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Long-term sustained release from a biodegradable photocross-linked network for intra-ocular corticosteroid delivery Brian G Amsden, and Dale Marecak Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.6b00358 • Publication Date (Web): 20 Jun 2016 Downloaded from http://pubs.acs.org on June 26, 2016

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Molecular Pharmaceutics

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Long-term sustained release from a biodegradable photo-cross-linked network for intra-ocular corticosteroid delivery Brian G. Amsden* and Dale Marecak Department of Chemical Engineering, Queen’s University

Abstract Intravitreal sustained delivery of corticosteroids such as dexamethasone is an effective means of treating a number of ocular diseases, including diabetic retinopathy, uveitis, and age-related or diabetic macular edema. There are currently marketed devices for this purpose, yet only one, Ozurdex, is degradable. In vitro release of dexamethasone from the Ozurdex device is limited to approximately 30 days, however. It was the objective of this study to examine the potential for prolonged and sustained release of a corticosteroid in vitro from a degradable polymer prepared from terminally acrylated star co- and terprepolymers comprised of D,L-lactide, ε-caprolactone, and trimethylene carbonate co-photo-crosslinked with poly(ethylene glycol) diacrylate. Through manipulation of the network polymer glass transition temperature and degradation rate, a sustained release of triamcinolone was achieved, with an estimated release duration greater than twice that of the Ozurdex system. Moreover, a period of nearly constant release was obtained using a network prepared from 5,000 Da star-poly(trimethylene carbonate-co-D,L-lactide) triacrylate (3:1 trimethylene carbonate: D,L-lactide) co-cross-linked with 700 Da poly(ethylene glycol diacrylate). These formulations show promise as implantable, intravitreal corticosteroid delivery devices.

keywords:

triamcinolone, intravitreal implant, macular edema, diabetic retinopathy, controlled delivery

* to whom correspondence should be addressed 19 Division St. Kingston, Ontario, Canada K7L 3N6 email: [email protected] phone: 613-533-3093 fax: 613-533-6637

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INTRODUCTION

Sustained intraocular delivery of corticosteroids such as dexamethasone, triamcinolone, triamcinolone acetonide, and fluocinolone acetonide, has emerged as a promising treatment approach for some chronic posterior segment disorders of the eye such as diabetic retinopathy, uveitis, and age-related or diabetic macular edema.1-4 The advantages of this means of administration are numerous. Prolonged therapeutic drug concentrations are achieved in ocular tissues, which are not readily accessible using conventional formulations, while limiting the impact of systemic drug exposure. Furthermore, the frequency of intraocular injections is reduced, decreasing the potential for complications secondary to the injection procedure, and patient compliance is enhanced.

There are currently three FDA approved polymer implants capable of multi-month intravitreal corticosteroid delivery. Retisert is a surgically implanted poly(vinyl alcohol)/silicone laminate tablet reservoir device that releases fluocinolone acetonide for up to three years and which has been approved for noninfectious uveitis.2,4 Iluvien is another fluocinoline acetinode releasing reservoir device also capable of three years of delivery. It is a polyimide/poly(vinyl alcohol) cylinder that is injected intravitreally through a 25 gauge needle. Iluvien is currently FDA approved for diabetic macular edema in patients that have not responded to other available therapies and who exhibit a lack of steroidresponsive intraocular pressure elevation.4 While these devices achieve long-term delivery, their nonbiodegradability is a notable disadvantage. The long-term safety implications of having a nondegradable implant in the posterior segment are unknown. Thus, patients using these devices may require implant removal, with accompanying potential complications. The only degradable implant clinically available is Ozurdex, which consists of dexamethasone (30% w/w) dispersed throughout a poly(D,L-lactide-glycolide) (PLG) matrix. Two types of PLG are utilized: a 50:50 D,L-lactide:glycolide repeating unit PLG terminated with alkyl groups (Resomer 502) and a 50:50 acid-terminated PLG (Resomer 502H).5 The device is a rod of 6.5 mm in length and 0.45 mm in diameter, and is implanted intravitreally via a 22 gauge needle.6 Release of dexamethasone from Ozurdex in vitro7 and in vivo in rabbits8 is essentially complete within 30 days. The implants were generally not visible in either rabbit or monkey eyes 3 months following implantation,9 suggesting complete degradation occurs within this time frame.


