Oral Formulations for Poorly Water Soluble Compounds schwerloesliche Wirkstoffe.pdf · Oral...

Oral Formulations for Poorly Water Soluble Compounds

SAQ - Fachgruppe Pharma & ChemieOskar Kalb, Novartis Pharma AG BaselOlten, 23. June 2009

2 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009

Oral Delivery of Poorly Water Soluble Compounds

For systemic activity of an API molecule after oral administration it must be absorbed from the intestine and reach the bloodstream / the site of action

from. P. D. Ward et.al. Pharmaceutical Sciences and Technology Today Vol. 3, No.10 Oct. 2000

Passive diffusion is the most dominant mechanism of drug absorption from the intestinal lumen (GIT)


Oral Delivery of Poorly Water Soluble Compounds

With a few exceptions, molecular dispersion of a drug is a prerequisite for its absorption across biological membrans

Tablet Powder Solution

Systemic circulation

Disintegration Dissolution Absorption

This implies that the dissolution of a poorly water soluble drug can become the rate limiting step for the onset of drug levels in the blood (if absorption is reasonable fast) Negative impact on Oral Bioavailability

This dictates that after oral administration the drug has to dissolve in the gastrointestinal fluid before partitioning into and across the enterocyte


Drug Dissolution – Noyes Whitney

dx/dt Dissolution rateA Interfacial surface areaD Diffusion coefficienth Thickness of diffusion layerXd Amount of drug dissolvedCs Saturation solubilityV Volume of dissolution medium

Key parameter that influence dissolution rate• Solubility of the API

- Polymorph, pKa, Gastro-intestinal pH, Buffer Capacity of the GIT

• Surface area (A)- Particle size, wetting properties

Physico-chemical properties of the API AND the physiological state of the GIT can have a significant impact on the in-vivo dissolution of the drug


Dose and Dose number (D0)

Solubility and Dose always have to be considered together

Do = Mo/VoCs

Mo = dose administered (mg)Vo = 250 ml (reference volume of human stomach, FDA-approach)Cs = solubility (mg/ml)

Remarks:• Do = > 20 at pharmacological doses -> already critical• In practice, Do values often between 20 and 100 for pharmacological and human doses.

• For TOX doses, Do up to 1000 and more are frequent …!


Absolute bioavailability vs. variability

From Hellriegel E.T et al. Clin. Phamacol. Ther. 1996; 60: 601-607.

Inverse relationship between the absolute bioavailability (F) of an oral dosage form and it‘s total intersubject variability (CV).

To lower the variability means for a formulation scientist in To lower the variability means for a formulation scientist in most cases to improve the bioavailability in the fasted statemost cases to improve the bioavailability in the fasted state


Biopharmaceutical Classification Scheme

Class IILow solubHigh perm

Class IHigh solubHigh perm

Class IIIHigh solubLow perm

Class IVLow solubLow perm

Class II Class I

Class IIIClass IV

Formulation

Limited formulation influence

Solubility and Permeability are key determinant of oral bioavailability Biopharmaceutical Classification System


Use of Drug Delivery Systems in Major Pharmaceutical Companies

47%

18% 16%11%

8%0%

10%

20%

30%

40%

50%

Ora

l

Pare

nter

al

Inha

latio

n

Tran

sder

mal

Oth

er

Source: Kermani, F., et.al., Drug Delivery Technology, Oct. 2001

Dis

tribu

tion

with

rega

rd to

ro

ute

of a

dmin

istra

tion


Approaches to improve Solubility, Dissolution of poorly water soluble APIs and decrease Variability

1. Physical modifications• Particle size reduction

(Nanosuspensions, micronization)• Dispersion of drug in a polymer matrix

(Solid Dispersions, solid solutions)• Polymorphs / Pseudopolymorphs• Complexation / Solubilization

2. Lipid-based systems• e.g. Microemulsions (SMEDDS)


Examples

Impact of a particle size reduction on dissolution and oral bioavailability of a poorly water soluble drug

