Acta Ophthalmologica Scandinavica 2002
`
`Cyclodextrins in eye drop
`formulations: enhanced topical
`delivery of corticosteroids to
`the eye
`
`Thorsteinn Loftsson1 and Einar Stefa´nsson2
`
`Faculties of Pharmacy1 and Medicine2, University of Iceland
`2Decode Genetics Inc., Reykjavik, Iceland
`
`ABSTRACT.
`Cyclodextrins are cylindrical oligosaccharides with a lipophilic central cavity
`and hydrophilic outer surface. They can form water-soluble complexes with lipo-
`philic drugs, which ‘hide’ in the cavity. Cyclodextrins can be used to form aque-
`ous eye drop solutions with lipophilic drugs, such as steroids and some carbonic
`anhydrase inhibitors. The cyclodextrins increase the water solubility of the drug,
`enhance drug absorption into the eye, improve aqueous stability and reduce
`local irritation.
`Cyclodextrins are useful excipients in eye drop formulations of various drugs,
`including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine, cyclo-
`sporins, etc. Their use in ophthalmology has already begun and is likely to
`expand the selection of drugs available as eye drops.
`In this paper we review the properties of cyclodextrins and their application in
`eye drop formulations, of which their use in the formulation of dexamethasone
`eye drops is an example. Cyclodextrins have been used to formulate eye drops
`containing corticosteroids, such as dexamethasone, with levels of concentration
`and ocular absorption which, according to human and animal studies, are many
`times those seen with presently available formulations. Cyclodextrin-based
`dexamethasone eye drops are well tolerated in the eye and seem to provide a
`higher degree of bioavailability and clinical efficiency than the steroid eye drop
`formulations presently available. Such formulations offer the possibility of once
`per day application of corticosteroid eye drops after eye surgery, and more
`intensive topical steroid treatment in severe inflammation.
`While cyclodextrins have been known for more than a century, their use in
`ophthalmology is just starting. Cyclodextrins are useful excipients in eye drop
`formulations for a variety of lipophilic drugs. They will facilitate eye drop for-
`mulations for drugs that otherwise might not be available for topical use, while
`improving absorption and stability and decreasing local irritation.
`
`Keywords: drug delivery – eye drops – cyclodextrin – steroids – solubility.
`
`Acta Ophthalmol. Scand. 2002: 80: 144–150
`Copyrightc ActaOphthalmolScand2002.ISSN1395-3907
`
`Anew group of pharmaceutical ex-
`
`cipients called cyclodextrins has
`recently been introduced into ophthal-
`mology (Table 1). This group of excipi-
`
`ents is able to solubilize many lipophilic
`water-insoluble drugs which previously
`were impossible to formulate in aqueous
`eye drop solutions. Aqueous cyclodextrin
`
`containing eye drop solutions have al-
`ready been registered in Europe. A chlor-
`amphenicol eye drop solution (Cloroc-
`ilA) was recently registered in Portugal;
`2001 saw the registration of a diclofenac
`eye drop solution (Voltaren Ophthal-
`micA) in France. Previous reviews on this
`subject
`include those by van Dorne
`(1993); Rajewski & Stella (1996); Lofts-
`son & Stefa´nsson (1997); and Loftsson &
`Järvinen (1999). The object of this short
`review is to describe how cyclodextrins
`enhance aqueous solubility and bioavail-
`ability of lipophilic water-insoluble drugs
`in aqueous eye drop formulations. The
`formulation and in vivo testing of dexa-
`methasone eye drops as performed within
`our own research group are used as
`examples.
`
`Corticosteroids in ophthalmology
`The most common use of corticosteroids
`in eye drops is for inflammation following
`eye surgery, such as cataract surgery and
`corneal operations. In mild cases it is
`usually adequate to apply the eye drops
`one to four times per day and in some
`cases topically applied nonsteroidal anti-
`inflammatory drugs may be sufficient.