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Despite its biodegradability, the relatively short release duration of Ozurdex in comparison to its nondegradable counterparts Retisert and Iluvien necessitates greater frequency of implantation, with accompanying potential negative complications. A further potential disadvantage is the possibility of the Ozurdex implant breaking into two or more pieces immediately upon injection.7,10,11 While this occurs rarely, and in the cases where it has occurred there were no further complications, it has been noted that patients with these fragmented implants should be monitored closely.12 This breakage is likely a result of the brittle nature of PLG, which has a glass transition temperature of 45 to 50 ºC.13 Given the advantages of a degradable implant, it was the objective of this study to develop a biodegradable polymer implant capable of long-term delivery of a corticosteroid. As a representative corticosteroid, triamcinolone was chosen. To prevent device fragmentation upon implantation, a crosslinked polymer formulation strategy was chosen. Cross-linking provides mechanical stability and fracture resistance to the implant. An additional benefit is that cross-linked degradable aliphatic polyesters retain form stability during degradation, providing predictable release kinetics.14 As a cross-linkable precursor, terminally acrylated star co- and ter-prepolymers comprised of D,Llactide, ε-caprolactone, and trimethylene carbonate were investigated, as their synthesis, form stability, degradation rate, and in vivo tolerance have been well characterized.15-18 These hydrophobic prepolymers were blended and co-cross-linked with low molecular weight poly(ethylene glycol) diacrylate (PEGDA) as a means of adjusting both corticosteroid release and device degradation rate. Specifically, cylindrical devices prepared from terminally acrylated three-armed star-poly(D,L-lactideco-ε-caprolactone) cross-linked with 10 % w/w 4,000 Da PEGDA were found to lose mass in a nearly linear fashion with time, while swelling to only 10% of their initial volume.19 This degradation behavior is in contrast to that of aliphatic polyester devices that typically demonstrate bulk erosion and its consequent accelerated mass loss with time due to autocatalysis within the interior of the device,20 a pattern that is observed the PLG-based Ozurdex.21 It was postulated that a linear mass loss with time would assist in providing a sustained corticosteroid release rate by eliminating the possibility of device fragmentation during hydrolysis, a feature characteristic of the degradation of Ozurdex.7,22

EXPERIMENTAL SECTION Materials. Trimethylene carbonate (TMC) monomer was purchased from LeapChem, (Hangzhou,


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China) and used without further purification. D,L-lactide (DLLA) monomer was used as provided from Altasorb, (Piedmont, South Carolina). ε-Caprolactone (CL) from Fisher Scientific (Ottawa, Canada), was dried with stirring over calcium hydride then distilled under vacuum before use. Triethylamine (TEA, Fisher Scientific, Ottawa, Canada) was dried over 4Å molecular sieves for a minimum of a week before use. Solvents, glycerol initiator and tin(II) 2-ethylhexanoate (catalyst) were from Fisher Scientific (Ottawa, Canada). All other reagents were obtained from Sigma-Aldrich (St. Louis, Missouri), and used as provided except where noted.

Methods Preparation of hydrophobic star prepolymers Hydrophobic star prepolymers were prepared via melt ring-opening polymerization using glycerol as initiator and tin(II) 2-ethylhexanoate as a catalyst. The targeted molecular weights were 2000 and 5000 g/mol. These molecular weights were chosen to provide a degree of elasticity to the cross-linked network.16 As a representative procedure, TMC (3.545 g, 34.75 mmole), CL (3.960 g, 34.74 mmole), and glycerol (0.141 g, 1.53 mmole) were placed into an oven-dry argon-purged glass ampoule and set in a 130 ºC oven for 3 min to allow sufficient melting of the solid for homogeneous mixing by vortex. Following another argon purge, the catalyst was added (15.2 mg, 0.038 mmole), the entire contents were fully mixed, and the ampoule was flame-sealed under vacuum. The reaction was placed in a 130 ºC oven for 5 min, removed for a final vortex mixing, then set back to 130 ºC for 23 h.

The prepared star copolymers were terminally acrylated via reaction with acryloyl chloride. Warmed, neat polymer (6-8 g) was transferred to a dry, argon-purged round bottom flask by inversion and application of gentle vacuum to draw out the viscous polymer. A magnetic stir bar and dimethylaminopyridine (DMAP) catalyst (100:1 mol ratio to terminal hydroxyl) were added prior to sealing with a rubber septum. Anhydrous dichloromethane (DCM, 80 mL) was added by canula-transfer and the contents dissolved with stirring. TEA (1.3:1 mol excess to terminal hydroxyl) was added by syringe and allowed 5 min mixing to fully dissolve. Acryloyl chloride was diluted in dry DCM (1.6:1 mol excess to hydroxyl and 30% w/v in DCM) then dropped by syringe into the stirring reaction over a 60 second period. Reactions were kept stirring in the dark at room temperature for at least 2 days. Rotary-evaporation under reduced pressure at 40 ºC afforded a crude paste, from which triethylamine salts were precipitated by the addition of cold (-20 ºC) ethyl acetate (ca. 20 mL per 6 g polymer).


