinger, 1903). The structure and chemistry of CDs and their inclusion complexes was already described in a book published in 1954 (Cramer, 1954). Every year CDs are the subject of about 4500 scientific publications and patents and they can be found in about 35 marketed pharmaceutical products in addition to numerous food and toiletry products.

There are numerous reports on the use of CDs in drug

formulations intended for topical drug delivery to the eye (Table 2).

4. ADME of cyclodextrins CDs are cyclic oligosaccharides and possess many of the same physiochemical and biological properties as linear oligosaccharides such as maltodextrins, including their absorption, distribution, metabolism and excretion (ADME).

However, unlike

maltodextrins CDs are able to form inclusion complexes and the natural CDs are less soluble in water than, for example, maltodextrins of comparable molecular weight. CDs are very hydrophilic and do not readily permeate lipophilic biomembranes such as skin and mucosa. They have negligible oral bioavailability (most frequently less than 1%)

and are metabolized in the GI tract, mainly by bacterial digestion (Loftsson, 2015a; Loftsson et al., 2016; Saokham and Loftsson, 2017). After parenteral administration CDs display low volume of distribution and are readily eliminated unchanged with urine (Loftsson et al., 2016). In general, CDs are regarded as non-toxic and are well tolerated after oral and parenteral administration, especially the natural γCD (Saokham and Loftsson, 2017; Stella and He, 2008). However, parenteral administration of αCD, βCD or methylated βCD can result in renal toxicity, and consequently the parent βCD and its methylated derivatives are not used in parenteral drug formulations. Small amounts of αCD are being used in parenteral formulations (0.6 mg in reconstituted CaverJect Impulse® parenteral solution or 0.13% w/v αCD). The natural γCD can be administered parenterally and is listed in FDA’s Inactive Ingredients Database (5% w/v in solution for intravenous injection). It has been shown that the natural γCD is the only CD that is readily metabolized by α-amylase that is found, for example, in the tear fluid, saliva and many other bodily fluids (French, 1957; Lumholdt et al., 2012; Lumholdt et al., 2015; Marshall and Miwa, 1981; Munro et al., 2004; Saokham and Loftsson, 2017; Szejtli, 1987; van Haeringen et al., 1975; van Haeringen et al., 1977). The water-soluble γCD derivatives, 2-hydroxypropyl-γ-cyclodextrin (HPγCD) and sulfobutylether γ-cyclodextrin sodium (SBEγCD), as well as inclusion complexes of γCD, are metabolized much more slowly.

5. Cyclodextrins and drug permeation of topically applied drugs Conventional penetration enhancers, such as fatty acids, surfactants and quaternary ammonium compounds, enhance drug permeation into and through biomembranes such as cornea by permeating into the biomembrane where they

temporary decrease its barrier properties.

These chemical penetration enhancers

enhance permeation of both lipophilic and hydrophilic molecules through the membrane barrier. The permeation enhancing properties of CDs are quite different. In general, CDs are very hydrophilic and relatively large molecules with numerous hydrogen bond donors and acceptors (Table 1) and, thus, their ability to permeate into and through lipophilic biomembranes such as mucosa is negligible (Kurkov et al., 2011; Loftsson et al., 2016; Saokham and Loftsson, 2017). Conventional penetration enhancers enhance drug permeation from both aqueous and non-aqueous media while CDs are only able to enhance permeation of relatively lipophilic drug molecules that have limited solubility in water and then only from aqueous media. There are numerous reports on the effects of cyclodextrins on topical drug delivery to the eye (Table 2) as well as through other types of membranes such as skin and mucosa (Kurkov et al., 2011; Loftsson, 2015b). These studies show that depending on the vehicle composition and the drug/CD molar ratio CDs can both enhance and hamper drug permeation through biomembranes. Although active drug transport through mucosa does exist drug molecules are mainly transported via passive diffusion through mucosa such as from the eye surface into the eye. The driving force for passive diffusion through an aqueous environment (e.g., mucus) into and through membranes such as conjunctive/sclera and cornea is not the concentration gradient but the gradient of chemical potential (µ), which is a continuous function across interfaces (Higuchi, 1960). Likewise, the partitioning of drug molecules from the membrane exterior into the outermost membrane layer is controlled by the chemical potential.