`However, in cases of severe inflammation,
`such as after complicated eye surgery,
`corneal
`transplant rejection or severe
`uveitis, applications as frequently as once
`every hour may not be adequate. In these
`severe cases the eye drops have to be
`supplemented with systemic
`steroids,
`such as prednisolone, or with subcon-
`junctival or subtenon injection of ster-
`oids. Rather than using commercially
`available eye drops,
`it would then be
`
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`
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`Acta Ophthalmologica Scandinavica 2002
`
`more advantageous to use corticosteroid
`containing eye drops of greater bioavail-
`ability. Furthermore,
`topically applied
`corticosteroids are generally not effective
`in the posterior segment of the eye and,
`therefore,
`systemic corticosteroids are
`needed to fight inflammatory disease in
`this area.
`Corticosteroids are generally lipophilic
`and dissolve very poorly in water. The
`commercially available eye drop formu-
`lations solve this dilemma by forming
`prodrugs, usually acetate or phosphate
`esters such as prednisolone acetate (Pred
`forte A, Pred mild A) and dexame-
`thazone phosphate or suspensions, such
`as dexamethazone alcohol
`suspension
`(MaxidexA).
`Various researchers have studied the
`penetration of topically applied ocular
`steroids into the anterior chamber of the
`human eye (Watson et al. 1988; McGhee
`et al. 1990). They found that of the com-
`mercially available formulations, those
`
`containing 1% prednisolone acetate (Pred
`forteA) gave the highest concentration in
`the aqueous humour per average 96 ng/
`mL. Eye drops containing 0.1% dexa-
`methasone alcohol suspension (Maxid-
`exA) gave a considerably lower concen-
`tration. However, if we take into account
`the fact that dexamethasone is seven times
`more potent than prednisolone, then the
`dexamethasone concentration obtained in
`the aqueous humour corresponded to
`about 60 ng/mL of prednisolone. The most
`effective corticosteroid eye drops available
`today give aqueous humour concentration
`of
`less
`than 100 ng/mL (prednisolone
`equivalents). This bioavailability can be
`improved through the use of cyclodextrin
`formulation, where a single drop topical
`application gives aqueous humour con-
`centration of about 140 ng/mL (pred-
`nisolone equivalents) and also extends its
`duration in the eye, as will be discussed
`later.
`The
`
`concentrations
`
`corticosteroid
`
`Table 1. Cyclodextrins in topical formulations for ocular drug delivery.
`
`Cyclodextrin
`
`References
`
`achieved in the aqueous humour from ap-
`plication of Maxidex A or Pred Forte A
`is usually sufficient for mild to moderate
`ocular inflammation. More potent for-
`mulations may allow topical treatment of
`more severe intraocular
`inflammation
`and also less frequent applications for
`mild to moderate inflammation.
`
`Physiological considerations
`In ophthalmology, local drug administra-
`tion in the form of topically applied low
`viscosity aqueous eye drop solutions is
`generally preferred. Topically applied
`drugs must be, at least to some degree,
`soluble in the aqueous tear fluid. How-
`ever, they must also be somewhat lipid-
`soluble in order to penetrate the lipophil-
`ic corneal epithelium, through the cor-
`neal stroma and the lipophilic endo-
`thelium into the aqueous humour (Ahm-
`ed et al. 1987; Wang et al. 1991). In other
`words, for successful formulation in an
`aqueous eye drop solution. a drug must
`be both water-soluble (i.e. hydrophilic)
`and
`lipid-soluble
`(i.e.