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Isolated dissolved polymer was further purified by precipitation in methanol (8x volume) at -20 ºC. The centrifuge-pelleted polymer was re-dissolved in a small volume of DCM (20 mL) and again precipitated with methanol (160 mL). This cycle was repeated once more to yield purified product. Number average molecular weight, monomer composition, and degree of acrylation were determined from 1H NMR spectra obtained in DMSO-d6 on a Bruker Avance 400 MHz spectrometer using triethylsilane as an internal reference. Peak assignments were determined and number average molecular were calculated as have been previously reported.18,23

Device Preparation To form cylindrical devices, the prepolymers, dissolved in solvent with or without added triamcinolone, were photo-cross-linked within glass tubing (Scheme 1). In a typical cross-linking procedure, 300 mg of hydrophobic prepolymer was dissolved in 120-150 mg of acetone containing 33 mg of 700 or 3400 g/mol PEGDA and 3 mg of 2,2-dimethoxy-2-phenylacetophenone as photoinitiator. For devices containing triamcinolone, the drug was added into the prepolymer solutions following their dissolution and allowed to dissolve. Two triamcinolone loadings, 5 and 10 %w/w, were investigated. The prepolymer/drug solution was drawn up into a 1 mm inner-diameter glass capillary, and irradiated at 810 mW/cm2 for 2 min using UV irradiation centred at 365 nm. The capillary was then rotated 180º and exposed to UV irradiation of the same intensity for another 2 min. The UV source was a Lightningcure™ Series LC8 by Hamamatsu, fitted with a A9616-05 filter for reducing heat, and output was measured by a C6080-03 Hamamatsu light power meter. Post irradiation, the rods were dried at least 24 h before being broken out of the capillaries, cut to sizes of approximately 20 mm in length and then allowed to dry another 24 h.


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Scheme 1. Procedure for preparing triamcinolone-loaded biodegradable networks. The hydrophobic prepolymer and poly(ethylene glycol) diacrylate are pre-dissolved in acetone and the triamcinolone is then dissolved in the prepolymer solution. A volume of this solution is drawn up into a glass capillary, and then exposed to UV irradiation to cross-link. Following cross-linking, the acetone was allowed to evaporate for 24 h, the glass was broken, and the remaining acetone was allowed to evaporate for at least 24 h.

Device Characterization The sol content of networks prepared without added triamcinolone were measured by soaking the rods in 15 mL DCM three times with fresh DCM added between soaking. The rods were then dried in an oven at 50 °C under vacuum for 3 days. The sol content was calculated from the difference in weight before soaking and weight following drying after sol removal in DCM. Following sol extraction, the thermal properties of the networks were measured after soaking in water at 37ºC overnight via differential scanning calorimetry. Thermal analysis was preformed using a Mettler Toledo DSC 1 Star System and the following heating/cooling program: ambient to -80 ºC, heating to 50 ºC, cooling to -80 ºC and heating to 50 ºC using a heating/cooling rate of 10 ºC/min. The glass transition temperatures were


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obtained from the second heating cycle.

Release Studies All the release experiments were performed in quadruplicate. Prior to release, the initial mass and diameter of each cylinder was measured. The mass of the cylinder was then used to calculate the initial amount of triamcinolone loaded within. The cylinders were then placed in glass screw cap vials with 20 mL of phosphate buffered saline (PBS). The vials were placed on a rotating wheel at a speed of 8 rpm and maintained at 37 ºC in an incubator oven. At each sampling period the PBS was removed and replaced with fresh solution, and the length, diameter and wet mass were measured. The releasate samples were filtered and the triamcinolone concentration measured by high performance liquid chromatography on a Waters 717 plus autosampler, 600 controller and 2487 dual absorbance detector. The solvent concentrations were as follows: mobile phase A: MilliQ H2O with 10 mmol acetic acid, mobile phase B: 90% acetonitrile, 8% MilliQ H2O, 10 mmol acetic acid. A calibration curve was previously prepared using standard solutions of triamcinolone in Milli-Q H2O. The concentration at each time point was converted to a mass of triamcinolone, which was then used to calculate the cumulative amount released. The data was then plotted as the mass % of triamcinolone released versus time by dividing the cumulative amount released by the total mass of triamcinolone within the cylinder.

Statistics The data points represent average values, and the error bars the standard deviation about the average. Significant differences at 95% confidence were determined via ANOVA with a Tukey post-hoc test.

RESULTS

Polymer Properties The composition and number average molecular weights (Mn) of the hydrophobic star-prepolymers examined are listed in Table 1. In every case, the monomer composition and molecular weight of the star prepolymers were close to the target values, indicating nearly complete monomer conversion during polymerization. Moreover, the termini of the star copolymers were efficiently acrylated, as each copolymer had a degree of acrylation greater than 80 %.