High chemical potential of a drug in the tear fluid is a

prerequisite for its good ophthalmic bioavailability (Loftsson and Brewster, 2011):

μ2 = μө2 + RT lna2 = μө2 + RT ln(γ2 m2 )

(1)

a2 = γ2 m2

(2)

and

where μ2 is the chemical drug potential in the aqueous tear fluid, μө2 is the chemical potential in a given standard state, a2 is the thermodynamic drug activity, R is the gas constant, T is the temperature in Kelvin, γ2 is the activity coefficient and m2 the molality of the drug. The thermodynamic definition of the partition coefficient (Ko/w) of a drug between lipophilic phase, frequently referred to as the organic phase (o), and aqueous phase (w) is:

μөw - μөo RT

= ln

ao aw

≈ ln

γo ∙C

o

γw ∙C

w

= ln

γo γw

+ lnKo/w

(3)

Equation 3 states that equilibrium between the two phases is attained when the chemical potential of the drug in one phase (e.g., the aqueous membrane exterior such as the tear fluid [μw]) is equal to the chemical potential in the other phase (e.g., the lipophilic membrane [μo]). In a given medium the thermodynamic activity (a) increases with increasing drug concentration approaching unity in a drug saturated medium. Addition of solubilizers, such as CDs, to an aqueous drug solution will lower the drug activity (i.e. it lowers γw in Eqn. 3) and, thus, under normal conditions CDs lower the potential of the drug to exit the tear fluid and enter the cornea or conjunctiva/sclera. Increasing the amount of dissolved drug in the aqueous tear fluid by addition of solubilizer such as CD while keeping the tear fluid saturated with drug will however not

lower the drug activity. Under such condition the thermodynamic activity of the drug in the tear fluid will remain equal to unity and, thus, the dissolved drug molecules are at their highest ‘exiting’ potential while the total amount of dissolved drug is increased. This addresses the first (i.e. drug solubility in the tear fluid) and the third (i.e. entering of the drug molecules into and permeation through the membranes) of the three major obstacles to topical drug delivery to the eye. Figure 3 shows how the permeability coefficient (P) of arachidonylethanolamide (AEA) from aqueous medium through isolated rabbit cornea is affected by the 2hydroxypropyl-β-cyclodextrin (HPβCD) concentration. The total concentration of solid and dissolved AEA in the donor phase was kept at 0.5 mg/ml and the aqueous solubility of AEA in the donor phase is about 0.4 µg/ml. At low HPβCD concentrations AEA is in an aqueous suspension.

AEA forms a water-soluble complex with HPβCD and is

solubilized upon addition of HPβCD to the donor phase. When 0.025 mol/L HPβCD has been added to the donor phase all AEA has been solubilized and the apparent permeability coefficient has reached its maximum. From 0 to 0.025 mol/L HPβCD the thermodynamic activity of the drug in the donor phase remains equal to unity and, thus, the dissolved AEA molecules are at their highest ‘exiting’ potential while the total amount of dissolved drug is increased with increasing HPβCD concentration. When the HPβCD concentration is increased further, in excess of what is needed to solubilize all AEA in the donor phase, the AEA activity is lowered (i.e. γw in Eq. 3 is lowered) and this lowers the potential of AEA to exit the tear fluid and enter the cornea and, thus Papp decreases (Fig. 3).

AEA permeation through cornea is proportional to the AEA concentration

gradient within the cornea and addition of excess HPβCD to the donor phase decreases the ability of AEA to partition from the donor phase into the cornea (i.e. decreases the

concentration gradient).

