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Published in final edited form as: Eur J Pharm Sci. 2020 Jun 12;152:105413. doi: 10.1016/j.ejps.2020.105413

In vitro release of hydrophobic drugs by oleogel rods with biocompatible gelators

Russell Macoon a, Mackenzie Robey a, Anuj Chauhan b,*
PMCID: PMC8991997  NIHMSID: NIHMS1605761  PMID: 32535213

Abstract

Purpose:

Currently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. Injections of oleogels into the vitreous have the potential for extended release of both hydrophobic and hydrophilic drugs for extended durations which could decrease the frequency of injections. The type of gelator used is critical because it may impact drug release and also the biocompatibility of the device.

Methods:

Oleogels containing soybean oil as the liquid component and beeswax, a combination of β-sitosterol and lecithin, sorbitan monostearate, sunflower wax, ethyl cellulose, or a combination of γ-oryzanol with β-sitosterol as the gelator were loaded with the drugs dexamethasone, cyclosporine, triamcinolone, vancomycin above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. Images of the devices were taken to observe the dispersal of drug particles. In vitro drug release in buffer solutions was measured and effective drug diffusivity was determined from a fitted model. Effect of molecular weight and drug binding to the gelator on diffusivity was explored.

Results:

At loading above the solubility limit, the oleogel formulation contains drug particles that act as distributed depots resulting in extended release. The oleogels prepared with different gelators presented a wide range of drug release profiles. The release durations for 10% loading dexamethasone are 35 days for the β-sitosterol/lecithin gel and 135 days for the sorbitan monostearate gel. The γ-oryzanol/β-sitosterol gels released 81% after 135 days and the beeswax and sunflower wax gels released about 78% and 79% of the loaded dexamethasone after 30 days, respectively. In ethyl cellulose gels, the release duration of 28% cyclosporine was 13 days, 28% loaded dexamethasone released 66% after 125 days, 28% triamcinolone released 46% after 108 days, and vancomycin released 80% after 21 days. The solubility limit of the drug in the oleogel was increased in presence of gelator suggesting significant drug binding to the gelator. The effective diffusivity decreased with drug binding likely because the bound drug does not diffuse. The model based on accounting for drug particle depots fit the release data. Dissolution of the particles results in void formation that increases tortosity impacting effective diffusivity.

Conclusions:

Oleogel based rods can provide extended release of many hydrophobic drugs. Solubility of drugs in the gels are affected by gelator type, which suggests some interaction between the drug and the gelling agent. Drug dissolution, diffusion, binding as well as tortuosity due to the formation of voids must be considered to model drug release.

Hypothesis:

Currently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. Consequently, oleogels have been explored as an extended release ocular implant for delivery of drug to the retina. The gelator component in these gels is ethyl cellulose, a polysaccharide that is not readily degradable in the eye. Comparing various biocompatible gelator molecules’ ability to form drug incorporated oleogel formulations and their effect on drug release profiles could provide significant insight into development of oleogel devices.

Experiments:

Oleogels containing soybean oil as the liquid component and beeswax, a combination of β-sitosterol and lecithin, sorbitan monostearate, sunflower wax, ethyl cellulose, or a combination of γ-oryzanol with β-sitosterol as the gelator were loaded with the drugs dexamethasone, cyclosporine, triamcinolone, vancomycin above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. Images of the devices were taken to observe the dispersal of drug particles. In vitro drug release in buffer solutions was measured and effective drug diffusivity was determined from a fitted model.

Findings:

At sufficient loading concentrations, drug particles are suspended in the gel and slowly release. The oleogels prepared with different gelators presented a wide range of drug release profiles. The release durations for 10% loading dexamethasone are 35 days for the β-sitosterol/lecithin gel and 135 days for the sorbitan monostearate gel. The γ-oryzanol/β-sitosterol gels released 81% after 135 days and the beeswax and sunflower wax gels released about 78% and 79% of the loaded dexamethasone after 30 days, respectively. In ethyl cellulose gels, the release duration of 28% cyclosporine was 13 days, 28% loaded dexamethasone released 66% after 125 days, 28% triamcinolone released 46% after 108 days, and vancomycin released 80% after 21 days. Solubility of drugs in the gels are affected by gelator type, which suggests some interaction between the drug and the gelling agent. Drug dissolution, diffusion, as well as tortuosity due to the formation of voids must be considered to model drug release.