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Table 1. Prepolymer properties

TMC:DLLA:CL monomer ratio

Mn (NMR)

Degree of

target

actual

target

actual

acrylation (%)

1:1:0

1:1.03:0

2000

2350

81

1:1:0

1:1.03:0

5000

5800

81

0:1:1

0:1:0.98

5000

5560

99

2:1:1

2:0.96:1.03

5000

5450

81

3:1:0

3:0.96

5000

4970

81

These prepolymers were then photo-cross-linked with 700 or 3400 Da PEGDA in the presence of a photoinitiator. The following abbreviation will be used to refer to the cross-linked networks. The hydrophobic star prepolymer monomer composition will be listed first, followed by the monomer ratio, then the molecular weight. Finally, the PEGDA molecular weight will be provided. For example, a network formed from 5500 g/mol, 1:1 molar ratio star-poly(D,L-lactide-co-ε-caprolactone) triacrylate cross-linked with 700 g/mol poly(ethylene glycol) diacrylate will be abbreviated DLLA:CL 1:1 5.5k PEGDA 700.

The prepolymers were effectively co-cross-linked yielding networks that on average had low sol contents (Table 2). The glass transition temperatures (Tg) of the samples obtained after hydration ranged from - 18 to 1 ºC, varying with the monomer composition and the molecular weight of the PEGDA incorporated. In all cases a single Tg was observed, indicating that the two prepolymers were well mixed in the resulting cross-linked network.


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Table 2. Cross-linked polymer properties.

Hydrophobic prepolymer

PEGDA Mn (Da)

Tg (ºC) (wet)

sol (%)

TMC:DLLA 1:1 2.3k

700

2

14

TMC:DLLA 1:1 5.8k

700

-1

1

CL:DLLA: 1:1 5.5k

700

- 11

10

TMC:DLLA:CL 2:1:1 5.5k

700

- 18

6

TMC:DLLA:CL 2:1:1 5.5k

3400

- 18

14

TMC:DLLA 3:1 5k

700

-9

3

Triamcinolone Release The initial formulations examined utilized equimolar ratios of either TMC of CL with DLLA within the hydrophobic star prepolymer. These formulations were chosen based on previous work with these networks.19 Each of these prepolymers was co-cross-linked with PEGDA 700 to yield a final PEGDA content in the network of 10% w/w. Two TMC:DLLA 1:1 prepolymers of different molecular weights (5,800 Da and 2,000 Da) were compared to assess the influence of network crosslink density on triamcinolone release. The in vitro release profiles are given in Figure 1. For each time point, the triamcinolone concentration in solution was less than 10% of its saturation concentration at 25 ºC of 80 mg/L,24 and so near infinite sink conditions were maintained during the release.25


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100

Mass % released

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80

60

40 TMC:DLLA 1:1 5.8k 700 PEGDA DLLA:CL 1:1 5.5k 700 PEGDA

20

TMC:DLLA 1:1 2.3k PEGDA 700

0 0

30

60

90

120

150

180

Time (day)

Figure 1. The influence of hydrophobic prepolymer composition at a given molecular weight of approximately 5,500 Da on triamcinolone release, and the influence of hydrophobic prepolymer molecular weight at a given monomer composition (TMC:DLLA 1:1) on triamcinolone release.

The release profiles in each case have the same general shape, characteristic of drug release from aliphatic polyester matrices.26 Specifically, all the devices exhibited an initial release phase followed by a secondary, faster release phase. The initial release was faster for the networks prepared with CL:DLLA 1:1 5.5k prepolymer than for those prepared with TMC:DLLA 1:1 5.8k prepolymer (Figure 1), while the slowest initial release was observed with the samples prepared with the TMC:DLLA 1:1 2.3k prepolymer. For CL:DLLA 1:1 5.8k 700 PEGDA devices, the secondary release began at approximately 33 days, while for devices made with TMC:DLLA 1:1 5.8k or 2.3k, the secondary release began at approximately 103 and 55 days, respectively. The secondary release phase was less influential on the release of triamcinolone from the CL:DLLA 1:1 5.5k PEGDA 700 networks, and was particularly noticeable for the TMC:DLLA 1:1 2.3k PEGDA 700 network samples, which had the slowest initial release rate.