For more detailed description of how and under which

conditions CDs enhance drug permeation through biological membranes the reader is referred to (Higuchi, 1960; Loftsson and Brewster, 2011). In Table 2 ophthalmic drug formulations containing CDs are listed, all together 44 different drugs in CD ophthalmic formulations that are described in 75 research articles. In general the formulations are aqueous eye drop solutions although some are on sustained release drug delivery where CDs are used in combination with poorly soluble polymers such as chitosan (Mahmoud et al., 2011; Zhang et al., 2016), cross-linked cyclodextrin polymers (Moya-Ortega et al., 2013), in situ ophthalmic gelling systems (Basaran and Bozkir, 2012), mucoadhesive hydrogels (Kesavan et al., 2011; Liu et al., 2005) and contact lenses (Xu et al., 2010). Then there are few on drug/γCD nano- and microparticles in aqueous eye drops of low viscosity that will be described in more detail.

6. Cyclodextrins as drug carriers in eye drops Drugs in aqueous eye drops have very low bioavailability and have to be administered relatively frequently. They are difficult to administer, especially for older patients, and tend to deliver much more drug to the general blood circulation than to the eye. In spite of all these drawbacks patients prefer low-viscosity aqueous eye drops over other forms of ophthalmic drug delivery systems. Most frequently CDs are used to improve aqueous solubility of lipophilic drugs with limited solubility in aqueous formulations such as eye drops (Table 2). But CDs have also been shown to reduce drug irritation after topical administration to the eye and to enhance chemical stability of drugs in aqueous eye drop formulations (Ahuja et al., 2008; Bozkir et al., 2012; Jarho et al., 1996a; Loftsson and Jarvinen, 1999; Rodriguez-Aller et al., 2015; Saarinen

Savolainen et al., 1997; Suhonen et al., 1995). Furthermore, the studies show that for optimum bioavailability it is important not to add excess CD to the aqueous vehicle, more than is needed to dissolve the drug dose in the vehicle (Fig. 3). Here we describe formulation of two poorly soluble drugs in aqueous low-viscosity eye drop media.

6.1 Dorzolamide Dorzolamide is a carbonic anhydrase inhibitor, an antiglaucoma agent that decreases production of aqueous humor. In aqueous solutions dorzolamide is mainly in its cationic form at pH below 6.4, mainly unionized at pH between 6.4 and 8.5, and mainly in its anionic form at pH above 8.5. The solubility of dorzolamide is only 6.7 mg/ml (or 0.67% w/v) at pH 7.4 and, thus, to obtain sufficient solubility the pH of an eye drop media has to be lowered (Fig. 4). The lipophilicity of dorzolamide is at its maximum at pH between approximately 7 and 8. Dorzolamide is marketed as a 2% (w/v) eye drop solution (Trusopt®, Merck, USA) containing dorzolamide hydrochloride as the active ingredient in aqueous solution containing hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. The pH pf the eye drop solution is 5.6 and the viscosity about 100 cps (Loftsson et al., 2012). The low pH, and the relatively high buffer capacity and high viscosity of the eye drop media results in a stinging sensation after topical administration to the eye. In an effort to reduce the local irritation of the eye drops dorzolamide was formulated as 2 and 4% (w/v) pH 7.45 low viscosity aqueous solutions (viscosity 3 to 5 cps) containing randomly methylated β-cyclodextrin (RMβCD) as a solubilizer and evaluated in rabbits (Sigurdsson et al., 2005).