`hydrophobic)
`(Loftsson & Stefa´nsson 1997). The con-
`tinuous secretion of tear fluid adds to this
`difficulty by limiting the contact time of
`topically applied drugs with the eye sur-
`face, which again reduces their ocular
`bioavailability,
`especially after appli-
`cation in low viscosity aqueous eye drop
`solutions
`(Chrai et al. 1973). Conse-
`quently, less than 5% of a topically ap-
`plied drug is absorbed through the cor-
`nea into the eye (Gangrade et al. 1996;
`Loftsson & Järvinen 1999; Washington
`et al. 2001). Steroids used to treat ocular
`inflammation are lipophilic water-insol-
`uble compounds that have to be intro-
`duced into aqueous eye drop formu-
`lations as suspensions or as water-soluble
`prodrugs. In both cases, ocular bioavail-
`ability is seriously hampered by the low
`aqueous
`solubility or
`the hydrophilic
`properties of the penetrating molecules,
`respectively.
`In addition,
`insufficient
`chemical stability of the steroid prodrugs
`in aqueous solution, as well as poor in
`vivo conversion to parent steroid, has
`limited their use in ophthalmology (Tam-
`mara & Crider 1996).
`Common adjuvants to aqueous eye
`drop formulations can enhance ocular
`bioavailability of steroids by reducing the
`barrier function of, for example, the cor-
`nea (e.g. benzalkonium chloride and
`other surfactants (Lang & Stiemke 1996)
`or by increasing the contact time of the
`drug with the eye surface (e.g. viscosity
`enhancers such as water-soluble poly-
`
`145
`
`Drug
`
`Acetazolamide
`
`Anandamides
`Cannabinoids (various)
`Cyclosporin
`
`Dehydroepiandrosterone
`Dexamethasone
`
`Diclofenac
`Dipivefrine
`Fluorometholone
`Hydrocortisone
`
`Loteprednol etabonate
`Pilocarpine
`
`Prostaglandins
`Talidomide
`Tropicamide
`D9-Tetrahydrocannobinol
`
`HPbCD
`
`HPbCD
`HPbCD
`aCD
`
`HPbCD
`HPbCD
`
`(Loftsson et al. 1994;
`Loftsson et al. 1996)
`(Jarho et al. 1996;Pate et al. 1996)
`(Pate et al. 1998)
`(Kanai et al. 1989;
`Sasamoto et al. 1991;
`Cheeks et al. 1992
`(Kearse et al. 2001)
`(Usayapant et al. 1991;
`Loftsson et al. 1994;
`Kristinsson et al. 1996;
`Gavrilin et al. 1999)
`(Reer et al. 1994)
`(Jarho et al. 1997)
`(Morita et al. 1996)
`(Davies et al. 1997;
`Bary et al. 2000
`(Reddy et al. 1996)
`HPbCD, DMbCD
`aCD, bCD, HEbCD, HPbCD (Freedman et al. 1993;
`Järvinen et al. 1994;
`Keipert et al. 1996;
`Siefert & Keipert 1997)
`(Wheeler 1991)
`(Siefert et al. 1999)
`(Cappello et al. 2001)
`(Green & Kearse 2000;
`Kearse & Green 2000)
`
`HPbCD, RMbCD
`SBEbCD
`HPgCD
`HPbCD
`
`SBEbCD
`
`HPbCD
`HPbCD
`HPbCD
`aCD, bCD, HPbCD, gCD
`
`HPbCD 2-hydroxypropyl-b-cyclodextrin
`aCD a-cyclodextrin
`RMbCD randomly methylated b-cyclodextrin
`SBEbCD sulfobutylether b-cyclodextrin
`HPgCD 2-hydroxypropyl-g-cyclodextrin
`DMbCD heptakis (2,6-di-O-methyl)-b-cyclodextrin
`HEbCD hydroxyethyl-b-cyclodextrin
`bCD b-cyclodextrin
`gCD g-cyclodextrin
`
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`Acta Ophthalmologica Scandinavica 2002
`
`water-insoluble steroids as aqueous eye
`drop solutions (Usayapant et al. 1991;
`Loftsson et al. 1994; Kristinsson et al.
`1996; Morita et al. 1996; Reddy et al.
`1996; Davies et al. 1997; Gavrilin et al.
`1999; Bary et al. 2000; Kearse et al.