For cylindrical devices wherein the drug is below its saturation concentration within the polymer and is


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being released from the polymer via diffusion, the initial mass fraction release versus time is given by,27

Mt  Dt  = 4 2  Mo  πr 

1/2

−

Dt r2

(1)

in which Mt is the cumulative mass of drug released at a given time, Mo is the initial mass of drug within the device, D is the drug diffusivity within the polymer, r is the device radius, and t is time. Equation 3 is valid for mass fraction released less than 40%. For mass fractions released less than 25%, the contribution of the second term on the right hand side is negligible and the mass fraction released can therefore be expressed as,

Mt  Dt  = 4 2  Mo  πr 

1/2

(2)

Thus, plotting the mass % of drug released versus t1/2 should yield a straight line if the initial release phase was diffusionally controlled. As can be seen in Figure 2, the data plotted in this fashion does result in a linear relationship, indicating that the initial release of triamcinolone from each of the devices shown in Figure 1 was diffusionally controlled. The slope of the resulting curve fit was used to calculate the diffusivity of the triamcinolone within each network. These results are given in Table 3.

40

TMC:DLLA 1:1 5.8k PEGDA 700 CL:DLLA 1:1 5.5k PEGDA 700

Mass % released

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30 20 10 0 0

1

2

3

4

5

(day)1/2


10

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Figure 2. Application of equation (1) to the initial release phase for the data in Figure 1. The solid lines represent linear curve fits to the data. In each case the coefficient of determination was greater than 0.99.

Table 3. Diffusivity of triamcinolone within the photo-cross-linked networks of Figure 1 at 37 ºC. The ± values represent the 95% confidence interval about the calculated value.

Network

D (cm2/s) x 1011


1.75 ± 0.3


0.65 ± 0.1

CL:DLLA 1:1 5.5k PEGDA 700

3.36 ± 0.4

The objective was to obtain a multi-month in vitro release duration without a secondary release phase. For purely diffusion-controlled release from a cylinder, wherein the diffusivity remains constant, the release rate decreases with time because the drug in the interior of the cylinder needs to diffuse further to be released. In a device wherein the polymer is degrading whilst the drug is being released, a secondary release phase is often observed. The secondary release phase results from an increase in drug diffusivity with time within the polymer due to bulk polymer erosion.26 Thus, to reduce or eliminate this phase required adjusting the network degradation rate. Furthermore, to prolong the release duration the triamcinolone diffusivity within the polymer needed to be reduced. To achieve these objectives, the hydrophobic prepolymer composition was adjusted. The overall release duration was longest for the networks prepared with the TMC:DLLA 1:1 hydrophobic prepolymers and so subsequent formulation design was based on incorporating TMC and DLLA into the hydrophobic prepolymer, while attempting to reduce or eliminate the secondary release phase. The secondary release phase was less prominent for the 5.5k TMC:DLLA 1:1 prepolymer and so this molecular weight was retained for further formulation development.

The diffusivity of a solute within a polymer at a given temperature is known to be highly dependent on the polymer glass transition temperature (Tg), decreasing exponentially as the Tg increases.28,29 The diffusivities of triamcinolone within the network devices (Table 3) were in the opposite order of the


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glass transition temperatures of the as-prepared networks (Table 2). This observation suggested a means of manipulating triamcinolone diffusivity by increasing the hydrophobic prepolymer Tg. At a given molecular weight, a polymer’s Tg can be readily altered by changing its monomer composition, with the Tg of the copolymer increasing as the amount of monomer having the highest homopolymer Tg is increased. The Tg of poly(TMC) is approximately -20 ºC,30 while that of poly(CL) and poly(DLLA) are -60 ºC 31 and 57 ºC,13 respectively. Thus, increasing the DLLA content in the prepolymer would be one means of increasing its Tg. However, DLLA hydrolyses more rapidly than CL32 while TMC is highly resistant to hydrolysis,30 so increasing the DLLA content in the prepolymer would also likely still result in a secondary release phase. Hence, the glass transition temperature was adjusted by altering the TMC monomer ratio while retaining CL and/or DLLA to facilitate degradation. More specifically, the next formulations examined were prepared with 5,000 Da hydrophobic prepolymers having TMC:DLLA:CL ratios of 2:1:1 and 3:1:0.

100

Mass % released

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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80 60 40 TMC:DLLA:CL 2:1:1 5.5k PEGDA 700

20

TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400

0 0

50

100

150

200

250

300

Time (day) Figure 3. Triamcinolone release from devices prepared with TMC:DLLA:CL: 2:1:1 5.5k prepolymers co-crosslinked with PEGDA 700 or PEGDA 3400. The line represents a fit of equation 3 over the region indicated.


