Aqueous Prostaglandin Eye Drop Formulations: History
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Contributor:
Phatsawee Jansook
,
Thorsteinn Loftsson

Glaucoma is one of the leading causes of irreversible blindness worldwide. It is characterized by progressive optic neuropathy in association with damage to the optic nerve head and, subsequently, visual loss if it is left untreated. Among the drug classes used for the long-term treatment of open-angle glaucoma, prostaglandin analogues (PGAs) are the first-line treatment and are available as marketed eye drop formulations for intraocular pressure (IOP) reduction by increasing the trabecular and uveoscleral outflow. PGAs have low aqueous solubility and are very unstable (i.e., hydrolysis) in aqueous solutions, which may hamper their ocular bioavailability and decrease their chemical stability. Additionally, treatment with PGA in conventional eye drops is associated with adverse effects, such as conjunctival hyperemia and trichiasis. It has been a very challenging for formulation scientists to develop stable aqueous eye drop formulations that increase the PGAs’ solubility and enhance their therapeutic efficacy while simultaneously lowering their ocular side effects.

  • ocular hypertension
  • prostaglandin analogues
  • aqueous solubility
  • chemical stability
  • drug delivery

1. Introduction

Glaucoma is a group of eye diseases that causes the progressive degeneration of the retinal ganglion cells and the retinal nerve fiber layer. The most common type of glaucoma is primary open-angle glaucoma (POAG), representing 74% of all glaucoma cases [1]. POAG is caused by the obstruction of the aqueous humor outflow within the trabecular network which increases the intraocular pressure (IOP) with consequent optic nerve damage [1][2]. Prostaglandins (PGs) are eicosanoids derived from arachidonic acid and other polyunsaturated fatty acids which have diverse biological activities, including the relaxation of smooth muscles. In general, PGs are lipophilic, chemically unstable, and poorly water-soluble compounds composed of a cyclopentane ring with two side chains [3][4].
In 1977, Camras, Bito and Eakins [5] showed that PGF2α lowered the IOP in rabbits. It was discovered that PGs reduce the IOP by enhancing the aqueous humor outflow, and the first antiglaucoma prostaglandin analog (PGA), latanoprost, received the Food and Drug Administration’s approval between August 2000 and March 2001 [6]. Now PGAs are considered the drugs of choice for the treatment of POAG [7][8]. Currently there are five PGAs marketed as aqueous eye drops. These are 0.01% bimatoprost ophthalmic solution (Lumigan®, Allergan, Irvine, CA, USA), 0.005% latanoprost ophthalmic solution (Xalatan®, Pfizer, New York, NY, USA) and emulsion (Xelpros®, Sun Ophthalmics, Cranbury, NJ, USA), 0.024% latanoprostene bunod ophthalmic solution (Vyzulta®, Bausch & Lomb, Bridgewater, NJ, USA), 0.0015% tafluprost ophthalmic solution (Taflotan®, Santen, Osaka, Japan, and Zioptan®, Akron, Lake Forest, IL, USA/Merck, Kenilworth, NJ, USA), 0.004% travoprost ophthalmic solution (Travatan®, in Europe) and Travatan Z® (in the USA, Novartis, Cambridge, MA, USA). All these PGA are PGF2α derivatives; four are ester prodrugs of the corresponding acids, while one, bimatoprost, is an amide prodrug (Table 1). For example, latanoprost is an isopropyl ester (i.e., a prodrug) of latanoprost acid, which is a PGF2α analog. Likewise, tafluprost and travoprost are isopropyl ester prodrugs of tafluprost acid and travoprost acid, respectively. Latanoprost is hydrolyzed by the corneal esterase to yield the biologically active agent latanoprost acid [6]. Bimatoprost is also rapidly hydrolyzed by ocular esterase to the biologically active bimatoprost acid [9].
Table 1. Structure and physicochemical properties of prostaglandin F2α and its analogs, which are currently used in ophthalmology.
Prostaglandin Analog Structure Molecular Weight Calculated Values a
LogP(o/w) b Solubility in Water c
Prostaglandin F2α
(pKa 4.76)		 Pharmaceutics 14 02142 i001 354.48 2.6
(LogD7.0 0.4)		 30 mg/mL (at pH 7.0)
Latanoprost acid Pharmaceutics 14 02142 i002 390.51 2.8
(LogD7.0 0.6)		 7 mg/mL (at pH 7.0)
Bimatoprost
(Lumigan®)		 Pharmaceutics 14 02142 i003 415.57 2.8 40 µg/mL
Latanoprost
(Xalatan®, Xelpros®)		 Pharmaceutics 14 02142 i004 432.59 4.3 6 µg/mL
Latanoprostene bunod
(Vyzulta®)		 Pharmaceutics 14 02142 i005 507.62 4.8 1 µg/mL
Tafluprost
(Taflotan®, Zioptan®)		 Pharmaceutics 14 02142 i006 452.53 3.8 10 µg/mL
Travoprost
(Travatan Z®)		 Pharmaceutics 14 02142 i007 500.55 4.1 4 µg/mL
Bimatoprost, latanoprost, tafluprost and travoprost appear to have very comparable efficacy regarding IOP reduction in patients with primary open-angle glaucoma [10]. Latanoprostene bunod is a prodrug of two active entities, latanoprost acid and butanediol mononitrate, which yields nitric oxide [11]. Nitric oxide lowers the IOP and improves the ocular blood flow, both of which can result in neuroprotection [12]. Thus, latanoprostene bunod might have some therapeutic advantages over the other PGAs, although the difference was shown to be insignificant with regard to the reduction in IOP [13]. An enhanced therapeutic efficacy has been obtained by combining the PGAs with non-prostaglandin IOP-lowering drugs. Examples of such combinations are 0.005% latanoprost with 0.02% netarsudil (Roclanda®, Aerie Pharmaceuticals, Durham, NC, USA), 0.005% latanoprost with 0.5% timolol (Xalacom®, Pfizer, New York, NY, USA), 0.03% bimatoprost with 0.5% timolol (Ganfort®, Allergan, Irvine, CA, USA), 0.004% travoprost with 0.5% timolol (DuoTrav®, Novartis, Basel, Switzerland) and 0.0015% tafluprost with 0.5% timolol (Taptiqom®, Santen, Osaka, Japan).