Methylated βCD is somewhat more lipophilic than other

commonly available CDs (Table 1) and has been used as absorption enhancer in nasal

drug formulations (Davis and Illum, 2003; Schipper et al., 1995). However, although less irritating these RMβCD-containing aqueous eye drop solutions delivered about 50% less dorzolamide to the aqueous humor than the commercially available product, Trusopt®. Then dorzolamide was formulated as eye drop microsuspension containing dorzolamide/γCD complex microparticles (mean particle size 2.2±0.1 µm) in aqueous eye drop medium (pH 7.42±0.06; viscosity 38.6±0.6 cps and osmolarity 371±25 mOsm/kg) where the total dorzolamide concentration (i.e. both solid and dissolved) was 3.0% (w/v) (Jansook et al., 2010b). In this formulation about two-thirds of dorzolamide is present as solid dorzolamide/γCD complexes and about one-third of the drug was in solution as free drug molecules, solubilized drug/γCD complexes and solubilized drug/γCD nanoparticles. The solubility of the dorzolamide/γCD complex in the aqueous eye drop medium and the aqueous tear fluid is greater than that of the free drug but still somewhat low allowing solid dorzolamide/γCD microparticles to be retained on the eye surface (Johannesson et al., 2014b). microparticles

dissolved

in

the

aqueous

concentrations of dissolved dorzolamide.

Over time the solid dorzolamide/γCD tear

fluid

providing

sustained

high

This again enhanced the amount of

dorzolamide being absorbed through cornea into the aqueous humor (Fig. 5). In rabbits the aqueous dorzolamide/γCD microsuspension provided sustained high dorzolamide concentration in the aqueous humor for more than 24 hours while after single administration of Trusopt® the dorzolamide concentration was essentially zero at 8 hours.

Consequently, in a human study aqueous eye drops containing the

dorzolamide/γCD microsuspension had the same intraocular pressure (IOP) lowering effect give once a day as Trusopt® given three times a day (Gudmundsdottir et al., 2014).

6.2 Dexamethasone Dexamethasone is a corticosteroid and used in ophthalmology in the form of eye drops (e.g., Maxidex®, Alcon, USA) to treat inflammation caused by surgery, infections or injury. Dexamethasone is also injected to treat inflammation or implanted into the eye to treat patients with macular edema. Macular edema is swelling of the center of the retina.

Dexamethasone is relatively lipophilic (LogKo/w = 2) and has very limited

solubility in water (0.1 mg/ml). Due to its very limited solubility dexamethasone does not readily permeate from the eye’s aqueous exterior into the eye. Thus, it is commonly thought that dexamethasone and related steroids cannot be administered topically as aqueous eye drops to treat inflammation in the posterior segment of the eye. Dexamethasone

implants

are

currently

used

to

treat

macular

edema

and

dexamethasone loaded lenses, microparticles, nanoparticles, micelles, liposomes and dendrimers are being developed (Rodríguez Villanueva et al., 2017).

Studies have

shown that CDs are able to enhance topical bioavailability of dexamethasone from aqueous eye drops (Gavrilin et al., 1999; Kristinsson et al., 1996; Loftsson et al., 1994a; Loftsson and Stefánsson, 2007; Sigurdsson et al., 2007; Usayapant et al., 1991). Although improved, the absorption enhancement from aqueous eye drop solutions was not sufficient (Table 3). Replacing HPβCD by the more lipophilic RMβCD appeared to offer some improvement (Sigurdsson et al., 2007). RMβCD enhanced the aqueous solubility of dexamethasone and, since it is known to enhance drug absorption through mucosa, it might also enhance dexamethasone permeation through cornea and conjunctiva addressing two of the three main barriers to drug permeation from the eye surface into the eye (see Section 2.2).

For further enhancement of the topical

bioavailability the third obstacle, the drug’s short contact time with the eye surface, has to be addressed. Only sustained high concentrations of dissolved dexamethasone in the aqueous tear fluid will allow sufficient time for the drug to permeate into the eye. To maximize drug permeation into the eye the tear fluid has to be close to saturated with the drug for extended duration of time. Under such condition the thermodynamic activity of the drug in the tear fluid will be close to unity and, thus, the dissolved drug molecules will have high tendency to participate from the tear fluid into the membrane barriers (see Section 5).