Nanosuspenions


I. Nanosuspensions

Technology• Downstream Process (e.g. Milling)• Up-stream Process (e.g. Precipitation)• Drying of nanosuspension Solid Dosage Form

Working principleIncreased dissolution rate by reducing particle size to the nanometer range (and thereby increasing the surface area)

Noyes Whitney (modified)


I. Nanosuspensions

Nanosizing• Most prominent manufacturing technology

(e.g. NanoCrystal® wet milling technology by Elan)

Ref. E. Merisko-Liversidge et.al. Eur. J. Pharm.Sci. 18 (2003), 113-120

Particle size distribution of Naproxen crystals before milling (triangle, mean 24.2 um) and after milling (circle 0.147 um)

• Addition of stabilizers (polymers, surfactants) to prevent agglomeration of nanosized particles


I. NanosuspensionsImpact of particle size reduction on dissolution rate

Example: Cilostazol (BCS II)

Particle size (median)- Hammer-milled (□) 13 μm- Jet-milled (◊) 2.4 μm- NanoCrystal (∆) 0.2 μm

Dissolution rate testing- water 37°C, 900ml- 50rpm, USP apparatus 2- 5 mg cilostazol

Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64

Dissolution rate of Cilostazol from a suspension is clearly increased by a reduction of the drug substance particle size


I. NanosuspensionsPharmacokinetic of Cilostazol suspensions in fasted and fed beagle dogs

Major increase in bioavailability with minimal food effect observed for the Cilostazol nanosuspension (NanoCrystal®)

D

Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64

Serum concentration vs. time after oral administration of cilostazol suspensions (100mg/body) in fasted (open) and fed (closed) beagle dogs (n=4) (mean; SD)

(C) Hammer-milled (□)

(B) Jet-milled (◊)

(A) NanoCrystal (∆)


Examples

Impact of a formulation parameter on oral bioavailability of a poorly soluble compound

Solid dispersion


II. Solid Dispersions

DefinitionA poorly water soluble drug that is highly dispersed and stabilized in a hydrophilic carrier

Working principle• „Ultimate“ particle size reduction • No crystal structure• Hydrophilic carrier

improved wetting of the drugimproved wetting of the druginhibits recrystalization/precipitationinhibits recrystalization/precipitation of supersaturated solutionof supersaturated solution

• Surfactant (optional)increase solubilization of the drugincrease solubilization of the drug


Solvent evaporation

Melting

II. Solid DispersionsOral Absorption of Poorly Water Soluble Drugs

Solid Dispersions

Melt-extrusion

NOT bioavailable

Organic Solution

Bioavailable


II. Solid Dispersions In-vitro dissolution rate and in-vivo pharmacokinetic data of NVS02 (BCSII)

Dissolution rateWater, 0.1% SDS(20mg NVS02)

- Crystaline drug - Amorphous drug- Solid Dispersion- Solid Dispersion with 10% SDS

Same rank order of tested formulations in in-vitro dissolution rate and in-vivo plasma level curves

Fasted dogs, 20mg/animal (n=8)


II. Solid Dispersions Impact of surfactant on pharmacokinetic of NVS02 (BCSII)

30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)

Who

le blo

od co

ncen

tratio

n (ng

/mL)

-10

0

10

20

30

40

50

60

70

80

90

100

Time post-dose (h)0 12 24 36 48 60 72

SD with 10% surfactantSD without surfactant

30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)

Who

le blo

od co

ncen

tratio

n (ng

/mL)

-10

0

10

20

30

40

50

60

70

80

90

100

Time post-dose (h)0 12 24 36 48 60 72

SD with 10% surfactantSD without surfactant

The formulation containing a surfactant showed a higher and less variable absorption of the drug from the GIT

47

51

CV %CV %

1.0

1.5

ttmaxmax

23

36

CV %CV %

72 (16)296 (130)+10% Polox.

28 (9)214 (97)- Polox.