1. Introduction

Treatment of diseases in the posterior segment of the eye, such as macular degeneration, diabetic retinopathy, and glaucoma pose difficulty due to barriers for delivery of drugs to the back of the eye. Topical medicinal applications, such as eye drops, are ineffective because of rapid clearance from tears (RK and NR, 2009). Systemic delivery requires high dosing, which leads to significant toxicity (Reddy, 1982, Farid et al., 2017). Currently, intravitreal injections, or injections into the vitreous humor, are the most commonly prescribed treatment method (Tian et al., 2016, Grzybowski et al., 2018, Fagan and Al-Qureshi, 2013). Due to the relatively short half-life of many injected drugs through multiple clearance routes, patients are often treated monthly with a series of injections (Kwak and D’amico, 1992, Shikari and Samant, 2016, Ahn et al., 2013). This invasive mode of delivery poses serious risks, including include increased intraocular pressure (Arikan et al., 2011), subconjunctival or vitreous hemorrhage (Il et al., 2018) and rarely retinal detachment (Storey et al., 2019). Even successful intravitreal injections may have considerable patient discomfort, and often patients who must make monthly visits to a doctor have poor compliance with a treatment regimen (Polat et al., 2017). Recently, researches have explored a myriad of novel treatment systems which may offer improved pre-corneal residence time and increase ocular bioavailability (Patel, 2013, Souto et al., 2019). The drug delivery approaches include nanoemulsions, microemulsions, liposomes, nanoparticles, or microspheres, and the use of implants, inserts, subtenon injections, ionotophoresis, and microneedles (Deepthi and Jose, 2019, Lallemand et al., 2012, Agarwal et al., 2016, Christopher and Chauhan, 2019, Than et al., 2018, Alhalafi, 2017).

Recently, gels have become developed for applications in the pharmaceutical, cosmetic, and food industries (O’Sullivan et al., 2016). Oleogels, or vegetable oil based organogels, may be a potential vehicle for targeted delivery of both hydrophobic or hydrophilic drugs. These gels are typically composed primarily of a liquid component and an added gelator that results in formation of a stabilized three-dimensional matrix (Ye et al., 2019, Aguilar-Zárate et al., 2019, Demirkesen and Mert, 2019). They are considered inexpensive, often biocompatible, have a long shelf life, are resistant to microbial contamination, and may be thermoreversible (Harris et al., 2019, Zhang et al., 2019, Hu et al., 2020). Oleogels are non-newtonian, and thus exhibit shear thinning properties which allow them to be injected by syringes, but they still retain their shape once implanted (Martins et al., 2016, Onacik-Gür and Żbikowska, 2019).

We have previously developed oleogel formulations which can be injected into the posterior chamber of the eye for extended release of the drug. This preliminary work focused on oleogel devices composed of soybean oil, the polysaccharide ethyl cellulose, and the active ingredient dexamethasone (Macoon et al., 2019). Ethyl cellulose is biocompatible, but the polymer chain formed during the gelation process does not readily break down. After all of the drug has been released from the gel, the device may remain in the eye. This limitation is not uncommon, as commercially available posterior segment sustained release devices Iluvien® and Retisert® are both synthetic and remain in the eye indefinitely after treatment (Cao et al., 2019). However, a biocompatible gelator molecule that provides extended drug release and also dissolves over time may have many potential ocular applications.

There are two general types of oleogel gelator agents, Low molecular mass organogelators, (LMOGs), or polymeric gelators (Oleogels, 2016). The most commonly used polymeric type of gelator is ethyl cellulose (Rogers et al., 2014). LMOGs readily assemble into supramolecular structures via noncovalent interactions. The gelation mechanism is based on aggregation processes governed by either molecular self-assembly or crystallization. Because of the nature of the structuring of these gels, they are more prone to dissolution and dispersion than ethyl cellulose gels (Cornwell and Smith, 2015). The stability of the gel depends upon a delicate balance between the gelator’s solubility and insolubility in a given chemical environment. For example, solvent characteristics, temperature and external stresses can all play a role in disintegration (Oleogels, 2016).