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Adding TMC to the CL:DLLA hydrophobic prepolymer decreased the Tg of the resulting network (Table 2) and so an increase in triamcinolone diffusivity would be anticipated. However, the enhanced resistance to hydrolysis provided by TMC resulted in a reduced degradation rate, and thereby a relatively non-increasing diffusivity with release time, and thus a prolonged release profile without a secondary release phase, was obtained (Figure 3). Promisingly, triamcinolone was released from the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 cylinders for almost 200 days. Also shown in Figure 3 is the influence of the molecular weight of the PEGDA used on the release kinetics. For these experiments, the TMC:DLLA:CL 2:1:1 5.5k prepolymer was co-cross-linked with PEGDA 700 and PEGDA 3400. Increasing the molecular weight of the PEGDA up to 3400 Da had no significant influence on the release rate. This result indicates that triamcinolone release was principally controlled by the nature of the hydrophobic prepolymer used.

To ascertain whether the release was diffusionally controlled, an equation for radial solute diffusion from a cylinder (equation (3)33) was fit to the data. In equation (3), αn values are the positive roots of Jo(rαn) = 0, which is the Bessel function of order zero. The fitted line can be seen in Figure 3. ∞ 4 Mt = 1− ∑ 2 2 exp ( −Dα 2n t ) Mo n=1 r α n

(3)

The fitted curve provides very good agreement to the majority of the release kinetics, beginning to deviate from the data points after about 70% of the triamcinolone was released. After this point, it is likely that the degradation of the polymer began to significantly increase triamcinolone’s diffusivity. From this curve fit, the diffusivity of triamcinolone in the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 network was calculated to be 4.21 x 10-11 cm2/s, which is approximately twice as large as that in the TMC:DLLA 1:1 5.8k PEGDA 700 network. The larger value is expected based on the lower Tg of the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 network. Similarly, the diffusivity of triamcinolone in the TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400 network was calculated to be 6.05 x 10-11 cm2/s.

Increasing the TMC monomer content in the TMC:DLLA hydrophobic prepolymer decreased the Tg of


13


the resulting network (Table 2). However, the Tg of the TMC:DLLA 3:1 5k PEGDA 700 was higher than that of the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 (Table 2), due to the absence of CL. This higher Tg resulted in a lower triamcinolone diffusivity, as indicated by the slower initial release phase of triamcinolone within these devices (Figure 4). Interestingly, for the TMC:DLLA 3:1 5k PEGDA 700 cylinders, a period of nearly constant release was obtained following an initial diffusion controlled phase, as indicated by the solid line representing a linear regression to the data from day 31 (31% released) to day 253 (99% released), or 222 days of nearly constant release at 0.3% (w/w)/day. The coefficient of determination of the regression was 0.99.

100

Mass % released

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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50

0 0

100

200

300

Time (day)

Figure 4. Triamcinolone release profile from TMC:DLLA 3:1 5k PEGDA 700 devices. The solid line represents a linear curve fit over the region indicated.

The change in hydrated mass of the cylinders used in these latter experiments was also measured with time. The results are shown in Figure 5. Given the time frame of release, the change in hydrated mass of the releasing cylinders was used as an indicator of their degradation. Upon significant degradation of the polymer network, the devices begin to swell.16


14

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90

% increase in hydrated mass

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400 TMC:DLLA 3:1 5k PEGDA 700

60

30

0 0

100

200

300

400

500

Time (day)

Figure 5. Change in device hydrated mass with time during in vitro release.

For all the devices, there was an initial increase in hydrated mass upon immersion into the release medium, reflective of an increase in volume of the device. The mass of the device then remained constant for a prolonged time, and eventually the hydrated mass began to increase. The TMC:CL:DLLA 2:1:1 5.5k devices prepared with the lower molecular weight (700 Da) PEGDA swelled to a lesser extent within the constant volume region than those prepared with 3400 Da PEGDA, indicative of a lower molecular weight between cross-link points within the hydrated regions of the network. The CL containing devices (TMC:DLLA:CL 2:1:1 5.5k PEGDA 700) swelled to a lesser extent than the TMC:DLLA 3:1 5k PEGDA devices, a result that can be attributed to the hydrophobicity of CL being greater than that of TMC. Importantly, the swollen volume of the device remained constant over the majority of the release duration of approximately 200 days for the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 and the TMC:DLLA 3:1 5k PEGDA 700 devices. For the TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400 devices, significant swelling and accompanying mass increase was observed beginning from day 140. An increase in swelling was observable in the other devices beginning at day 393. This increase in swelling is attributed to significant degradation of the polymer network due to hydrolysis, as has been noted in previous studies.19

The form stability, or the maintenance of a cylindrical geometry with time, was also assessed with time