2. Physicochemical Properties and Eye Drop Formulations

PGAs reduce the IOP by ciliary muscle relaxation and increased aqueous humor outflow [14]. Thus, when applied topically to the eye, the PGA molecules must permeate the cornea into the aqueous humor to access their receptors. Po/w is the partition coefficient (i.e., the concentration ratio at equilibrium) of an uncharged molecule between 1-octanol and water, while Do/w is the partition coefficient of an ionizable compound at some fixed pH or ionization. Compounds with low Po/w are hydrophilic and, in general, water-soluble, while compounds with high Po/w are lipophilic and poorly soluble in water. The optimal LogPo/w value (i.e., 10-logarithm of Po/w) for drug permeation from the aqueous tear fluid, through the cornea and into the aqueous humor is between 1 and 3, in which the drugs with LogPo/w values less than 1 or greater than about 3 display a decreased ability to permeate the lipophilic cornea [15]. Prostaglandin F2α and latanoprost acid are fully ionized in the tear fluid with a LogDo/w value much less than unity, while their PGAs (i.e., ester prodrug analogues) have LogPo/w values between 3.8 and 4.8, except bimatoprost (i.e., the amide prodrug analog) which has a LogPo/w value of 2.8 (Table 1). Accordingly, bimatoprost has the optimal LogPo/w value for transcorneal permeation, while the acids are too hydrophilic at a physiologic pH and the other PGAs a bit too lipophilic.
All the PGAs in Table 1 are practically insoluble in water, although bimatoprost appears to be slightly more soluble than the other PGAs in the table. The more optimal lipophilicity and slightly greater solubility increases the ability of bimatoprost to permeate from the aqueous tear fluid into the eye and can explain the slightly greater efficacy of bimatoprost compared to the other PGAs [10][13]. The PGAs are very potent drugs with low aqueous solubility which are administered topically to the eye in close to PGA saturated aqueous eye drop solutions. In other words, the dissolved PGA molecules will possess a high level of thermodynamic activity in the aqueous exterior and, thus, the molecules will have the maximum tendency to partition from the aqueous tear fluid into the lipophilic cornea [16][17]. This enhances their ability to permeate into the eye in spite of their greater than optimum LogPo/w value.
The PGs are derivatives of long chain fatty acids containing a substituted cyclopentane ring which are rapidly dehydrated in aqueous solutions and known to form epimers under strong acidic and alkaline conditions [18][19][20]. Additionally, PGs and their analogs contain one or more double bonds and, thus, are sensitive towards oxidation. While PGE2 and related PGs are very unstable in aqueous environment, PGF2α and its derivatives are, in general, less susceptible to chemical degradation. The major degradation pathways of PGAs in aqueous media are hydrolysis to form the PG acids (i.e., the active form of the PGAs), epimerization, trans isomerization and oxidation. For example, known degradation products of latanoprost in aqueous solutions are latanoprost acid, the latanoprost 15-epi diastereomer and the latanoprost 5,6-trans isomer, as well as oxidation products, such as the latanoprost 5-keto and 15-keto derivatives (Figure 1). Latanoprost undergoes photoinduced degradation and the highly lipophilicity drug is absorbed into plastic containers [21][22][23].
Pharmaceutics 14 02142 g001
Figure 1. The main degradation products of latanoprost. Based on USP43-NF38 and Ph. Eur. 10.3, as well as reference [22]. Other degradation products have also been identified during forced degradation under somewhat extreme conditions [22].
