1. LONG TERM DRUG RELEASING BIODEGRADABLE IMPLANTS:
OSTEOARTHRITIS PAIN MANAGEMENT
Anurag Ojha; Namdev B. Shelke, Ph.D.; Matthew D. Harmon, Sangamesh G. Kumbar *, Ph.D.
Department of Orthopaedic Surgery, Institute of Regenerative Engineering, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT
* Correspondence to: Sangamesh G. Kumbar Ph.D., Assistant Professor, Departments of Orthopaedic Surgery, Materials Science & Engineering, and Biomedical Engineering, University of Connecticut, Farmington, CT 06030, USA E-mail: Kumbar@uchc.edu
ABSTRACT
Osteoarthritis (OA) is caused by the breakdown of cartilage. The deterioration of
cartilage directly exposes joints to bone surfaces causing excruciating pain, decreased
range of motion, and other forms of disability to patients. To combat the pain, oral
non-steroidal anti-inflammatory drugs (NSAIDS) and intra-articular injections are
used to manage pain from 24 hours to 7 days. However, both NSAIDS and intra-
articular injections clear out of the system rapidly and require repeated dosages
(leading to infection and excessive drug concentration at target site). The purpose of
this project is to develop a biodegradable microparticle (MP) implants for long lasting
delivery of the NSAID celecoxib (CLX) for effective pain management of OA. Five
different co-polymers of PLLA and PCL such as PLLA, Poly (LA-co-CL)(95:05), Poly (LA-
co-CL)(85:15), Poly (LA-co-CL)(80:20), and Poly (LA-co-CL)(70:30) were used to
fabricate MPs and release profiles were evaluated in vitro. The microparticles were
fabricated by an oil-in-water emulsification technique followed by a solvent
evaporation process. The drug loading efficiencies were determined using an
extraction technique. The microparticles were characterized using FT-IR and light
microscope.
BACKGROUND
•Osteoarthritis (OA) is a major cause of disability amongst adults in the US and is
prominent in the military due to increased physical activity. An estimated 67 million
adults will have OA by 2030. It is a multi-billion dollar industry which reached $128
billion in 2003.
•Methods to cure OA involve surgical treatments, however such methods are
invasive.
•Intra-articular drug delivery using injections avoid hepatic first pass drug
metabolism, physical barriers of drug transportations to the target site and minimize
overall systemic drug exposure and toxicity to the body. However, injections must be
administered regularly because they clear quickly. This method is also very harmful
due to repeated excessive dose in the beginning and eventually leading to side
effects.
•An FDA approved NSAID celecoxib (CLX), is used for OA acute pain management. The
long term use of NSAIDS, such as CLX, has severe side effects such as heart attacks or
strokes which can be fatal.
•Intra-articular delivery of CLX has proved to improve the therapeutic efficacy while
minimizing such side effects.
•We hypothesize that it is possible to provide therapeutic doses of CLX up to 6
months from an implant by altering the polymer matrix
hydrophilicity/hydrophobicity, molecular weight, drug loading and particle size that
constitutes the implant.
METHODS
Drug loaded microparticles were prepared using polymer-drug solution containing a
calculated amount to CLX. In brief, CLX dissolved in polymeric solution was emulsified
in an aqueous environment containing 2% solution of polyvinyl alcohol (PVA) under
stirring. We employed 30% theoretical drug loading for 5 different polymers with
altered composition as shown in Table 1.
Drug loaded microparticles were repeatedly washed (to remove surface adhered
PVA), dried, and kept desiccated under vacuum. The size of the microparticles were
determined using a light microscope.
The amount of drug present in the microparticles was determined by extracting the
drug in DCM and analyzing using UV spectrophotometer at 252 nm. The amount of
drug present in the microparticles was calculated using the standard curve.
These microsphere formations along with actual drug loadings are shown in Table 1.
CLX release studies: Weighed microparticles were dispersed in a drug release
medium (1X phosphate buffered saline [PBS] pH 7.4 with 0.1% Tween 80) and then
this dispersion was transferred to dialysis bags (MW cut off 12kD-14kD). The media
from each test tube was collected and UV analysis was done and was compared with
the standard curve of the drug to calculate the concentration of the drug released
daily. Drug loaded microparticles were tested for drug release profiles in three
different temperature: 37o
C, 47o
C, and 57o
C. Use of high temp to conduct in vitro
release will allow characterization of the drug release in less amount of time. Our
ongoing studies will make use of Arrhenius plots to correlate the drug release. Also
we will test the release profiles of these polymer loaded with 20 w% CLX.
CONCLUSIONS
• The polymer matrix hydrophobicity PLLA < Poly (LA-co-CL) (95:5) < P(LA-co-CL)
(85:15) < P(LA-co-CL) (80:20) < P(LA-co-CL) (70:30) and hence, resulted in different
drug release patterns.
• CLX diffusion rate is higher at evaluated temperatures (37<47<57o
C) (results not
shown). Hence, higher temperature release studies allow characterization of the
formations in less time. Studies are currently underway to analyze these release
patterns using Arrhenius plots and to establish a conversion pattern.
• Initial drug release characterization suggest that these formulations were able to
provide therapeutic doses of CLX up to 60 days and translate into more than 6
month release.
Polymer and drug (CLX) dissolved
in volatile solvent (DCM)
Overhead
stirrer
2% PVA solution Magnetic
stirrer
Polymer and drug
solution
suspension
Stir
bar
Particle isolation by
Buchner funnel vacuum
system
ACKNOWLEDGEMENTS
Dr. Kumbar acknowledges the funding from the National Science Foundation Award numbers IIP-
1311907, and IIP-1355327 and EFRI-1332329.
Health Opportunity Program of the University of Connecticut School of Medicine, Department of
Community Medicine and Health Care, Granville Wrensford – Ph.D. C.R.A. Assistant Dean and
Associate Director for Health Career Opportunities Program, Marja M. Hurley – Associate Dean and
Director, Office of Health Career Opportunities Program, Jan Figueroa, Aetna Foundation,
Connecticut State Legislative Fund, Connecticut Office of Higher Education, Fisher Foundation,
William and Alice Mortensen Foundation, John and Valerie Rowe Health Professions Scholars
Program, University of Connecticut Foundation – Friends of the Department of Health Career
Opportunity Programs, University of Connecticut Health Center.
RESULTS
y = 0.0367x + 0.0015
R² = 0.9999
0
0.5
1
0 5 10 15 20
UVabsorbanceat252
nm
CLX conc. (ug)
CLX Standard Curve in PBS
Schematic diagram representing the fabrication process of microparticles.
Standard curve of CLX in PBS with 0.1% Tween 80.
FT-IR of CLX, PLLA, PLLA + CLX, and PL(LA-co-CL)(70:30) + CLX
Drug release profile for PLLA microparticles loaded with CLX (21 w%) over the course of 55 days.
Drug releaseprofile for P(LA-co-CL)(80:20) loaded with CLX (27 w%) over the course of 55 days.
CLX release was faster and also more consistent than PLLA-CLX microparticles.
Samples (Initial Weight) CLX %
PLLA 21
PLLA(LA-co-CL)(95:05) 24
PLLA(LA-co-CL)(85:05) 27
PLLA(LA-co-CL)(80:20) 27
PLLA(LA-co-CL)(70:30) 29
Extraction efficiency 95
Table 1. CLX loadings in various formulations and average
extraction efficiency.
FTIR study indicates that CLX peaks (1596 cm-1
, 1555 cm-1
) remain unaffected in the microparticle
formulations, indicating that there is no interaction between polymer and drug.