In this work, we specifically focus on several LMOG agents and their effect on drug release of an ophthalmic drug. The gelators chosen were beeswax, a combination of β-sitosterol and soy lecithin, sorbitan monostearate, sunflower wax, and a combination of γ-oryzanol and β-sitosterol. Beeswax is a non-synthetic long chain lipid, containing esters of fatty acids and different long-chain alcohols (Tinto et al., 2017). β-Sitosterol is a phytosterol found in many plants and is commonly derived from South African star grass, Hypoxis rooperi, or from species of Pinus and Picea. (Wilt et al., July 1999). Soy lecithin, a common food additive, has many commercial uses including flavor protector, emulsified, lubricant, moisturizer, and antioxidant (Han et al., 2013). It is also currently being used as an ingredient in several eye medications (Garrigue et al., 2017). Sorbitan monostearate is a nonionic synthetic ester commonly used as a food additive or in health care products (Trujillo-Ramírez et al., 2019). It acts as a surfactant, aiding in dispersing, wetting, and emulsifying the respective product (Genot et al., 2013). Although not extensively investigated for its gel forming capabilities, it was used by Pisal et al. in oleogels developed for sustained trans-nasal drug delivery (Pisal et al., 2004). Sunflower wax is a lipid derived from Helianthus annuus, the common sunflower, that contains varying length saturated carbon chains composed predominantly of esters of fatty acids with fatty alcohols (Tinto et al., 2017). It is commonly used as an ointment base in cosmetics (Maru and Lahoti, 2018). γ-Oryzanol is a mixture of ferulic acid esters of phytosterols and tri-terpenoids commonly derived from rice bran oil (Saenjum, 2012). It acts as a free radical scavenger for lipophilic compounds, giving it antioxidant and anti-inflammatory properties. Current research in the gelator aims to use it in food products containing a high concentrations of fats to possibly prevent the diseases associated with obesity (Zhang et al., 2019).

In this work, triamcinolone, cyclosporin A, vancomycin hydrochloride, and dexamethasone are the model drugs incorporated into gels. Triamcinolone is a glucocorticoid used to treat a number of different medical conditions, including uveitic macular edema (Thorne et al., 2019). Cyclosporin A is a commonly prescribed immunosuppressant that is incorporated into eye drops to treat dry eye syndrome (Schultz, 2014). Vancomycin hydrochloride is a glycopeptide antibiotic used to treat bacterial infection (Khangtragool et al., 2011). Dexamethasone is a glucorticosteroid commonly used for a wide variety of indications including treatment of brain edema, allergic rhinitis, spinal cord compression, lymphangitis carcinomatosa, exacerbations of asthma, adjunctive treatment in bacterial meningitis, and many more (Wang et al., 2015, Spoorenberg et al., 2014, Cronin et al., 2012, Hardy et al., 2001). Ocular indications include allergic conjunctivitis, toxoplasmic retinochoroiditis, diffuse posterior uveitis, and diabetic macular edema (Kishore et al., 2001, Bassett et al., 2015, Tan et al., 2016, Iglicki et al., 2019). Additionally, dexamethasone is the active ingredient in commercially available sustained release device Ozurdex® (Mehta et al., 2015).

2. Materials and Methods

2.1. Materials Used in Experiments

Soybean oil USP (Spectrum Chemical) was used as the oil phase for the oleogel formulations. Soybean oil used in experiments met United States Pharmacopeia standards for chemical purity. Beeswax (purity: 100%) used in experiments was obtained from Nature’s Oil. The lecithin gelator was organic soy lecithin obtained from New Directions Aromatics. β-sitosterol (contains campesterol, purity: 40.7%) was obtained from TCI America. Sorbitan monostearate (Sigma-Aldrich) met Food Chemicals Codex analytical specifications. Sunflower wax (Helianthus Annuus seed wax) was obtained from MakingCosmetics. γ-Oryzanol was obtained from TCI America. Ethyl cellulose was purchased from Sigma-Aldrich. Ethyl cellulose used was viscosity 90 cP in a 5% (w/w%) in an 80:20 solution of toluene/ethanol, with 48.9% ethoxy content. Medical grade Gibco™ Phosphate Buffered Saline (PBS 1X) was obtained from Fisher Scientific. The drug dexamethasone (purity: 99%), triamcinolone (purity 97%), and vancomycin HCL (vancomycin) (purity: 93.9%) were obtained from Carbosynth Limited. Cyclosporin A (cyclosporine) (purity: 99%) was obtained from LC Laboratories.

2.2. Preparing Drug Loaded Oleogels

The oleogels studied in this work were formulated with the following gelator molecules: beeswax, sunflower wax, sorbitan monostearate, a combination of β-sitosterol and lecithin, a combination of γ-oryzanol and β-sitosterol, and ethyl cellulose. The gels were prepared using methods established in the literature for each gelator molecule (Bot and Flöter, 2018, Moghtadaei et al., 2018, Han et al., 2013, Hwang et al., 2015, Singh et al., 2015, Gravelle et al., 2012). These methods are similar to each other, and to other previously established methods for preparing oleogels (Marangoni and Garti, 2018). In each formulation, decreased gelator concentration lead to a reduced viscosity. For these experiments, the percent loading chosen for each gelling agent was the minimum amount required to consistently obtain a cylindrical rod-like shape after injection. Because the gelling agents are excipients, using minimum amounts could possibly reduce toxicity and costs.