In order to obtain sustained high dexamethasone concentrations in the

aqueous tear fluid the drug was formulated as eye drop microsuspension containing dexamethasone/γCD complex microparticles (mean particle size 2.2±0.1 µm) in unbuffered aqueous eye drop medium (pH between 4 and 5; viscosity 2.5 cps and osmolarity 140 mOsm/kg) where the total dexamethasone concentration (i.e. both solid and dissolved) was 1.5% (w/v) and the concentration of dissolved dexamethasone was 0.5% (w/v) or approximately 50 times the solubility of the pure drug (Loftsson et al., 2007a). In a study in humans the eye drops gave sustained high concentrations of dexamethasone in the tear fluid and although the commercial product Maxidex® (contains 0.1% w/v or 1 mg/ml dexamethasone as an alcoholic suspension) also gave sustained dexamethasone concentrations in the tear fluid the concentration was much lower (Fig. 6).

The concentration of dissolved dexamethasone in Maxidex® is

approximately 0.1 mg/ml whereas the concentration of dissolved dexamethasone in the dexamethasone/γCD microsuspension is approximately 5 mg/ml.

The topical drug

delivery from eye drops containing the 1.5% (w/v) dexamethasone microsuspension to various eye tissues was compared to that obtained after topical administration of aqueous 1.5% (w/v) dexamethasone eye drop solution where RMβCD was used to

solubilize the drug (Table 4). The eye drops were administered to the left eye of rabbits (weight about 3 kg) and the dexamethasone concentration measured in both eyes. The rabbit eyes are almost as large as human eyes but their average body weight is only about 4% of that of humans. Topical bioavailability of drugs in aqueous eye drops is generally well below 5% with most of the drug entering the general blood circulation and, thus, the data obtained in rabbits has to be corrected for systemic drug delivery to the eye. In this study drug delivered topically into the eye was calculated by subtracting the concentration in the right eye (i.e. the untreated eye) from the concentration in the left eye (i.e. the treated eye).

Results in Table 4, obtained at 120 min after topical

administration of the eye drops, show that the dexamethasone/γCD microparticles target the posterior segment of the eye, especially the retina, while almost 80% less drug was absorbed into the systemic blood circulation.

The rabbit studies indicate that the

microparticles target drug delivery to the posterior segment of the eye and especially to the retina, and at the same time decrease significantly the amount of dexamethasone that reaches the general blood circulation. Also, the concentration of dexamethasone in the aqueous humor at 120 min was about 60% lower after administration of the microsuspension.

Beside cataract (i.e. clouding of the eye lens) systemic side effects

are most commonly observed after topical dexamethasone administration and, thus, the dexamethasone/γCD microsuspension targets dexamethasone delivery to the site of action (the retina) and decreased dexamethasone delivery to the sites of the unwanted side effects (e.g., to the lens and general body). Aqueous

eye

drops

containing

the

1.5%

(w/v)

dexamethasone/γCD

microsuspension have been clinically tested in patients with diabetic macular edema (DME) (Ohira et al., 2015; Tanito et al., 2011) and intermediate uveitis with cystoid

macular edema (Krag and Hessellund, 2014; Shulman et al., 2015). After administration for up to two months the two DME studies showed that the eye drops reduced the swelling of the retina and improved significantly the visual acuity or by 5.5 to 7.5 ETDRS letters, a common visual test based on letters of decreasing size on a chart. This was similar improvement as after intravitreal steroid injection. The studies in patients with intermediate uveitis and cystoid macular edema did also show that the aqueous eye drops containing dexamethasone/γCD complexes in a microsuspension gave significant improvements.

