Viadur Leuprolide Osmotic Implant

Viadur Leuprolide Osmotic Implant

Leuprolide Acetate

Metastatic Prostate Cancer

Future directions

Huggins and Hodges (1942)

Prostate cancer is androgen dependent

[O'Hanlon Brown & Waxman 2012]

Formulation Considerations

Peptide-like drug:

Susceptible to digestive and metabolic enzymes

Poorly absorbed from the digestive tract

Poor oral bioavailability

Injections

Skips first pass metabolism

Introduced in 1980

[O'Hanlon Brown & Waxman 2012]

Therapeutic Concern

Clinically significant increases in serum testosterone levels reported with delay in dosage greater than two weeks

Therapeutic efficacy challenged

[Wright et al. 2001]

Extended Release Formulations

1989:

Formulations for 1,3,4 months

Issues

Consistent release rate

Stability of the drug formulation

2000:

Viadur Leuprolide Acetate launched

[Wright et al. 2001]

Synthetic nonapeptide analogue of GnRH/LHRH

[Wright et al. 2001; [O'Hanlon Brown & Waxman 2012]

Replacement formulations of Leuprolide Acetate

Replacement Therapy

Replacing formulations of Leuprolide Acetate

Resistance to castrate testosterone levels and expression of Androgen receptor in Chronic Refractory Prostate Cancer

New line of treatment:

Inhibits adrenal androgen synthesis

[O'Hanlon Brown & Waxman 2012]

Hypothalamic-Pituitary-Gonadal Axis

[Perez-Merrero & Tyler 2004]

Other approved sustained release formulations of LHRH analogues:

Eligard

Lucrin Depot Intramuscular Injections

Goserelin acetate Subcutaneous Injection

Triptorelin pamoate

[Therapeutic Goods Administration 2010;

Fujii, Yonese,Kawakami, Yamamoto, Okubo & Fukui 2007]

Eligard

1,3, 4, 6 months formulations (7.5, 22.5, 30, 45 mg)

Contains API & Atrigel: poly (D,L - lactide-co-glycolide)

Better pharmacodynamic, clinical, side effects profile

[Therapeutic Goods Administration 2010; Sartor 2003; Perez-Merrero & Tyler 2004]

Androgens continue to be synthesised by the adrenals: serum androgen levels at one-fifth of pre-castrate levels

[O'Hanlon Brown & Waxman 2012]

Harper et al. 1947

[O'Hanlon Brown & Waxman 2012]

Replacement formulations of Leuprolide Acetate

Further Applications

Viadur

Omega DUROS

Intrathecal Opioid delivery

Site directed drug delivery: Attach miniaturised catheter

Therapeutic concentration at target site: reduced side effects

Local delivery of potent agents requiring precise rate control

Applications

Opioid delivery in chronic pain

Localised chemotherapy for brain tumours

[Wright & Culwell 2008]

Omega Interferon: Hepatitis C Viral Infection

Non-aqueous formulation

Why DUROS?

Omega Interferon is a protein: stability

Eliminates need for weekly injections: Compliance

Reduced side effects

Reduced viral breakthrough

[Wright & Culwell 2008]

Suitability for high or low dose markets

[Therapeutic Goods Administration 2010]

Lucrin

5mg/mL daily Subcutaneous injection: Intermittent therapy

Three depot Intramuscular injections (High and low dose)

Encapsulated in poly-lactic acid microspheres

[Therapeutic Goods Administration 2010]

Viadur

Non-biodegradable, osmotically driven subcutaneous implant containing Leuprolide Acetate

[Rohloff et al. 2008]

Release Kinetics

DIMETHYL SULFOXIDE

dM/dt = k(A/h)ΔIIc

DUROS® Osmotic Engine

Miniature system that acts like a syringe, releasing minute quantities of drug over time

After implantation

Water enters system via membrane

Saturated solution of NaCl formed

Osmotic engine expands, moving piston

Drug pumped through orifice

[Wright et al. 2001]

120mcg of Leoprolide Acetate released per day

[Marks 2003]

k = membrane permeability

A = membrane area

h = membrane thickness

ΔII = osmotic pressure difference (membrane vs tissue)

c = drug concentration

Zero order kinetics

- Dependent upon all parameters remaining constant

Solvent for Leuprolide

- Improves dissolution allowing for better delivery

Minimizes risk of degradation through hydrolysis, isomerisation, oxidation, aggregation

[Wright et al. 2001]

Cylinder - 45mm long with a 4mm diameter

[Wright 2010]

[Rohloff et al. 2008]

Wright & Culwell 2008

DUROS®

Components: Osmotic tablet

DUROS Pump Excipients

Excipients

Sodium chloride

Osmotic agent in excess

Sodium carboxymethyl cellulose

Gelling agent

Povidone

Binder for tablet Formulation

Magnesium stearate

Lubricant during manufacturing

Silicone medical fluid

Acts as a piston lubricant

Polyethylene glycol

Fills space between osmotic tablets and piston

DUROS® Technology

[FDA 2000]

[FDA, 2000; Rowe, Sheskey & Cook 2013]

"Sterile, non-biodegradable, drug dedicated system that operates like a miniature syringe, driven by osmosis and releasing minute quantities of the drug"

Functional Excipients

For normal functioning of implant

Dimethyl sulphoxide

- Highly polar substance

- Effective solvent for Leuprolide acetate

- Minimises hydrolytic reactions of the peptide API

- Improved stability

[Wright et al. 2001]

Alteration of pumping rate

Convenient implantation

Precise delivery kinetics

Aqueous/Non-aqueous

Organic solvents delivered

[Wright et al. 2001]

In-vitro testing of five different lots of the implant

Testing

[Wright & Culwell 2008]

Biocompatibility

Raw materials are clean and quality is consistent

Design avoids sharp corners and edges

Drug content and purity

Long-duration nature of system is considered

Drug stability/degradants (shelf life and while implanted)

Particularly relevant to peptide drugs that can hydrolyse

Sterility

Osmotic implants must be sterile

[Wright 2010]

Advantages

Advantages of Viadur

Therapeutic Benefit

Compliance

> 80% Consistent safe therapy

- Zero order kinetics:

Therapeutic efficacy without reaching toxic levels

>90% Effective Testosterone suppression

No death or clinically significant changes

-Bruising & hot flashes (50%)

100% Satisfaction with treatment

91.5% Comfortable and convenient

94.1% No impact on daily activities

96% Choose reimplantation

[Wright et al. 2010]

Serum testosterone < Castrate threshold

Suppression maintained for 1 year of the implant treatment, and 2 months following its removal

Fowler, Flanagan, Gleason, Klimberg, Gottesman & Sharifi 2000

Market Withdrawal

VIADUR is no longer on the market

2000: Product launch

2007: Phasing out of the product began

2008: Complete withdrawal from the market

"Diminished demand and growing manufacturing costs"

[Bayer HealthCare Pharmaceuticals 2007]