To prepare beeswax, sunflower wax, and sorbitan monostearate drug loaded oleogels, gelator particles were added to soybean oil at room temperature to a loading of 10% (w/w) for beeswax and sunflower wax, and 19% for sorbitan monostearate. The mixture was stirred as the gelators were added to disperse the particles. With continued stirring, the vial was then heated to 100 °C, well above the melting point of each gelator (Jibry et al., 2004, Kanya et al., 2003, Buchwald et al., 2006), to create a homogenous molten liquid. The temperature was then brought down to 90 °C, and dexamethasone particles were added to achieve the desired drug loading of 100 mg/mL. For γ-oryzanol/β-sitosterol gels, β-sitosterol particles were added to soybean oil at room temperature to a loading of 4%. This mixture is stirred and heated to 150 °C to melt the gelator components (Sawalha et al., 2015). While the mixture is stirring and temperature is increasing from 25 °C to 150 °C, γ-oryzanol is slowly added to reach a loading of 6%. Thus, the ratio of γ-oryzanol to β-sitosterol in the combination is 6:4, and the combined gelator concentration is 10%. Sitosterol/lecithin gels are prepared by adding both gelators together at a ratio of 8:2 to a loading of 19% combined gelator concentration. This mixture was also stirred and heated to 150 °C (Zhang et al., 2017). In mixtures containing γ-oryzanol/β-sitosterol or sitosterol/lecithin, the temperature was brought down to 90 °C and dexamethasone particles were added to the vials under continuous stirring until a loading of 100 mg/mL is achieved. To prepare ethyl cellulose oleogels, gelator particles were added to soybean oil at room temperature to a loading of 10% (w/w). The mixture was stirred and heated to 180 °C (69). The temperature was then brought down to 90 °C and dexamethasone, cyclosporine, triamcinolone, or vancomycin particles were added to achieve the desired drug loading of 280 mg/mL in each gel.

For control experiments with no drug, the specific procedure for each gelator is followed until a molten liquid is formed, but no drug is added. In all oleogels, after drug particles have been evenly dispersed, and the gelator component has adequately melted, the molten liquid is added to a 1 mL syringe and allowed to cool at room temperature.

2.3. Drug Release Experiment

Oleogels formulations were expunged from 1mL syringes with attached 22-gauge needles to create a cylindrical devices The needle is large enough to allow injection of the viscous oleogel, but is also small enough that the injection could be performed in an in-office procedure (Meyer et al., 2014). The diameter of expunged oleogels is set by the needle gauge (0.413 mm), but the length can be adjusted to control the volume of the device. Formulations with 10% dexamethasone were used for drug release measurements, while oleogels with appropriate gelator and no drug loaded were used as control. This device was placed into a 20 mL vials filled with PBS 1X. Human vitreous humor is tissue that contains over 99% water (Le Goff and Bishop, 2008). Thus, phosphate buffered saline was used as the release medium for our in vitro experiments. Saline has also been used in research as well as clinically as biocompatible aqueous humor and vitreous body (Donati et al., 2014, Wang et al., 2012). Dynamic drug concentration was measured using a ThermoSpectronic GENESYS ultraviolet–visible (UV-Vis) spectrometer. 0.05 mg/mL standard solutions of dexamethasone, triamcinolone, and vancomycin hydrochloride, and a 0.025 mg/mL standard solution of cyclosporine were prepared in PBS 1X. The standard solutions measured by UV-Vis had absorbance peaks at 241, 239, 267, and 202 nm for dexamethasone, triamcinolone, vancomycin hydrochloride, and cyclosporine, respectively. Spectra of drug release samples were obtained over the range of wavelengths 190 nm–400 nm. After measurement, the sample was returned to the vial. Each experiment was conducted in triplicates.

2.4. Imaging

The oleogel devices were imaged periodically with a camera 10 cm above each scintillation vial to visualize observe the dissolution of the device over the course of drug release. Microscopic images at 2x magnification were taken of sectioned oleogels to determine solubility, confirm the dispersion of drug particles, or to show the effects of drug release on the interior of the gel. Sections were made by removing oleogels from release medium, cutting a thin slice perpendicular to the length of the expunged rod, and placing on a microscope slide.

