Enhancing Solid Dosage Bioavailability with Size, Crystal Form, and Formulation

Second U.S.-Korea Nano Forum

Tony Meehan, Ph.D.Director, Pharmaceutical DevelopmentFebruary 17, 2005

Drug Delivery Forms

parenteral

oral

pulmonary transdermal

The Impact of Size on Efficacy

• Most drugs in solid form fall in the range of 10-500 microns

• Poor aqueous solubility may limit oral bioavailability or ability to deliver as a parenteral formulation

• Absorption may depend on rate of dissolution, which in turn is controlled by particle size, crystalline form, and aqueous environment

Drug dissolved in gastric fluid

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NanoCrystals

µm sizedrugparticles

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Dissolved drug is absorbed

Dissolved drug uptakeinto mixed micelles of bilesalts & lipid digestion products

Drug is absorbed

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o

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MK-869 Particle Size Effects in Dogs

0

200

400

600

800

1000

1200

1400

0 4 8 12 16 20 24

NanoCrystal, 0.12 umWet-Milled, 0.48 umJet-Milled, 1.85 um004H004, 5.49 um

ng/m

L M

K-0

869

Hours (Expanded View, 0-24 Hours)

Total Exposure (AUC) in Humans

0

2 0

4 0

6 0

8 0

1 00

1 20

0 5 0 1 0 0 1 5 0 2 0 0 2 5 0 3 00 3 5 0

AU

C, u

g hr

/mL

Dos e (m g)

Nanoc aps u le Fed

NanoC rys ta l Susp ens ionFas ted

NanoCaps u le , Fas ted

Tab let Fe d

Table t, f as ted

Improving Oral Bioavailability

• Particle Size Reduction– Jet-milling, high energy ball milling– Spray drying– Super critical fluid extraction– High supersaturation crystallization

• Solid Form Thermodynamics– Amorphous– Salts– Higher Free Energy Polymorphs

• Improve Solubility

Jet Milling

• Relies on particle-particle interaction• Narrow size distribution• Minimal heating• Mean size 1-10 microns

www.comex-group.com

Oct: Beclomethasone Dipropionate (after micronization) - Jet-milling

Beclomethasone Dipropionate (after micronization), www.hovione.com

High Energy Ball Milling• Mean size range from 100 o 1000 nm • Particles stabilized via adsorbed GRAS excipients • (Nanosystems’ technology)• Enhances dissolution rate of oral drugs• Enables parenteral forms of poorly soluble drugs

Asada

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Other Methods of Size Reduction

Spray Drying Supercritical Fluid Extraction

• PSD < 1,000 nm

• Applicable for pulmonary, oral, or parenteral delivery.

• Generally amorphous; may agglomerate or pick up moisture; less chemically stable

Particle Size Reduction Summary

• Particle size reduction generally successful in improving oral, pulmonary, and parenteral bioavailability

• However, problems exist…– Downstream processing, material handling– Chemical and physical stability

• Manufacturing processes for crystalline particles < 100 nm really don’t yet exist, but could present an opportunity for improving drug delivery efficacy

Improving Oral Bioavailability

• Particle Size Reduction– Jet-milling, high energy ball milling– Spray drying– Super critical fluid extraction– High supersaturation crystallization

• Solid Form Thermodynamics– Amorphous– Salts– Higher Free Energy Polymorphs

• Improve Short Term Solubility

CrystalMaxCrystalMaxTMTM

Solid Oral Forms

FASTFASTTMTM/SFinX/SFinXTMTM

Liquid/Injectable Formulations

DerMaxDerMaxTMTM

Transdermal

TransForm Pharmaceuticals Platforms

HTE in Pharmaceutical Formulations

Parallel experimentation: > 10,000 crystallizations/week Typically 0.25 - 2 mg of compound per testCooling, evaporative, melt, anti-solvent, and other modes

CrystalMaxTM Process Flow

Clustering of Glycine Polymorph Raman Spectra

α

γ

Rapid, automated crystal form classificationMethod can be used with other types of data

