Enhanced kientic solubility of indomethacin amorphous solid dispersions in hydrogel

Dajun Sun

Supervisor: Professor Ping Lee

Department of Pharmaceutical Science

University of Toronto

April 11, 2012

Story of Itraconazole (an -azole antifungal drugs)

1960 1970s 1980s

AIDS era w/o antiretroviral treatment

Not used for a broad spectrum of fungal infections

Low therapeutic index Low potency

- Minimum inhibitory concentration: 100-fold smaller than ketoconazole - Higher therapeutic index

Solubility 0.1 mg/mL

Solubility 8 mg/mL

Absorption of Oral Dosage Form

Drugs in oral dosage forms

(tablets or capsules)

Absorbed by the body and

transferred by blood stream

to the site of action for

therapeutic purposes

Solublized in GI fluids

Cross the biological

membranes

Biopharmaceutics Classification System

Lipophilic

High Permeability

Low Solubility Flurbiprofen

Naproxen

Diclofenac

Piraxicam

Carbamazeppine

Phenytoin

Amphiphobic

Low Permeability

Low Solubility Famotidine

Atenolol

Ranitidine

Nadolol

Cimetidine

Hydrophilic

Low Permeability

High Solubility Terfenedine

Ketoprofen

Hydrochorothiazide

Furosemide

Solubility

Pe

rme

ab

ilit

y

Improvement at

chemical levels

(difficult)

Formulation design

Amphiphilic

High Permeability

High Solubility Propranolol

Metoprolol

Labetalol

Enalapril

Captopril

Diltiazem

Nortriptyline

Marketed drug

New Chemical Entity

Solubility: highest required dose is soluble in 250ml or less of

aqueous media over the pH 1 to 7.5.

Permeability: the extent of absorption in humans is determined to

be 90 % or more of the administered dose in comparison to iv. www.fda.gov/cder/guidance/2062dft.pdf

Physical modifications to improve solubility

Particle size reduction 1

Polymorph of crystal 2

Complexation / solubilization 3

Creation of salt forms 4

Amorphous solid dispersions (ASD) 5

Micronization

Nanosuspensions

Surfactants

Cyclodextrin

Solubility enhancement of ASD

Crystalline Amorphous

Metastable

(Amorphous)

Stable

(Crystalline)

Unstable

Free Energy

Yu, L Adv Drug Del Rev , Nov 48, 2000, 27-42

Amorphous: lack of long range of molecular orientation

symmetry (randomness of molecular conformation). But, it

may have short range of molecular lining.

Polymeric carriers: amorphous drugs molecularly

dispersed in polymer which retards nucleation/crystallization.

Polymeric matrix

ASD example – hard candy

Methods of preparing amorphous solid dispersions

(1) Solvent method: dissolved in solvent and dry the solvent off

(2) Melt quenching: rapid cooling after melt

Example: Hard candy – melt sugar is rapidly cooled

Crystalline sugar:

Hard, lower solubility Amorphous sugar

(hard candy):

Brittle (glass)

Higher solubility

Drug release from water-soluble polymers

Water-soluble

carriers

Body

Fluids

Polymer

matrix

Drug molecule

Curatolo et al. Pharm Res, Vol. 26, No. 6, 2009, 1419-1431

Kinetic / apparent solubility

Crosslinked Poly(2-hydroxyethyl methacrylate)

Immerse dry

beads in drug

loading

solution

Swelling

hydrogel imbibes

loading solution

Remove

excess loading

solution and

dry hydrogel

Insoluble PHEMA hydrogel beads synthesis:

Indomethacin loading process:

Physicochemical characterization of ASD

Microscopy

FTIR

DSC

Dissolution Study XRD

Drug-polymer

interaction

Appearance

Degree of

crystallinity

Tg: molecular

mobility in

polymeric matrix

Solubility

enhancement

Indomethacin-loaded PHEMA hydrogel

Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted

Dissolution under the sink condition

- Dissolution volume is fixed (=250mL)

- Indomethacin aqueous solubility ~ 10 mg/mL

- Dose required = 20 mg

Sink Index (SI)

SI=10

Perfect sink

condition

SI=0.125

Physiological condition

with required dosage

sink condition Non-sink condition

Kinetic solubility enhancement between soluble polymers and insoluble PHEMA at low loading

Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted

Kinetic solubility enhancement between soluble polymers and insoluble PHEMA at high loading

Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted

Effect of drug loading on dissolution

Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted

Effect of particle size on dissolution

Sun, D.D. and P.I. Lee, Eur. J. Pharm. Biopharm. Jan 2012, accepted

Conclusion

Insoluble PHEMA hydrogel shows a different release

mechanism of ASD drugs from soluble polymeric carriers Soluble polymers (PVP, HPMCAS): instantaneous release, resulting in an

initial surge of drug concentration, followed by rapid drop of drug

concentration due to nucleation and crystallization

Insoluble polymer (PHEMA): gradually releasing drugs to avoid a sudden

surge of supersaturation

The solubility enhancement of PHEMA falls between those

of HPMCAS and PVP at 10% loading and outperforms both

at 33%

Immediate to controlled release of ASD drugs in PHEMA

can be achieved by controlling the particle size

Dissolution rate might play a role in supersaturation and

kinetic solubility enhancement

Supervisor: Professor Ping Lee

Advisory Committee: Professors Edgar Acosta, Christine Allen & Shirley Wu

Abbott Laboratory: Dr. Rob Ju

PIL Lab Members