2.5. Model

The drugs incorporated into the oleogels are dexamethasone, cyclosporine, triamcinolone, and vancomycin. As confirmed by microscopic images of gel formulations (Fig. 2), the concentration of drugs used in these experiments is much higher than the solubility limit in the gel, so the devices contain suspended drug particles which have not dissolved into the oil phase. Additionally, because of the viscous nature of the gels, as they maintain a cylindrical shaped as they are expunged from a needle. Therefore, drug release from oleogels can be modeled by the same equations first used by Higuchi to describe transport of solid drugs suspended in ointment bases (Higuchi, 1961). This model assumes the systems are in sink conditions and that the rate of drug release is not affected by the concentration of drug in the release medium. These equations were previously used to describe oleogel rods with dexamethasone loaded above the solubility limit and therefore will not be detailed here (Macoon et al., 2019). The experimental data obtained from drug releases can be fitted to this model to estimate diffusivity, D.

Fig. 2.

Fig. 2.

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(A, B, C, D, E, F, G, H, I): Microscopic images of oleogel formulations formed by beeswax (A), β-sitosterol/lecithin (B), sorbitan monostearate (C), sunflower wax (D), and γ-oryzanol/β-sitosterol (E) with and without 10% loading of dexamethasone. Images (F-J) show ethyl cellulose gels with 28% dexamethasone (F), with 28% cyclosporin (G), with 28% triamcinolone (H), with 28% vancomycin (I), and without drug (J). Red arrows point to drug particles in drug incorporated formulations. All images shown are under 2x magnification.

3. Results and Discussion

3.1. Gel Properties

Oleogels of each gelator were prepared with different drug loadings. For beeswax, β-sitosterol/lecithin, sorbitan monostearate, sunflower wax, and γ-oryzanol/β-sitosterol gels, drug loading was 10% by mass dexamethasone. The gelator content of each gel was the minimum required concentration to consistently maintain a cylindrical rod-like shape after injection from a 22-gauge syringe. The concentration of each gelator was 50 mg/mL, 100 mg/mL, 150 mg/mL, 50 mg/mL, and 100 mg/mL for beeswax, β-sitosterol/lecithin, sorbitan monostearate, sunflower wax, and γ-oryzanol/β-sitosterol gels, respectively. The ratio of β-sitosterol and lecithin mixture gels was 8:2, i.e. 80 mg/mL β-sitosterol and 20 mg/mL lecithin. The ratio in γ-oryzanol and β-sitosterol mixture gels was 6:4, (60 mg/mL γ-oryzanol and 40 mg/mL β-sitosterol). Ethyl cellulose gels were loaded with 28% dexamethasone, 28% cyclosporine, 28% triamcinolone, and 28% vancomycin. The ethyl cellulose concentration in these gels was 100 mg/mL. A summary of all drug release samples is included in Table 1. Solubility limit of the drug in oleogel was determined by observation of formulations under microscope. The presence of drug particles indicated that the concentration of drug in the gel was above solubility limit. For these samples, the concentration of gelator was kept the same as the concentration of gelator used in drug release devices. The solubility of dexamethasone in each gel sample and in soybean oil at room temperature are shown in Table 1. The solubility limit of the drugs in PBS 1X was measured by UV-Vis. The solubility limit in PBS 1X was 89 μg/mL, 70 μg/mL, 0.85 mg/mL, 100 mg/mL for dexamethasone, cyclosporine, triamcinolone, and vancomycin, respectively.

Table. 1.

Summary of formulations used in drug release.