Each dot = value of ‘similarity’ for a pair of spectra

High

Low

Similarity measure

Pharmaceutical Co-Crystals

Pure drugCo-crystal with new structure, properties

Co-crystal former

Can impact:SolubilityDissolution rateHygroscopicityStabilityHabitProcessability

Many of the potential benefits of a salt, without the limitations

> 30% of compounds lack “saltable” functional groups

Broad potential applicability

A stable higher energy form

Itraconazole: Succinic Acid Co-Crystal

Remenar, J. F. et al. J. Am. Chem. Soc. 125, 8456 (2003)

The acid groups of the co-crystal former do not interact with the strongest base on itraconazoleGeometry of co-crystal former drives crystal formation

a=30.145(4)Åb=5.7435(7)Å β=105.133(2)ºc=21.580(3)Å

P21/c

Improved Dissolution of Itraconazole

50µm8x10-4

6

4

2

0

[1] (M

)

4003002001000Time (min)

■ Sporanox® beadsl-malic acid co-crystal

● l-tartaric acid co-crystalsuccinic acid co-crystal

◆ cis-itraconazole

Co-crystals of itraconazole showed improved dissolution compared to the free baseEnables alternative formulation options

New Crystal Form of Celecoxib

40% bioavailableSlow onsetNon-linear PK

Issues Impact~95% bioavailableFaster onsetLinear PK

Potential implication

0

500

1000

1500

2000

0 5 10 15 20 25

TPI-336Marketed product

t, hours

Lower doseNew indication7+ years add’l patent life

Approach Novel crystal forms enable new formulation technique

Precipitation Inhibition: Spring and Parachute

Concentration

New Form

Free drug in equilibrium

Time

“Spring” “Parachute”

Problem: API with poor solubility & low bioavailability

PrecipitationInhibition

Solution: “Spring” and “parachute” concept

Precipitation: Celecoxib salt in water

Poor Solubility Problem

• Compound PropertiesCrystallineVery low aqueous solubilityUnstable salts(pKa compound 0.9, 14.6)

Room Temperature Solubility

< 25

28Ethanol

71PEG 400

0.000060Water, pH 3-7

Solubility (mg/ml)Vehicle

triglycerides

28Ethanol

71PEG 400

0.000060Water, pH 3-7

Solubility (mg/ml)Vehicle

Challenge: Poorly soluble drug crashes out instantly upon dilution, limiting bioavailability

Approach:HT formulation studies to identify excipient combinations that delay precipitation or accelerate resolubilization in SGF

Precipitation Inhibition Solution

• Compound used: <5 g• Project duration: 8

weeks• >4,500 experiments

– 2 HT studies– Optimization

Dissolution Profiles of 2 Lead Formulations in SGF(20 mg/ml, 10X dilution, 37C)

0

0.1

0.2

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0.9

1

0 20 40 60 80 100 120 140time (min)

API

(mg/

ml)

AV21

AV22

PEG400

• Solubility improvement vs. diluted PEG400: > 19,000X at 2 hours• Enabled > 50% improvement in bioavailability

Parenteral Reformulation: PropofolParenteral Reformulation: Propofol

• Very effective I.V. anesthetic• Formulated as a lipid emulsion

• Complex / expensive manufacturing process• Thermodynamically metastable• Difficult to handle aseptically• Risk of contamination

• Opportunity for improved product

• Lipid-free, preserved formulation• Thermodynamically stable pluronic

based colloidal self assembly• Equivalent PK to Diprivan• Enables multi-dose vials

Marketed product TPI-213M

Enabling Transdermal Technology

ALZA in 2002 • Limited screening capacity• Few transdermal candidates• Slow formulation

development

TransForm + ALZA in 2004• 100x conventional capabilities • Improved/enabled transdermal

products with broad IP

SkinReceptor

compartment

Transdermalpatch

Franz Diffusion Cell

1 – 2 experiments / in2

of skin

Adhesive formulations

25 – 100 experiments / in2 of skin

Skin

Receptor compartment

TransForm Permeation Cell Array

Summary

• Form, size, and environment impact the rate and extent of drug bioavailability

• Manufacturing processes for creating crystalline pharmaceuticals actives < 100 nm do not exist, yet may represent the next tool to improve drug delivery

• High throughput experimental methods present new opportunities to enable effective but poor performing molecules with new crystalline forms and formulations