=

Improved drug delivery incorporating the degradation of poly(β-amino ester) polymerized hydrogels

Curtis BethelDr. David Puleo

Department of Biomedical Engineering

Methods

Results DiscussionIntroduction

Synthesis of poly(β-amino esters)

• Tissue regeneration is a natural occurrence, but can be greatly hindered by abnormally traumatic tissue injury or inheritable tissue degenerative diseases2.

• Specific drugs can be administered to treat these special cases and aid in the regeneration process based on their pharmacological properties.

• Simvastatin possesses osteogenic, anti-inflammatory, anti-microbial and angiogenic properties, but is a small molecule drug and therefore prone to rapid release rates4.

• Drug delivery is a potential area of improvement in the biomedical engineering field. Oral dosage is subject to first-pass metabolism while injections deliver a bolus of drug at high concentration4.

• Poly(β-amino ester) (PBAE) biodegradable hydrogels are easily synthesized, relatively inexpensive, do not require purification, and have a variety of tunable properties5.

• PBAE hydrogels provide an intriguing alternative to traditional drug delivery methods for tissue regeneration. Loaded with drug, the hydrogels may act as a delivery vehicle and achieve an ideal release rate.

References

1. Anderson, D. G., et. al., 2006. A combinational library of photocrosslinkable and degradable materials. Advanced Materials.

2. Badylak, S. F., Dearth, C. L., Sicari, B. M., 2014. Tissue engineering and regenerative medicine approaches to enhance the functional response to skeletal muscle injury. The Anatomical Record.

3. Baoge, L., et. al., 2012. Treatment of skeletal muscle injury: a review. Hindawi Publishing Corporation.

4. Fisher, P. D., et. al., 2014. Improved small molecule drug release from in situ forming poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) and hydroxyapatite microparticles. J Biomater Sci Polym Ed.5. Hawkins, A. M., et. al., 2013. Tuning biodegradable hydrogel properties via synthesis procedure. Polymer Communication.

• The high-performance liquid chromatography (HPLC) retention time for pure simvastatin is approximately 3.05 minutes. The relatively low cumulative mass could be due to impurities in the simvastatin that display varying retention times.

• Although mass degradation was visibly accelerated at lower pHs, the accelerated systems initially released simvastatin at a slower rate. After several days, the release became more accelerated. This could be due to the low solubility of simvastatin in water.

• Hydrogel samples at a lower pH displayed more shrinkage, cracking, and opacity at earlier time points than samples at pH 7.4.

• AH6 3:1 hydrogels displayed shrinkage, cracking, and opacity at earlier time points than AH6 5:1 hydrogels. These observations began at the same point that the release rate increased. This could be due to the stronger bonds formed in the 5:1 hydrogels during UV polymerization.

• Degradation profile and release profile may be related, but release profile is not necessarily dependent on degradation due to the fact that the system could reach equilibrium concentration without all simvastatin permeating the hydrogel and entering the supernatant solution.

Conclusions

• Decreasing pH is not a valid method of accelerating release profiles of simvastatin in AH6 5:1 polymer or AH6 3:1 polymer.

• The release profile of simvastatin is more accelerated in AH6 3:1 polymer than in AH6 5:1 polymer.

• The cumulative release of simvastatin of AH6 3:1 and AH6 5:1 biodegradable hydrogels is gradual and does not release a initial bolus of high concentration.

References

Figure 1: Cumulative Release of Simvastatin inPBS Solution at pH 7.4

(Blue = AH6 5:1, Red = AH6 3:1)

Isobuytlamine (6)

+ +

Poly(ethylene glycol) Diacrylate (PEGDA) (H)

Di(ethylene glycol) Diacrylate (DEGDA) (A)

Time (days)M

ass o

f Sim

vast

atin

Rele

ased

(mg)

0 1 2 3 4 5 6 7 8 9 100

0.2

0.4

0.6

0.8

1

1.2

1.4

0 1 2 3 4 5 6 7 8 9 100

0.2

0.4

0.6

0.8

1

1.2

1.4

Figure 2: Cumulative Release of Simvastatin inPBS Solution at pH 6

(Blue = AH6 5:1, Red = AH6 3:1)

Time (days)

Mas

s of S

imva

stati

n Re

leas

ed (m

g)

0 1 2 3 4 5 6 7 8 9 100

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Figure 3: Cumulative Release of Simvastatin inPBS Solution at pH 5

(Blue = AH6 5:1, Red = AH6 3:1)

Time (days)

Mas

s of S

imva

stati

n Re

leas

ed (m

g)

0 1 2 3 4 5 6 7 8 9 100

0.02

0.04

0.06

0.08

0.1

0.12

0 1 2 3 4 5 6 7 8 9 100

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Time (days)

Time (days)

Time (days)

Conc

entr

ation

(mg/

mL)

Conc

entr

ation

(mg/

mL)

Conc

entr

ation

(mg/

mL)

Figure 4: Instantaneous Release of Simvastatin inPBS Solution at pH 7.4

(Blue = AH6 5:1, Red = AH6 3:1)

Figure 6: Instantaneous Release of Simvastatin inPBS Solution at pH 5

(Blue = AH6 5:1, Red = AH6 3:1)

Figure 5: Instantaneous Release of Simvastatin inPBS Solution at pH 6

(Blue = AH6 5:1, Red = AH6 3:1)

0 1 2 3 4 5 6 7 8 9 100

0.05

0.1

0.15

0.2

0.25

0.3

0.35

AH6 X:Y biodegradable hydrogel(X:Y molar ratio of A:H)

• AH6 3:1 and AH6 5:1 biodegradable hydrogels were synthesized via UV polymerization using photoinitiator DMPA.

• The PBAE samples were loaded with simvastatin by allowing them to soak in a simvastatin solution with solvent ethanol.

• A phosphate buffered saline (PBS) solution was used to emulate the environment of the body.

• Five samples of AH6 3:1 and AH6 5:1 are placed in PBS solution at three pHs, pH 7.4 to emulate the body and pH 6 and pH 5 to accelerate the release profile. Each sample is at 37°C.

• Supernatant solution is collected and analyzed through high-performance liquid chromatography.