Name of Gelator Sample Name Drug Loading Percent Loading of Gelator Solubility Limit: Drug in Soybean Oil Solubility Limit:Drug in Oleogel
Beeswax A Dexamethasone 10% 5% 6 mg/mL 11 mg/mL
β-sitosterol /Lecithin (8:2) B Dexamethasone 10% 10% 6 mg/mL 15 mg/mL
Sorbitan Monostearate C Dexamethasone 10% 15% 6 mg/mL 30 mg/mL
Sunflower Wax D Dexamethasone 10% 5% 6 mg/mL 10 mg/mL
γ-oryzanol/β-sitosterol (6:4) E Dexamethasone 10% 10% 6 mg/mL 23 mg/mL
Ethyl Cellulose F Dexamethasone 28% 10% 6 mg/mL 30 mg/mL
G Cyclosporin 28% 38 mg/mL 40 mg/mL
H Triamcinolone 28% 1 mg/mL 2 mg/mL
I Vancomycin HCl 28% 0.1 mg/mL 0.5 mg/mL
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The density of the dexamethasone loaded formulations were 0.957, 0.963, 0.967, 0.957, and 1.040 g/mL, for beeswax, β-sitosterol/lecithin, sorbitan monostearate, sunflower wax, γ-oryzanol/β-sitosterol, and ethyl cellulose respectively. Once expunged, all of the devices except the β-sitosterol/lecithin and sorbitan monostearate gels dissolve very slowly, limited by the minute solubility of oil in aqueous solution. In the case of β-sitosterol/lecithin and sorbitan monostearate, the matrix that holds the gels together dissolves as the drug releases from the device, with complete dissolution occurring after about 2 and 5 months, respectively. Each formulation is heated to at most 180 °C to facilitate the melting of the gelator component. The literature suggests that there is no substantial mass loss or degradation of the formulations at the temperatures used in experiments, as evidenced by thermogravimetric profiles which show that degradation does not occur until above 300 °C for soybean oil (Zhang et al., 2014) and 200 °C for ethyl cellulose (Lai et al., 2010), sorbitan monostearate (Atakul Savrik, 2010), soy lecithin (Ross et al., 1985), and beeswax (EBRAHIM, 2015), 180 °C for γ-oryzanol (Khuwijitjaru et al., 2009) and sunflower wax (Makingcosmetics.com Inc 2017), and 150 °C for β-sitosterol (Christiansen et al., 2002).

3.2. Imaging

Pictures were taken of the oleogel formulations when they were initially expunged into the drug release medium, as well as throughout the drug release. Figs. 1A–E show the devices after initial insertion as well as after several months drug release. The viscosity of the formulations causes a rod-like shape as its expunged from the syringe, and this shape is maintained during drug release. β-sitosterol/lecithin and sorbitan monostearate gels show visible dissolution over the course of drug release. Full dissolution occurs after few months and is shown in Figs. 1B3 and 1C3. Fig. 2A–I shows 2X magnified images of the gels formed by the different gelators with and without incorporated drug particles. For all gelators, drug loading is above the solubility limit, as evidenced by the presence of rod-like particles (Shown by red arrows in Figs. 2A2, 2B2, 2C2, 2D2, 2E2, 2F2, 2G, 2H, and 2I).

Fig. 1.

Fig. 1.

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(A, B, C, D, E): Images of the dexamethasone loaded 10% w/w) oleogel devices expunged through a 22 gauge needle taken initially as well as at various times throughout drug release. (A) beeswax oleogel at (1) t = 0, (2) 30 days, (3) 110 days. (B) β-sitosterol/lecithin oleogel at (1) t = 0, (2) 30 days, (3) 60 days (C) sorbitan monostearate oleogel at (1) t = 0, (2) 30 days, (3) 110 days. (D) sunflower wax oleogel at (1) t = 0, (2) 30 days, (3) 110 days. (E) γ-oryzanol/β-sitosterol oleogel at (1) t = 0, (2) 30 days, (3) 110 days.

3.3. Drug release profiles

Drug release profiles for each oleogel formulation were obtained by periodically measuring drug concentration in the release medium using UV-Vis spectroscopy. The volume of the release medium was 10–15 mL. Because this volume is significantly larger than the volume of the oleogel inserts (0.0020–0.0040 mL) the systems are considered to be in sink conditions. The mass of drug in each device varied, and can be set by loading concentration as well as length of expunged rod. Nine devices were measured in total. To explore the effect of gelator component on release profiles of dexamethasone, five devices were made with different gelators including beeswax, β-sitosterol/lecithin, sorbitan monostearate, sunflower wax, and γ-oryzanol/β-sitosterol. all with 10% dexamethasone loading. Four devices were made with ethyl cellulose as the gelator with different drugs released, including 28% dexamethasone (450 μg), 28% cyclosporin (330 μg), 28% triamcinolone (610 μg), and 28% vancomycin loading (646 μg). The release profiles for 10% dexamethasone loading gels made of different gelators are plotted in Fig. 3. Fig. 4A–D shows profiles of ethyl cellulose gels loaded with dexamethasone, cyclosporin, triamcinolone, or vancomycin. Because the drug loading in all systems is much higher than the solubility limit of the drugs in the oleogel, theoretical fits are included in Figs. 3 and 4 based on the Higuchi model discussed earlier (Macoon et al., 2019, Higuchi, 1961). For all drug releases, the error bars in the data are standard deviation of three independent experiments.

Fig. 3.

Fig. 3.

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(A, B, C, D, E): Release profiles of dexamethasone from oleogel formulations made with different gelators. The drug loading was 10% in each formlation.(A) beeswax (275 μg), (B) β-sitosterol/lecithin (500 μg), (C) sorbitan monostearate (500 μg), (D) sunflower wax (210 μg), (E) γ-oryzanol/β-sitosterol (500 μg). The error bars are calculated from the standard deviation of three independent experiments.