Xalatan® contains 0.05 mg/mL of latanoprost in an aqueous solution of benzalkonium chloride (0.02%) as a preservative, sodium chloride for adjustment of the tonicity, a pH 6.7 phosphate buffer (sodium dihydrogen phosphate monohydrate 4.60 mg/mL and anhydrous disodium phosphate 4.74 mg/mL) and water for injection. In an unopened original package, the eye drops have a shelf-life of 36 months when stored in a refrigerator (2–8 °C) protected from light. The addition of non-ionic surfactants, such as polyoxyl 40 stearate and polyethylene glycol monostearate 25, and cyclodextrins to the aqueous eye drop media will increase the shelf-life of the latanoprost eye drops [23][24][25][26][27]. It was reported that latanoprost eye drops in the presence of 2-hydroxypropyl-β-cyclodextrin were stable at 25 °C and 60% relative humidity for at least six months, while the one containing a non-ionic surfactant remained stable for up to 24 months under the same storage conditions [23][24]. The proposed mechanism is that the interaction between the ester group of latanoprost and the complex micelle of those non-ionic surfactants results in hydrolysis being inhibited [27]. For the role of cyclodextrin, it shields the ester group of latanoprost inside the cavity, providing degradation protection [26].
The degradation profile of travoprost (Figure 2) is very similar to that of latanoprost, and in aqueous solutions, travoprost is most stable at pH 6.0 ± 0.2 [28]. Travatan® contains 0.04 mg/mL of travoprost, polyquaternium-1 (0.01 mg/mL) as preservative, polyethylene glycol 40 hydrogenated castor oil (2 mg/mL) which increases the chemical stability and solubility of travoprost, boric acid, propylene glycol (7.5 mg/mL), mannitol and sodium chloride in purified water. Travatan Z® contains 0.04 mg/mL of travoprost in an aqueous solution containing polyethylene glycol 40 hydrogenated castor oil, and a pH 5.7 buffer-preservative system (sofZia®) which is composed of boric acid, propylene glycol, sorbitol, zinc chloride and purified water [29].
Pharmaceutics 14 02142 g002
Figure 2. Degradation products of travoprost. Based on USP43-NF38 and reference [30].
The aqueous eye drops compositions of tafluprost and bimatoprost are also simple aqueous buffer solutions. Tafluprost is, like latanoprost and travoprost, an isopropyl ester with its maximum stability at pH between 5.5 and 6.7, while bimatoprost is an amide with its maximum stability between pH 6.8 and 7.8. In general, amides are more chemically stable than esters of comparable structures and studies have shown that bimatoprost eye drops are more stable than, for example, latanoprost and travoprost eye drops [31][32]. Tafluprost is the first preservative-free commercially available PGA (Zioptan®) containing 0.015 mg/mL of tafluprost in an aqueous solution containing polysorbate 80 as a solubilizer, glycerol, phosphate buffer and disodium edetate. Unopened cartons and foil pouches should be stored in the refrigerator (2–8 °C). After the foil pouch is opened, the unit-dose containers may be stored in the opened pouch for up to 28 days at room temperature (20–25 °C) [33].
Latanoprostene bunod is a double ester prodrug releasing two active drugs upon hydrolysis (Figure 3). Thus, one would expect that this double ester would be more chemically unstable than the other monoester prodrugs, such as latanoprost. However, the shelf-life of Vyzulta® in unopened containers is similar to those of the other ester PGAs. Vyzulta® contains 0.24 mg/mL of latanoprostene bunod in an aqueous solution containing polysorbate 80, glycerol, 0.2 mg/mL of benzalkonium chloride, pH 5.5 citrate buffer and disodium edetate. The shelf-life of Vyzulta® unopened containers is up to 3 years at 2 to 8 °C.
Pharmaceutics 14 02142 g003
Figure 3. Hydrolysis of latanoprostene bunod [11][34].

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14102142

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