`2001). Furthermore, the chemical sta-
`bility of the drug molecule is enhanced by
`the inclusion complexation (Loftsson &
`Brewster 1996). This increases the shelf-
`life of the aqueous eye drop formulation.
`Once included in the cyclodextrin cav-
`ity,
`the drug molecules may be dis-
`sociated from the cyclodextrin molecules
`through complex dilution in the aqueous
`tear fluid. The included drug may also be
`replaced by some other suitable molecule
`(such as lipids), or,
`if the complex is
`located in close approximation to a lipo-
`philic biological membrane (such as the
`eye cornea), the guest may be transferred
`to the matrix for which it has the highest
`affinity. Importantly, since no covalent
`bonds are formed or broken during the
`guest-host complex formation, the com-
`plexes are in dynamic equilibrium with
`free drug and cyclodextrin molecules.
`The effects of cyclodextrins on drug
`solubility, permeability, chemical stability
`and delivery through biological mem-
`branes have been investigated by a number
`of research groups (Rajewski & Stella
`1996; Uekama et al. 1998; Loftsson &
`Järvinen 1999; Masson et al. 1999; Stella
`et al. 1999; Uekama 1999; Loftsson &
`Masson 2001). Their studies show that hy-
`drophilic cyclodextrins act as true carriers
`by keeping the lipophilic water-insoluble
`drug molecules in solution and delivering
`them to the membrane surface where they
`
`form inclusion complexes with
`trins
`many lipophilic molecules through a pro-
`cess in which water molecules located in-
`side the central cavity are replaced by
`either a whole molecule, or, more fre-
`quently, by some lipophilic structure of
`the molecule. Cyclodextrin complexation
`of a drug molecule changes the physico-
`chemical properties of the drug, such as
`its aqueous solubility and chemical sta-
`bility (Loftsson & Brewster 1996). Since
`the cyclodextrin molecule is hydrophilic
`on the outside, the complex formation
`usually increases the water-solubility of
`lipophilic water-insoluble drugs. Thus, it
`has been possible through cyclodextrin
`complexation to formulate
`lipophilic
`
`Fig. 2. The mechanism of drug (D) penetration into the eye from an aqueous cyclodextrin (CD)
`containing eye drop solution in the tear film. Modified from Loftsson & Järvinen (1999) with
`permission from Advanced Drug Delivery Reviews.
`
`Fig. 1. b-Cyclodextrin.
`
`mers). Specialized ocular delivery systems
`such as hydrogels, microemulsions, solid
`inserts and liposomes have also been de-
`signed in order to enhance bioavailability
`of
`topically applied ophthalmic drugs
`(Reddy 1996). However, these have never
`gained much popularity, due to both their
`side-effects (such as blurred vision and
`local irritation) and their instability (i.e.
`limited shelf-life).
`Cyclodextrins are novel, chemically
`stable adjuvants that enhance ocular bio-
`availability of ophthalmic drugs without
`affecting the barrier function of the eye
`or increasing the viscosity of the aqueous
`eye drop formulation (Loftsson & Mas-
`son 2001).
`
`Cyclodextrins
`Cyclodextrins are a group of structurally
`related natural products formed during
`bacterial digestion of cellulose. These cyc-
`lic oligosaccharides consist of
`(a-1,4)-
`linked a-D-glucopyranose units with a hy-
`drophilic outer surface and a lipophilic
`central cavity. The natural a-, b- and g-
`cyclodextrins consist of six, seven and
`eight glucopyranose units (Fig. 1), respec-
`tively. The aqueous solubility of these
`natural cyclodextrins is somewhat limited
`and thus several different water-soluble
`derivatives have been synthesized. Cyclo-
`dextrin derivatives which have been ap-
`plied in ophthalmology include the hydro-
`xypropyl derivatives of b- and g-cyclodex-
`trin,
`the
`randomly methylated
`b-
`cyclodextrin and sulfobutylether b-cyclo-
`dextrin (Table 1).