Fig. 4.

Fig. 4.

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(A, B, C, D): Release profiles of different drugs from oleogel formulations made with the gelator ethyl celluose. (A) Dexamethasone 28% (=450 μg), (B) cyclosporin 28% (=330 μg), (C) triamcinolone 28% (=610 μg), and (D) vancomycin 28% (=646 μg), The error bars are calculated from the standard deviation of three independent experiments.

Although the drug devices with different gelators (Table 1 Samples A-E) all include 10% loading of dexamethasone, the release durations vary significantly from sample to sample. For example, β-sitosterol/lecithin and sorbitan monostearate devices release drug for about 35 days and 135 days, respectively. Comparatively, in the 135 days it takes for sorbitan monostearate to completely release, only 81% of the initially loaded dexamethasone has released from the γ-oryzanol/β-sitosterol gels. Beeswax and sunflower wax gels have very similar drug release profiles, releasing about 78% and 79% of the drug after 30 days, respectively.

In ethyl cellulose gels, the release duration of 28% cyclosporine was 13 days, 28% loaded dexamethasone released 66% after 125 days, 28% triamcinolone released 46% after 108 days, and vancomycin released 80% after 21 days. The relationship of loading concentration on drug release rate has been previously discussed (Macoon et al., 2019). The long release duration of the dexamethasone and triamcinolone can be attributed to high initial loading concentrations of drug as well as interaction of the drug with the gelator. The solubility limit of the drugs is much higher in the oleogel than it is in soybean oil, which indicates the drugs may interact with the gelator. Diffusion of the adsorbed drug molecules is likely slower than free molecules within the gel, which may lead to extended release. We test this hypothesis by plotting the diffusivity of the different systems with the same dexamethasone loading as a function of ratio of solubility (Fig. 5). The β-sitosterol/lecithin formulation is not included in this Fig. because the diffusivity is much higher than all other samples, which suggests other mechanisms such as the disintegration of the device may be affecting release. Fig. 5 shows the general trend that diffusion is slower in devices that have a high solubility of drug in the gel, which supports our hypothesis. Additionally, Fig. 5 includes a plot of diffusivity for gels with drug particles of different molecular weight. The largest particle, vancomycin HCl, had the highest diffusivity, further indicating that loading concentration and drug interaction with the gelator are the most significant parameters in gel optimization.

Fig. 5.

Fig. 5.

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(A, B): (A) Relationship between diffusivity and the ratio between solubility of dexamethasone in each oleogel formulation and the solubility of the drugs in soybean oil. (B) Relationship between diffusivity and molecular weight for of oleogels with different drugs and the same gelator.

3.4. Void Formation

A phenomenon in which voids are formed during drug release was previously explored in ethyl cellulose based oleogels containing dexamethasone particles above solubility limit (Macoon et al., 2019). When drug particles within the device solubilize during drug release, cavities, or voids, fill the spaces that the particles once were. The oleogels used in drug release have high viscosity, and so therefore maintain a rigid structure after being expunged from a needle. Because of the inability of the gel to conform, the voids remain spaces which are not filled with oil. Because water has very slow transport through the gel, the void spaces most likely contain air. Gels that were lower viscosity did not have prolific formation of voids, which implies that some oil phase conformation may have taken place. Under microscope, areas in which voids have formed appear as dark circles. Fig. 6 shows microscopic images of a dexamethasone drug loaded gels made of different gelators before (6A1, 6B1, 6C1, 6D1) and after 291 days of drug release (6A2, 6B2, 6C2, 6D2). To confirm that the presence of dark regions indicates void spaces, the same gels were heated to 140 °C and then allowed to cool. We hypothesized that due to the thermoreversible nature of oleogels, the gel would become less viscous at high heat. At low viscosity, the air voids would aggregate and be rescinded from the formulation, yielding a gel which, under a microscope, no longer had dark regions and only the features of the gelator molecules. The results of this heating test are shown in Fig. 6A3, 6B3, 6C3, and 6D3.

Fig. 6.

Fig. 6.

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(A, B, C, D, E): 5% drug loading dexamethasone oleogels made with beeswax (A1), sorbitan monostearate (B1), sunflower wax (C1), and γ-oryzanol/β-sitosterol (D1) showing the presence of particles. Gels after drug release (A2, B2, C2, D2). Particles have been replaced by small circular voids which spread from the boundary to the interior of the gels. Gels after melting (A3, B3, C3, D3, E3). The oil phase conforms and fills the void space during the melting process. All images are shown at 2x magnification.