7. Conclusions It has been generally believed that it is not possible to obtain therapeutic drug concentrations in the posterior segment of the eye, such as in the retina, after topical administration of aqueous low viscosity dexamethasone eye drops to the eye surface. Thus, drug implants are currently used to treat diseases such as macular edema (e.g., DME) and uveitis. Through proper analysis of the permeation barriers from the surface to the anterior segment and posterior segment of the eye, and by applying the basic principles of physical pharmacy, it was possible to design aqueous eye drops that are able to deliver significant amounts of drugs to both the posterior segment and the anterior segment of the eye using well-known excipients that are already used in numerous marketed pharmaceutical products. The eye drops can replace intravitreal injections and implants that are currently used to treat ophthalmic diseases and decrease frequency of drug administration, both of which will improve patient compliance.

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Fig. 1. Schematic drawing of the eye.

Fig. 2. Schematic drawing showing forming of a guest/host inclusion complex (e.g., drug/CD inclusion complex), small nano-size aggregate consisting of guest/host complexes, and then micro-size aggregate. Diameter of the nano-size aggregates is frequently between 20 and 300 nm and that of the micro-size aggregates between 1 and 10 µm.

Fig. 3. Permeability coefficient (P; n = 2-6) of arachidonylethanolamide (AEA) through the isolated rabbit cornea as a function of HPβCD concentration (solid curve) and calculated unbound concentration of AEA on the aqueous donor phase as a function of HPβCD concentration (broken curve). The aqueous donor phase contained 0.5 mg/ml of AEA in a suspension or a solution containing from 0 to 0.155 mol/L HPβCD. Modified from (Jarho et al., 1996b).

Fig. 4. Ionization of dorzolamide and sketches of Log(solubility) (LogS) and Log(octanolwater partition coefficient) (LogKo/w) as a function of pH for dorzolamide at room temperature.

Based on (Pfeiffer, 1994; Sigurdsson et al., 2005) and SciFinder

(scifinder.acs.org).

Fig. 5. Dorzolamide concentration (µg/ml) in aqueous humor after topical administration to rabbits (mean ± standard deviation; n = 6-8).

Trusopt® containing 2% (w/v)

dorzolamide in aqueous eye drop solution (●) and aqueous dorzolamide/γCD microsuspension containing 3% (w/v) dorzolamide (○). The figure is based on data from (Jansook et al., 2010b; Sigurdsson et al., 2005).

Fig. 6. Dexamethasone concentration in tear fluid (mean ± standard error of the mean; n = 6) after topical administration of one drop to humans. Maxidex® containing 0.1% (w/v) dexamethasone in aqueous eye drop suspension (●) and aqueous dexamethasone/γCD microsuspension containing 1.5% (w/v) dexamethasone (○). The figure is based on data from (Johannesson et al., 2014b).

Table 1. Physiochemical properties of the most common natural cyclodextrins and some of their derivatives that are of pharmaceutical interest.

a

R = H or

Synonyms

MSb

MW (Da)

Solubilityc (mg/ml)

LogKo/wd

n

α-Cyclodextrin

0

αCD

alfadex

EUR, USP, JPC

-

β-Cyclodextrin

1

βCD

betadex

EUR, USP, JPC

-

1135

2-Hydroxypropyl-β-cyclodextrin

1

-CH2CHOHCH3

HPβCD

0.65

1400

> 600

-11

Randomly methylated β-cyclodextrin

1

-OCH3

RMβCD

1.8

1312

> 600

-6

Sulfobutylether β-cyclodextrin sodium

1

-(CH2)4SO3- Na+

SBEβCD

0.9

2163

> 500

< -10

γ-Cyclodextrin

2

-

1297

249

-17

2-Hydroxypropyl-γ-cyclodextrin

2

0.6

1576

> 500

-16

-CH2CHOHCH3

Abbreviation

PCa

Cyclodextrin

hydroxypropyl betadex

betadex sulfobutyl ether sodium

EUR, USP

USP

γCD

USP, JPC

HPγCD

-

972.8

130 18.4

Pharmacopoeia monographs: EUR (European Pharmacopoeia), USP (United States Pharmacopoeia - National Formulary), JPC (Japanese Pharmaceutical Codex). b Molar substitution (MS) is defined as the average number of substituents per glucopyranose repeat unit. c From references (Kurkov et al., 2011; Sabadini et al., 2006). d Calculated logarithm of the octanol/water partition coefficient at neutral pH. From SciFinder (scifinder.cas.org). These are approximate values. The exact values for the cyclodextrin derivatives depend on their MS well as the location of the substituents.