`In an aqueous environment, cyclodex-
`
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`Acta Ophthalmologica Scandinavica 2002
`
`methasone for a space in the cyclodextrin
`cavity, thereby reducing the solubilizing
`effect of the cyclodextrin. At the same
`time, some other ingredients may have a
`solubilizing effect on the drug, thereby re-
`ducing
`the
`amount of
`cyclodextrin
`needed to solubilize the drug. Conse-
`quently, the amount of cyclodextrin in-
`cluded in the aqueous eye drop formu-
`lation has to be based on availability
`studies performed on the actual eye drop
`formulation which must
`contain all
`necessary excipients (e.g. preservatives,
`polymers and buffer salts).
`It is possible to increase drug availabil-
`ity in aqueous cyclodextrin formulations
`by including small amounts of water-sol-
`uble polymer. Polymers enhance the
`cyclodextrin complexation of the drug,
`thereby reducing the amount of cyclodex-
`trin needed in the formulation, while sim-
`ultaneously enhancing the absorption of
`the drug/cyclodextrin complex to the eye
`surface through the formation of ternary
`complexes or co-complexes (Kristinsson
`et al. 1996). This increases the drug avail-
`ability at the eye surface (Loftsson 1998;
`Loftsson & Järvinen 1999). The addition
`of 0.10% hydroxypropyl methylcellulose
`increases the apparent stability constant
`of
`dexamethasone/2-hydroxypropyl-b-
`cyclodextrin complex from 1200 m»1 to
`1600 m»1 (Loftsson & Stefa´nsson 1997).
`At the same time, the polymer increases
`the availability of dexamethasone in the
`aqueous eye drop formulation (Kristins-
`son et al. 1996). Using the described op-
`
`Fig. 3. The effect of 2-hydroxypropyl-b-cyclodextrin (HPbCD) concentration on the flux of dexa-
`methasone from an aqueous HPbCD solution containing 0.5% (w/v) dexamethasone through a
`4). The dexamethasone was in suspen-
`semipermeable cellophane membrane (mean ” SEM, n
`sion at HPbCD concentration below 5% but in solution at higher HPbCD concentrations. Modi-
`fied from Loftsson et al. (1994) with permission from the International Journal of Pharmaceutics.
`
`enough cyclodextrin is added to the ve-
`hicle to solubilize the entire drug. Figure
`3 shows that it is very important to
`optimize the dexamethasone release from
`an aqueous eye drop formulation by ad-
`justing the cyclodextrin concentration in
`the aqueous eye drop formulation. Too
`much or too little cyclodextrin will result
`in less than optimum drug availability.
`Some of the ingredients of the eye drop
`formulation will compete with dexa-
`
`partition from the cyclodextrin cavity into
`the lipophilic membrane. The relatively
`lipophilic membrane has low affinity for
`the large hydrophilic cyclodextrin mol-
`ecules or the hydrophilic drug/cyclodex-
`trin complexes, which thus remain in the
`aqueous skin exterior, e.g. the aqueous
`tear fluid. Conventional penetration en-
`hancers, such as benzalkonium chloride,
`disrupt the ophthalmic barrier, whereas
`hydrophilic cyclodextrins enhance drug
`penetration into the eye by carrying the
`lipophilic water-insoluble drug molecules
`through the aqueous mucin layer and
`thereby increasing drug availability at the
`lipophilic eye surface (Fig. 2) (Loftsson &
`Masson 2001).