15


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Page 18 of 26

and is presented as the change in the diameter and length of the cylinders, normalized to their respective time zero values (Figure 6). In each case, there was an initial increase in diameter of the devices, which was greatest for those prepared with the TMC:DLLA:CL 2:1:1 5.5k prepolymer (Figure 6A). Following this increase in diameter, which was less than 10%, the diameter of the devices remained effectively constant over the majority of the release period. There was no significant effect on the increase in diameter of the devices with respect to the molecular weight of the PEGDA used for the devices prepared with the TMC:DLLA:CL 2:1:1 5.5k prepolymer, until the very late time points. For these time points, the devices prepared with the PEGDA 3400 increased to a significantly greater extent, reaching between 115 to 122% of their initial values. For devices prepared with PEGDA 700, regardless of the hydrophobic prepolymer used, the length of the device remained essentially constant throughout the release period (Figure 6B). Conversely, the length of the devices prepared with the PEGDA 3400 hydrophilic prepolymer (TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400) exhibited an initially small increase (~ 5%) increase in length initially, which, similarly to the change in diameter of these devices, remained constant until the later time points, ultimately reaching an increase of up to 133% of the initial length of the device. These changes in the form stability of the devices are consistent with the observed changes in their hydrated mass.


16

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Normalized Diameter (mm/mm)

TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400

1.2 TMC:DLLA 3:1 5k PEGDA 700

1.1

A

1.0

0

100

200

300

Time (day) 1.3

TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 TMC:DLLA:CL 2:1:1 5.5k PEGDA 3400

Normalized Length (mm/mm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TMC:DLLA 3:1 5k PEGDA 700

1.2

B

1.1

1.0

0.9 0

100

200

300

Time (day)

Figure 6. Change in (A) diameter and (B) length of the cylinders with time, normalized to their time zero values.

The analysis to this point has assumed that the triamcinolone was below its saturation concentration within the prepared polymer networks. To verify this assertion, we attempted differential scanning calorimetry of drug-loaded devices of varying triamcinolone content to see whether a melting endotherm for triamcinolone could be observed. However, the melting point of triamcinolone (270 ºC)24 is greater than the decomposition temperature of the networks (~ 200 ºC) and so this approach was not successful. Instead, we compared the release of triamcinolone from TMC:DLLA:CL 2:1:1 5.5k PEGDA 700


17


networks prepared with 5 versus 10% w/w triamcinolone loading (Figure 7). If the triamcinolone was incorporated above its saturation concentration, the release kinetics would be given by,27

 M t  M t 4DtCsat Mt   ln 1− 1−  M   M  + M = r 2C o o o o

(4)

wherein Csat is the saturation concentration of triamcinolone in the network and Co is its concentration within the device. Equation 4 predicts that the release rate would be dependent on the initial drug loading within the network. The data in Figure 7 indicates that the release rate was independent of initial drug loading, as predicted by equation 3, which was taken as evidence that the triamcinolone was below its saturation concentration in the devices examined. If the triamcinolone content in the polymer network was above its saturation concentration, and thus crystalline triamcinolone along with dissolved triamcinolone was present, it could also have been possible that pores would have been formed in the device as the crystalline drug was release, increasing the effective diffusion coefficient of the triamcinolone within the device with time. Thus, the results shown in Figure 7 could potentially be explained by this mechanism. However, that this increase in diffusion coefficient would so closely match that of the 5% loading condition was considered unlikely.

100

Mass % released

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 26

80 60 40

5% triamcinolone

20

10% triamcinolone

0 0

100

200

300

Time (day)

Figure 7. Influence of initial triamcinolone loading (% w/w) on release from TMC:DLLA:CL 2:1:1 5.5k PEGDA devices.


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DISCUSSION

The objective of this study was to prepare an implantable, biodegradable device capable of long term and sustained intravitreal delivery of a corticosteroid. We have shown that a prolonged release of the corticosteroid triamcinolone is achievable using a degradable polymer network comprised of a hydrophobic prepolymer co-cross-linked with hydrophilic PEGDA. This cross-linking was achieved using long-wave UV light, which allows for the reaction to occur rapidly at room temperature and is scalable to large-scale manufacture. There was no evidence of triamcinolone degradation due to the cross-linking reaction observable within the HPLC output; nevertheless, future work should examine this possibility.

The kinetics of release from the formulations examined was principally dependent on the properties of the hydrophobic prepolymer. A suitable release profile was obtained by manipulating the composition of the hydrophobic prepolymer so as to increase its Tg while slowing down its hydrolytic degradation. Of the hydrophobic prepolymers examined this was most effectively achieved using a 5,000 Da TMC:DLLA hydrophobic prepolymer with a 3:1 monomer ratio. These devices exhibited a period of nearly constant release, which was a result of the increase in triamcinolone diffusivity with time due to degradation of the polymer network. This nearly constant release period may be highly desirable for the treatment of intraocular inflammatory diseases. Utilizing solely TMC in the hydrophobic prepolymer was considered; however, cross-linked 3-armed star-poly(TMC) trimethacrylate has been reported to undergo only limited degradation following intravitreal implantation in rabbits.34