A β-sitosterol/lecithin oleogel is not included in Fig. 6 because total drug release from the device results in dissolution of the gel. The hypothesis that viscosity plays a role in void formation is supported by Figs. 6A2 and 6B2. Beeswax gels (Fig. 6A2) were rigid, and also were observed to have many voids. It is possible that as these voids form around imbedded drug particles, the contact area between the particle and the oil phase becomes smaller. With enough voids around a particle, this phenomenon may lead to particles remaining trapped within the gel. Trapped particles may be observed in Fig. 6A2. In contrast, sorbitan monostearate gels have a very low viscosity, and it is observed that voids are not numerous after drug release (Fig. 6B2). The hypothesis that the oil phase of the gel can conform when heated and fill the voids is consistent with Fig. 6A3, 6B3, 6C3, and 6D3, which do not appear to have voids after this procedure.

The formation of voids is important because they are potentially an additional barrier to transport. The voids increase the tortuosity within the gel, and the effect of tortuosity in drug release has been established for Higuchi model based systems (ISHINO and SUNADA, 1993). As particle loading is increased, the porosity of the gels decreases. If more particles are dispersed through the formulation, the tortuosity increases, which leads to a lower effective diffusivity, Deff. The effective diffusivity obtained from fitting experimental data can be defined,

Deff=Dετ=D1−Ø−Øsτ (1)

where D is the molecular diffusivity in the gel, ϕ is the particle loading, Øs is the solubility limit, ε (=1- ϕ−Øs) is the porosity and τ is the tortuosity (De Backer and Baron, 1993, Ledesma-Durán et al., 2017). The estimated Deff from release data can be used to solve for tortuosity. To obtain a measurement of molecular diffusivity, a fitted value from a release for a gel which has drug loading below the solubility limit can be utilized.

4. Conclusion

This study shows promising alternative biocompatible gelators for developing drug loaded oleogels as inserts in ophthalmic drug delivery. Previous work has shown ethyl cellulose to be an effective biocompatible gelator, but its dissolution is very slow, and it must be cleared via uptake into retina cells or transport into the aqueous humor. We examined 6 different types of gelators and created oleogels in which drug particles were incorporated directly to the liquid oily phase. Although the drug release duration’s dependency on drug loading concentration was previously discussed, this work further shows the drug release duration’s dependency on drug solubility in the oleogel. Using several different gel compositions, we have shown that the incorporated drugs interact or absorb with the gelators, which may have a role in extending the duration of drug release. The oleogel formulations achieve extended drug release, which may eliminate the need for frequent intravitreal injections of ophthalmic drugs in solution. A reduction in frequency of injections may have numerous significant benefits, including lower costs, reduced risk of complications from the injection procedure, and better patient compliance. A factor that must be taken into account when modeling drug release is tortuosity due to the formulation of voids due to drug particle dissolution. Because tortuosity increases drug release duration, by further understanding how these voids develop we may be able to extend drug release. The varying effects each biocompatible gelator had on drug release is encouraging, because by considering all variables concerning oleogels, including drug loading concentration, solubility of drug in the oil phase and subsequent oil choice, as well as gelator choice, we may optimize a gel for specific indications. Gelator choice also plays an important role in the final dissolution of the gel after drug release. The controlled dissolution of the oleogel is an exciting improvement to non-biodegradable implants, which remain in the eye until they are removed manually (Cao et al., 2019). Commercial devices such as Ozurdex® and Iluvien® are able to achieve similar drug release as the oleogel devices studied here (Teja et al., 2019, Mello Filho et al., 2019, Chakravarthy et al., 2019, Meira et al., 2019). However, fully optimized oleogel formulations may surpass the currently available devices due to their versatility and ease in incorporating a myriad of different drug particles. Although many of the gelators chosen for this work are promising, there remains many other possible candidates for oleogel gelling agents, which may have even more desirable characteristics. Future work should be aimed at transitioning this work from bench to patient, including customizing oleogel formulations for specific indications and testing selected formulations in animal models while also addressing toxicity concerns.

Acknowledgements

This work was supported in part by training grant EY007132 from the NIH.

Footnotes

CRediT authorship contribution statement

Russell Macoon: Investigation, Methodology, Writing - original draft. Mackenzie Robey: Investigation, Writing - original draft. Anuj Chauhan: Conceptualization, Project administration, Supervision, Writing - review & editing.

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