`
`Formulation with cyclodextrin
`their
`Since neither cyclodextrins nor
`complexes are absorbed into lipophilic
`barriers, cyclodextrins can both increase
`and decrease drug availability at the eye
`surface. For example, the effect of cyclo-
`dextrin
`concentration
`on
`the
`per-
`meability of the lipophilic water-insoluble
`drug dexamethasone through semiperme-
`able membrane is shown in Fig. 3. At low
`cyclodextrin concentrations, when the
`drug is in suspension, the flux of the drug
`increases with increasing cyclodextrin
`concentration. At higher cyclodextrin
`concentrations, when the entire drug is in
`solution, the flux decreases with increas-
`ing cyclodextrin concentration. Maxi-
`mum permeability is observed when just
`
`Fig. 4. Dexamethasone concentration in aqueous humour of rabbits after administration of 50 mL
`of 1.3% dexamethasone in an aqueous cyclodextrin solution or a 0.1% dexamethasone alcoholic
`suspension (MaxidexA) (O) (mean ” SEM, n
`3). Modified from Loftsson et al. (1994) with per-
`mission from the International Journal of Pharmaceutics.
`
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`Acta Ophthalmologica Scandinavica 2002
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`eye
`timization technologies, aqueous
`drops containing 0.32, 0.67 and 1.3% (w/
`v) dexamethasone were prepared and
`tested both in animals and humans.
`
`In vivo observations
`Dexamethasone (1.3% w/v) was tested in
`English brown rabbits in an aqueous eye
`drop solution containing 2-hydroxyprop-
`yl-b-cyclodextrin and MaxidexA (Lofts-
`son et al. 1994). A single drop of the
`solution was applied in the rabbit’s eye
`and aqueous humour
`samples with-
`drawn at specified times following the
`administration. Dexamethasone
`(0.1%
`w/v) alcohol suspension (MaxidexA, Al-
`con Inc, Texas, USA) was used for con-
`trol. The 1.3% dexamethasone/2-hydro-
`xypropyl-b-cyclodextrin eye drops gave a
`significantly higher
`concentration of
`dexamethasone in the aqueous humour
`than did Maxidex, even though the dif-
`ference in concentration in the aqueous
`humour was less than the 13-fold differ-
`ence in the concentration of dexametha-
`sone in the eye drop. Four hours after
`the application of MaxidexA, the con-
`centration of dexamethasone
`in the
`aqueous humour was essentially zero,
`whereas the cyclodextrin-dexamethasone
`solution gave about 100 ng/mL (Fig. 4).
`The
`cyclodextrin-dexamethasone
`eye
`drop solution was well tolerated and no
`irritation was seen on clinical examina-
`tion of the rabbits.
`The ocular absorption of dexametha-
`sone eye drops containing 2-hydroxypro-
`pyl-b-cyclodextrin was also tested in hu-
`man patients and compared with Maxi-
`dexA (0.1% dexamethasone
`alcohol
`suspension). The patients received the
`eye drops at a certain time prior to cat-
`aract surgery and, at the time of catar-
`act surgery, an aqueous humour sample
`was withdrawn
`and
`dexamethasone
`levels determined. Figure 5 shows the
`dexamethasone
`concentration in the
`aqueous humour after administration of
`0.32% dexamethasone/2-hydroxypropyl-
`b-cyclodextrin and MaxidexA (Kristins-
`son et al. 1996). The concentration of
`dexamethasone in the aqueous humour
`was significantly higher (P , 0.001) and
`the area under the curve was 2.6 times
`higher with the 0.32% cyclodextrin-
`dexamethasone eye drop solution than
`with MaxidexA. The peak concentration
`of dexamethasone did not increase when
`the dexamethasone concentration in the
`aqueous
`cyclodextrin containing
`eye
`drops was increased from 0.32 to 0.67%
`(w/v) (Fig. 6). However, as can be seen
`
`148
`
`by concentration values obtained 9 hr
`after administration, the duration of ac-
`tivity was increased (Table 2). It is inter-
`esting to compare these results with the
`measurements of Watson and associates
`and McGhee and associates (see Table 2)
`(Watson et al. 1988; McGhee
`et al.
`1990). The 0.32% (w/v) dexamethasone
`solution gives a considerably higher ef-
`
`fective concentration in the aqueous hu-
`mour than does prednisolone acetate,
`which is the most potent corticosteroid
`eye drop on the market.