The PEGDA was incorporated into the networks as previous studies had shown that PEGDA co-crosslinked with star-poly(CL-DLLA) triacrylate cylinders lost mass in a linear fashion.19 Increasing the PEGDA molecular weight used in preparing the devices from 700 to 3,400 Da had no marked effect on the triamcinolone release rate, but did result in a much greater degree of swelling of the device. This greater swelling increased the effective diffusivity within the polymer, but this increase in diffusivity was countered by the increase in diffusional path length required for release; the radius of the 700 network devices was ~ 0.47 mm over the majority of the release phase, while that of the 3,400 Da was ~


19


0.6 mm.

It can be readily appreciated from equation 1, which is a short time approximation to equation 3, that drug release from a cylindrical device occurs principally in the radial direction, and so manipulation of the implant radius has an appreciable influence on the release rate, and duration, achieved. As the device diameter increases, the release rate decreases and the release duration increases. At present, the only marketed implantable corticosteroid delivery device that is biodegradable is the Ozurdex formulation, which is 0.45 mm in diameter. The devices examined in this study had diameters greater than 0.45 mm as we were limited in what we could manufacture using the materials we had available. The large diameter devices examined in this study are not suitable for implantation; however, an approximation of the in vitro release profile from these devices but having a smaller diameter can be obtained from equation 3, by using the calculated diffusivity for the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 device, and the radius of an Ozurdex cylinder (0.225 mm). The resulting predicted curve is given in Figure 8. This analysis shows that 95% of loaded triamcinolone would be released by 65 days. This is an approximately 100 % increase in the reported in vitro release duration of dexamethasone from Ozurdex (30 days). The triamcinolone release from the TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 networks was faster than for the TMC:DLLA 3:1 5k PEGDA 700 networks, and so it would be expected that the latter devices would release over an even longer time frame.

1.0

Mass fraction released

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 26

0.8 0.6 0.4 0.2 0.0 0

20

40

60

80

100

Time

Figure 8. Release profile predicted from equation 3 for a TMC:DLLA:CL 2:1:1 5.5k PEGDA 700 device with a radius equivalent to that of an Ozurdex cylinder (0.225 mm).


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Although the formulations examined yielded extended in vitro release, it may be possible to generate even longer release durations through a more extensive examination of the formulation parameters. For example, a fixed percent of PEGDA was utilized, which was based on previous studies that showed that this amount of PEGDA produces a linear decrease in mass during in vitro degradation. Using a lower amount of PEGDA might produce a longer release duration, by reducing even further the degree of swelling of the device, which has been shown to increase the effective diffusivity of the drug within the network formed. Moreover, the maximum initial drug loading used in this study was 125 µg/mm3, while the Ozurdex device contains approximately 700 µg dexamethasone /mm3. Further studies are also therefore needed to determine the influence of drug loading on release from these network devices.

The formulation parameters were explored using triamcinolone and it can be appreciated that different release kinetics would be obtained for different corticosteroids. For example, dexamethasone is structurally very similar to triamcinolone (Figure 8), and has a similar solubility in water at 25 ºC; the solubility of triamcinolone is 80 mg/L while that of dexamethasone is 89 mg/L.24 However, the logarithm of the octanol/water partition coefficient (logP) of triamcinolone is 1.16 while that of dexamethasone is 1.83.24 Thus, it would be expected that dexamethasone would be released more slowly from the implant due to its preference to remain in the hydrophobic phase. It may therefore be necessary to adjust the hydrophobic prepolymer composition to obtain desired release profiles for different corticosteroids.

Figure 8: Chemical structures of triamcinolone and dexamethasone.


21


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CONCLUSIONS

These studies have shown the potential advantages of using a cross-linked biodegradable network system for intravitreal corticosteroid delivery and illustrated the means by which the release rate and duration can be controlled. Of the polymer combinations examined, the network composed of 5000 Da 3-armed star-poly(trimethylene carbonate-co-D,L-lactide) triacrylated (3:1 trimethylene carbonate: D,Llactide) co-cross-linked 10% w/w 700 Da poly(ethylene glycol) diacrylate yielded the best release profile, with an extended period of nearly constant release. Ultimately, the potential of this formulation approach must be assessed in vivo. In such studies, the implications of the potential swelling of the device at the latter stages of its useful duration, as well as the degradation products, on the surrounding tissue would need to be determined.

Acknowledgements The authors gratefully acknowledge operational funding from the Natural Sciences and Engineering Research Council of Canada through the 20/20 Ophthalmic Biomaterials Network, and infrastructure support from the Canadian Foundation for Innovation and the Ontario Research Infrastructure Fund.

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