-13 -14

Table 2. Studies of cyclodextrin-containing ophthalmic formulations and topical drug delivery to the eye. Drug

Cyclodextrin a

Reference

Acetazolamide

HPβCD

(Granero and Longhi, 2010; Loftsson et al., 1994b; Loftsson et al., 1996; Palma et al., 2009)

Amphotericin B

γCD

(Serrano et al., 2012)

Anandamides

HPβCD

(Jarho et al., 1996c; Pate et al., 1996)

Cilostazol

HPβCD

(Okamoto et al., 2010)

Ciprofloxacin

HPβCD

(Basaran and Bozkir, 2012; Bozkir et al., 2012)

Clotrimazole

βCD

(Rasool and Salmo, 2012)

Cyclosporin A

αCD, γCD, HPβCD

(Aksungur et al., 2012; Cheeks et al., 1992; Johannsdottir et al., 2015; Kanai et al., 1989; Sasamoto et al., 1991)

Cysteamine

αCD

(Pescina et al., 2016)

Dehydroepiandrosterone

HPβCD

(Kearse et al., 2001)

Dexamethasone

HPβCD, γCD

(Gavrilin et al., 1999; Kesavan et al., 2011; Kristinsson et al., 1996; Loftsson et al., 1994a; Loftsson et al., 2007a; Loftsson et al., 2007b; Ohira et al., 2015; Sigurdsson et al., 2007; Usayapant et al., 1991)

Diclofenac

HPβCD, RMβCD

(Reer et al., 1994)

Dipivefrine

SBEβCD

(Jarho et al., 1997)

Disulfiram

HPβCD

(Kanai et al., 2012; Nagai et al., 2007; Nagai et al., 2015)

Dorzolamide

RMβCD, γCD

(Jansook et al., 2010b; Johannesson et al., 2014a; Sigurdsson et al., 2007)

Econazole

MβCD, HPβCD, SBEβCD

(Maged et al., 2016; Mahmoud et al., 2011)

Enalaprilat

HPβCD

(Loftsson et al., 2010)

Enalapril maleate

HPβCD

(Loftsson et al., 2010)

Enoxacin

HPβCD

(Liu et al., 2005)

Ethoxyzolamide

HPβCD

(Loftsson et al., 1994b)

Fluorometholone

HPγCD

(Malaekeh-Nikouei et al., 2009; Morita et al., 1996)

Fluocinolone acetonide

HPβCD

(Vafaei et al., 2015)

Fluconazole

HPβCD, SBEβCD

(Fernandez-Ferreiro et al., 2014)

Hydrocortisone

HPβCD

(Bary et al., 2000; Davies et al., 1997)

Indomethacin

βCD, HPβCD, SBEβCD

(Bucolo et al., 2011; Hippalgaonkar et al., 2013; Mohamed and Mahmoud, 2011)

Irbesartan

γCD

(Jansook et al., 2015; Muankaew et al., 2014)

Ketoconazole

HPβCD

(Zhang et al., 2008)

Latanoprost

αCD, βCD, γCD, HPβCD, PAβCD, HSβCD, HPγCD

(Rodriguez-Aller et al., 2015; Sawatdee et al., 2013)

Loteprednol etabonate

HPβCD, DMβCD

(Reddy et al., 1996)

Lutein

βCD, HEβCD

(Liu et al., 2014; Liu et al., 2015)

Mangiferin

HPβCD

(Zhang et al., 2010)

Naringenin

SBEβCD

(Zhang et al., 2016)

Orfloxacin

PCMβCD

(Chen et al., 2015)

