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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

ABSTRACTOsteoarthritis (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.

METHODSDrug 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: 37oC, 47oC, and 57oC. 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<57oC) (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

Stirbar

Particle isolation by Buchner funnel vacuum system

ACKNOWLEDGEMENTSDr. 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 + 0.0015R² = 0.9999

0

0.5

1

0 5 10 15 20UV

abso

rban

ce a

t 252

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 release profile 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) 24PLLA(LA-co-CL)(85:05) 27PLLA(LA-co-CL)(80:20) 27PLLA(LA-co-CL)(70:30) 29Extraction 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.