Meeting Formulation Challenges For Poorly Soluble Drugs

Challenges facing the Pharmaceutical Industry

Dramatic decrease of new actives partly due to low bioavailability

Revival of actives due to new excipients

New actives launched

year

43 24

1999 2010

Need for improved life cycle management

2011 – 2015: 171billion US $ exposed to generic competition (52 actives)

Dramatic loss of revenues due to patent expiry

2

The solubility and bioavailability challenge

The Venus de Milo is 10-times more soluble in water than many APIs

What cannot be dissolved cannot be absorbed and cannot cure 3

Soluble actives

Insoluble actives Future

situation

The Biopharmaceutical Classification Scheme (BCS)

Source: G.L. Amidon, H. Lennermäs, V.P Shah, J.R. Crison, Pharm. Res. 12 (1995) 413-420

Increasing number of Class II and IV APIs in the

Development Pipeline

Present

Future

I

I

II

II III

III

IV

IV

David Hauss, Oral Lipid Based Drug Delivery, Marcel Dekker 2007

Current

How to improve API aqueous solubility

Modification

• Particle size: Micronization, co-milling

• Crystalline structure: Amorphous structure

• Physical appearance: Solubilization, molecular disperse

solution (liquid or solid),

nanoparticles

Principle of solid solutions

7

The polymer matrix acts as a solid solvent for drug molecules

Enhanced rate of dissolution and solubility of drug molecules compared to the crystalline form

melt extrusion

Insoluble active formulated into a soluble drug product

Crystalline active + polymer Solid solution Tablets

Spray Drying

Kinetisol

Relevant Types of Solid Dispersions

Drug: crystalline amorphous molecularly dissolved Polymer: amorphous amorphous amorphous Thermo- dynamic almost stable unstable stable (drug below stability (kinetically controlled) saturation solubility)

Kaletra Dosage Forms: Products from both technologies

Dispersed System Solid Dispersion

Soft Gel Capsules Tablets 133.3 mg/33.3 mg (II/IV) 200 mg/50 mg (II/IV) 6 capsules/day 4 tablets/day

Lopinavir (Class II)

Ritonavir (Class IV)

Continuous process

melt extrusion

10 1) Modified from M. Thommes, Ph.D Thesis, University of Düsseldorf, 2006.

Temperature: above Tg of polymer (60 – 200 °C) Residence time: variable (0.5 – 5 min)

Melting Mixing Shaping

Engine

Extrudate

Die Tempering Cylinder Screw

Polymer Drug

1)

Basic Requirements for Polymers

Thermoplastic behavior deformability is essential

Suitable Tg 50 – 180°C

High thermal stability 50 – 180°C

Low hygroscopicity prevents crystallization

No toxicity application of large amounts

High or no solubilization thermodynamically stable capability formulation

Relevant Polymer Characteristics

Targeted release profile Long term

stability

Hygros- copicity

Physico- chemical

properties of active

Thermo- stability of

drug & polymer

Solution & solubilizing capability

Melt viscosity

Drug + Polymer

Glass transition tempera-

ture

Polymers for Different Release Profiles

Enteric IR SR

Kollidon® VA 64 Kollidon® VIT E TPGS

Soluplus® Lutrol® F grades HPMC HPC Eudragit® E PEG

Kollicoat® MAE 100P Eudragit® L 100-55 HPMCAP HPMCAS

Kollidon® SR Polyvinyl acetate EC Eudragit® RS

Solubilization Capability

Drug content [% dissolved in polymer] Polymer Carbamazepine 17-β-Estradiol Piroxicam Clotrimazole Itraconazole

Kollidon VA 64 33-50 >50 33-50 >50 >50

Kollidon 12 PF 25-33 33-50 33-50 33-50 33-50

Kollidon 30 33-50 >50 33-50 33-50 >50

Kollidon SR 33-50 >50 33-50 33-50 >50

Kollicoat MAE 100P 33-50 >50 33-50 >50 n.d.

Evaporates were prepared with 10, 25, 33 and 50% drug content

Glass Transition Temperatures of Polymers

39

57

114

156149

138

90

101

0

20

40

60

80

100

120

140

160

180

Kollido

n VA 64

Kollido

n 12P

F

Kollido

n 17P

F

Kollido

n 30

Kollido

n 90F

Kollido

n SR

Kollico

at MAE

Lutro

l F12

7

T g /

T m [°

C]

Tg [°C] Tm [°C]

152

39

Kollidon 12 PF

Kollidon VA 64

Kollidon SR

Kollicoat MAE

Kollidon 30

100

1000

10000

100000

1000000

120 140 160 180 200 220 240

Temperature [°C]

Visc

osity

[Pa

· s] Kollidon 12 PF

Kollidon SR

Kollicoat MAE

Kollidon VA 64

Kollidon 30

Melt Viscosity as a Function of Temperature

Kollidon 17 PF

Glass transition temperature (Tg)

Melt viscosity

Solubilization capacity

Processability Physical stability

of formulation

Chemical stability

of formulation

Plasticizer

Hygroscopicity

Non-saturated solutions allow more freedom for formulation super-saturated solutions require a very rigid matrix