Pilocarpine

αCD, βCD HPβCD, HPγCD, DMβCD

(Freedman et al., 1993; Järvinen et al., 1994; Keipert et al., 1996; Siefert and Keipert, 1997)

Prednisolone

DMβCD

(Couto et al., 2014)

Prostaglandins

HPβCD

(Wheeler, 1991)

Puerarin

βCD

(Xu et al., 2010)

Pyroglutamic acid

HPβCD

(Ito et al., 2013)

Riboflavin

αCD, βCD

(Morrison et al., 2013)

Rufloxacin

HPβCD

(Cappello et al., 2002)

Telmisartan

γCD

(Muankaew et al., 2016)

Thalidomide

HPβCD

(Siefert et al., 1999)

∆9-Tetrahydrocannobinol

αCD, HPβCD, RMβCD, SBEβCD

(Green and Kearse, 2000; Hippalgaonkar et al., 2011; Kearse and Green, 2000)

Tranilast

HPβCD

(Nagai et al., 2014)

Voriconazole

HPβCD

(Pahuja et al., 2014)

αCD (α-cyclodextrin), βCD (β-cyclodextrin), CMβCD (O-carboxymethyl-O-ethyl-βcyclodextrin), DMβCD (heptakis(2,6-di-O-methyl)-β-cyclodextrin), HEβCD (hydroxyethyl-βcyclodextrin), HPβCD (2-hydroxypropyl-β-cyclodextrin), HSβCD (highly sulphated-βcyclodextrin), MβCD (methylated β-cyclodextrin), PAβCD (6-monodeoxy-6-N-mono(3hydroxy)propylamino-β-cyclodextrin), PCMβCD (polycarboxymethyl-β-cyclodextrin), RMβCD (randomly methylated β-cyclodextrin), SBEβCD (sulfobutylether β-cyclodextrin sodium salt), γCD (γ-cyclodextrin), HPγCD (2-hydroxypropyl-γ-cyclodextrin). a

Table 3. The effect of HPβCD on absorption of dexamethasone from aqueous eye drops into the aqueous humor of human volunteers. Peak dexamethasone concentration (at approximately 2.5 to 3 h) and the concentration at 9 hours (mean ± stand error of the mean) from the topical administration. Based on data from (Kristinsson et al., 1996). Eye drops

Mean peak conc. (ng/ml)

Conc. at 9 h (ng/ml)

0.32% (w/v) dexamethasone solution with HPβCD as a solubilizer

141±36

~0

0.67% (w/v) dexamethasone solution with HPβCD as a solubilizer

130±50

18±5

60±21

~0

Maxidex®, 0.1% (w/v) dexamethasone in alcoholic suspension containing no HPβCD

Table 4. Dexamethasone concentration (mean ± standard deviation) in various eye tissues and blood 120 min after single topical administration to rabbits (in ng/g or ng/ml). The eye drops were administered to the left eye and the dexamethasone concentration measured in both eyes. The term topical denotes how much the topical absorption contributed to the dexamethasone level in a given tissue. Based on data from (Loftsson et al., 2007a).

Tissue

1.5% Dexamethasone/RMβCD solution

1.5% Dexamethasone/γCD microsuspension

Left eye

Left eye

Right eye

Topical

Right eye

Ratio a)

Topical

Anterior segment: Cornea Aqueous humor Iris-ciliary body Lens

1668±633 576±226 548±290 19±9

44±44 9±4 43±36 5±3

1624 567 505 14

1155±324 236±67 290±101 11±6

18±12 4±2 27±23 5±5

1137 232 263 6

0.70 0.41 0.48 0.43

231±121 22±9 66±49

31±20 6±3 57±41

200 16 9

404±300 29±16 57±22

23±12 4±4 29±15

381 25 28

1.19 1.56 3.11

Posterior segment: Sclera Vitreous Retina Blood: a)

Ratio =

45±24 Topical absorption after administration of the microsuspension Topical absorption after administration of the solution

10±7

0.22