`Figure 6 shows the effect of the co-
`complexation involving the water-soluble
`polymer, hydroxypropyl methylcellulose,
`on the dexamethasone bioavailability in
`vivo. The two eye drop solutions were
`
`Fig. 5. Dexamethasone concentration in aqueous humour after administration of 1 drop (50 mL) of
`0.32% dexamethasone in an aqueous cyclodextrin solution (?)or a 0.1% dexamethasone alcoholic
`suspension (MaxidexA) (O). The concentration (mean ” SEM, n
`3) is shown at appropriate time
`points after administration of the eye drops to human volunteers. Reprinted from Kristinsson
`et al. (1996) with permission from Investigative Ophthalmology and Visual Science.
`
`Fig. 6. Dexamethasone concentration in aqueous humour after administration of 1 drop (50 mL)
`of 0.67% dexamethasone in an aqueous cyclodextrin solution; the dexamethasone/cyclodextrin/
`polymer co-complex (?), the simple dexamethasone/cyclodextrin complex (O). The concentration
`3) is shown at appropriate time points after administration of the eye drops to
`(mean ” SEM, n
`human volunteers. Reprinted from Kristinsson et al. (1996) with permission from Investigative
`Ophthalmology and Visual Science.
`
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`Acta Ophthalmologica Scandinavica 2002
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`Table 2. Adjusted mean peak concentration (” SEM) of dexamethasone and prednisolone acetate,
`and the concentration at „9 hrs, in aqueous humour of human volunteers after topical adminis-
`tration. Concentrations are adjusted for potency of prednisolone, which is a seven-fold weaker
`steroid than dexamethasone.
`
`Eye drop solution
`
`Mean peak
`concentration
`(ng/ml)
`
`Concentration
`at „9 hrs
`(ng/mL
`
`141 ” 36
`Dexamethasone 0.32%
`130 ” 50
`Dexamethasone 0.67%
`60 ” 21
`Maxidex*
`96 ” 19
`Prednisolone acetate 1%
`*MaxidexA contains 0.1% dexamethasone alcoholic suspension
`Modified from Kristinsson et al. 1996; McGhee et al. 1990; Schoenwald et al. 1987).
`
`0
`18 ” 5
`0
`–
`
`for the study formu-
`identical except
`lation’s co-complex formation (induced
`through heating) between the drug/cyclo-
`dextrin complex
`and hydroxypropyl
`methylcellulose. The control formulation
`contained a simple drug/cyclodextrin
`complex. Formation of the co-complex
`resulted in significant enhancement of the
`bioavailability of the drug (Kristinsson et
`al. 1996).
`
`Clinical studies
`Saari et al. (1998) studied the use of de-
`xamethazone-cyclodextrin eye drops fol-
`lowing cataract surgery. Eye drops con-
`taining 0.67% dexamethazone-cyclodex-
`trin and used once per day were compared
`with a 0.1% dexamethazone used three
`times per day. Cell flare measurements of
`the aqueous humour and clinical evalu-
`ation indicated that the two treatment
`regimens were equally clinically efficient.
`Once per day application of the cyclodex-
`trin dexamethazone
`formulation was
`quite effective in controlling postoperative
`inflammation following cataract surgery.
`
`Conclusions
`Cyclodextrins make it possible to formu-
`late lipophilic drugs in aqueous eye drop
`solutions. This may be useful for the for-
`mulation of a variety of lipophilic drugs
`that hitherto have not been available as
`eye drops or in suboptimal formulations.
`Steroid drugs, including corticosteroids,
`are a good example of such drugs. They
`are lipophilic and have only been avail-
`able in eye drops as prodrugs or suspen-
`sions with limited concentration and bio-
`availability. With cyclodextrins, it is poss-
`ible to increase the drug concentration
`and bioavailability and create formu-
`lations that offer more effective and less
`
`frequent treatment schedules for patients
`with ocular inflammation.
`
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