Impact of Polymer Characteristics

Strategy for Formulation Development

Keep the formulation (and process) as simple as possible

Choose the appropriate polymer

+

+

For improved processability

For improved drug content and prevention of crystallization in gastric and intestinal fluid

Active + Polymer

Plasticizer

Solubilizer

Thermal Stability of Kollidon VA 64

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1,000 10,000 100,000 1,000,000 10,000,000

M/Da

w(lo

g(M

))

Kollidon VA 64 LOT 76964875L0extruded 160°C

Kollidon VA 64 LOT 76964875L0

SEC

Polymer Stability During Extrusion

Test parameter Requirements Results powder Results extrudate

Vinyl acetate [mg/kg] max. 10 <10 <10

2-Pyrrolidone [g/100g] 0,5 0.06 0.06

Saponification value [mg KOH/g] 230-270 237 246

pH-value [10% in solution] min. 3.0 max. 7.0 4.1 4.1

Vinyl pyrrolidone [mg/kg] <2 <2 max. 10

<10 <10 Acetaldehyde [m/kg] max. 500

Peroxide [400 mg/kg] <20 <20 max. 400

K-value [1% aqueous solution] 26.6 min. 25.2 max. 30.8 27.0

I: Solid solution

II: Solubilized drug

Drug complexation

Hydrophilic element Lipophilic element

Active

Gastric fluid

Tablet Gastrointestinal tract

Soluplus® – The solid solution

Soluplus® enables dissolution of drugs at extremely high concentrations

21

Soluplus® – The solid solution

22

PEG 6000 / vinylcaprolactam / vinyl acetate (13/57/30)

Appearance White to yellowish free flowing granules

Critical micelle concentration (CMC) 7.6 mg/L

Glass transition temperature ~ 70°C

Molecular weight ~ 118,000 daltons O

O

OH

O

OH

OO

*N

O

n m l

The first polymeric solubilizer

More than 1000 polymers were synthesized and tested to find the optimal structure

Honored with Silver Award:

5/10/2012 23

Solubility in organic solvents: clear solutions

Soluplus® is soluble in many organic solvents!

0

10

20

30

40

50

60Concentration of Soluplus® [%]

EtOH/ Aceton

(1:1 m/m)

MeOH/ Aceton

(1:1 m/m)

Methanol DMF Ethanol Aceton

Solid solution capacity

24

Increasing drug concentration (w/w-%)

25 % 30 % 35 % 40 % 45 % 50 %

Soluplus® takes up more in a solid state than any other material

Extrusion Studies

Extrusion lead to amorphous extrudates (XRD) in all cases

Soluplus® – The Solid Solution

Extrusion parameters 16mm ThermoFisher Polylab, 40D 200 rpm 1 kg/h mean residence time ~1 min

Polymer Itraconazole (15 % API)

Fenofibrate (20 % API)

Carbamazepine (15 % API)

Soluplus® 150 100 140

Extrusion temperature [°C]

Drug release – Soluplus® / Itraconazole

26

Time [min]

Antifungal drug

Soluplus® outperforms all other polymers

Crystalline itraconazole

USP apparatus 2 (paddle model), 50rpm, 700mL simulated gastric fluid, granulated extrudates, 100mg itraconazole

Drug release [%]

Soluplus®

0

150

300

450

600

750

0 10 20 30 40 50 60 70 80Time [hours]

27

Itraconazole

Bioavailability of Soluplus® extrudate: 26-fold compared to crystalline drug 2.3-fold compared to Sempera®

Bioavailability studies with Soluplus® formulations

The Soluplus® formulation outperforms the registered drug Sempera® by a factor of 2.3

Itraconazole – Soluplus®

extrudate Sempera® Itraconazole crystalline

Bioavailability = area under the curve (AUC) Plasma level [ng/mL]

Beagle Dogs, dose: 30 mg / kg bw Danazol

0,0

200,0

400,0

600,0

800,0

1000,0

1200,0

1400,0

0 5 10 15 20t [h]

bloo

d co

ncen

tratio

n [n

g/m

l]

crystalline danazolphysical mixture danazolsolid solution danazol

Soluplus® – The Solid Solution

Bioavailability Studies - Danazol

Beagle Dogs, dose: 10 mg / kg bw Fenofibrate

0

1000

2000

3000

4000

5000

6000

0 5 10 15 20

t [h]

bloo

d co

ncen

tratio

n [n

g/m

L]

solid solution fenofibratecrystalline fenofibratephysical mixture fenofibrate

Soluplus® – The Solid Solution

Bioavailability Studies - Fenofibrate

The challenge is increasing

Solid solutions / solid dispersions offer hope

Melt Extusion, Spray drying are main technologies

Choice of an appropriate polymer is crucial for the formulation and the process

Most important polymer features are Tg and melt viscosity Solubilization capacity Stability Toxicity/regulatory status

Kollidon VA 64 is the current polymer gold standard for melt extrusion (IIG 854 mg)

Soluplus is a novel excipient showing excellent extrusion and spray drying characteristics and tremendously enhances bioavailability of drugs

Summary

Meeting Formulation Challenges For Poorly Soluble Drugs