CCmaxmaxAUC AUC 00--∞∞[ng h/ml][ng h/ml]

SolidSolidDispersionDispersion

Arithmetic mean ± SD whole blood concentration of NVS02 following administration of 30 mg tablets in healthy volunteers (n=18)


II. Solid Dispersions Physical and chemical stability

time (years)

0

20

40

60

80

100

0 1 2 3 4

%

chemical degradation

physical stability of amorphous state

time (years)

0

20

40

60

80

100

0 1 2 3 4

%



0

20

40

60

80

100

0 1 2 3 4

%



RISK: Recrystalization of amorphous drug during storage


II. Solid DispersionsPharmacokinetics of NVS02 solid dispersions (with diff. % of crystalline DS)

Data indicate that exposure is significantly reduced when drug Data indicate that exposure is significantly reduced when drug crystalizes out during storage of the solid dispersioncrystalizes out during storage of the solid dispersion

0

2

4

6

8

1 0

1 2

1 4

0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )

NK

P608

pla

sma

conc

entr

atio

n in

ng/m

LH HG GE E

SD-tablet, 100% amorphous drugSD-tablet, 70% amorphous drugSD-tablet, 50% amorphous drug

NVS

02 p

lasm

a co

ncen

trat

ion

in

ng/m

l

0

2

4

6

8

1 0

1 2

1 4

0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )

NK

P608

pla

sma

conc

entr

atio

n in

ng/m

LH HG GE E


0

2

4

6

8

1 0

1 2

1 4

0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )

NK

P608

pla

sma

conc

entr

atio

n in

ng/m

LH HG GE E


NVS

02 p

lasm

a co

ncen

trat

ion

in

ng/m

l

Single dose, 3-arms, crossover study in fasted dogs (n=9)

Physical stability can cause significant variability in pharmacoPhysical stability can cause significant variability in pharmacokinetics kinetics of solid dispersionsof solid dispersions


Example

Formulation approach for a lipophilic, poorly water soluble drug

Microemulsion


III. Lipid based formulationsEnhancement of oral absorption of poorly water soluble drugs (PWSD)

Fig from Porter CJH et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007, 231-248

3. Interacting with enterocyte-based transport and metabolic processes

2. Affecting absorption pathway of drug transport to the systemic circulation

1. Increasing solubilizationand drug disposition in the intestinal lumen

SOLUBILIZATION

permeation


III. Lipid based formulationsIncreasing solubilization and drug disposition in the intestinal lumen


Increase solubilization capacity for lipid digestion products and drugs in the small intestine

Formation of colloidal structures with endogenous bilary lipids

Digestion of exogenous lipidsby pancreatic enzymes (lipase, co-lipase) TG DG MG + FA


III. Lipid based formulationsIn-vivo performance


Risk: Precipitation on Dispersion of the formulation

Risk: Precipitation on Digestion of the formulation

Lipid-based formulations must maintain drug in solution in the GIT

to enhance oral bioavailability


III. Lipid based systems Micellular systems, Microemulsions, Emulsions

20 – 150 nm(< 200 nm)

Up to a few µm

Micelle (o/w) Microemulsion (o/w):

Thermodynamically stable

Translucent, isotropic

Emulsion (o/w):

Thermodynamically unstable

Milky apperance


III. Lipid based systems: Microemulsions: Phase diagram screening – Potential formulations

Surfactant

Lipophilicphase

Hydrophilic phase

I00%

90 10

80 20

70 30

60 40

50 50

40 60

30 70

20 80

10 90

I00% 90 80 70 60 50 40 30 20 10I00%

Undiluted Preconcentrate

Diluted

•Clear, homogenousformulation

•No precipitation with a reasonable drug loading

•Self-dispersing•Stable and no precipitationin physiological relevant time frame


Solubilisation

Organic or lipid-based solutions

III. Lipid based SystemsOral Absorption of Poorly Water Soluble Drugs

Microemulsion

Filling

Encapsulation

NOT bioavailable

Bioavailable


In-situ formation of the microemulsion

Soft gel capsule filledwith microemulsion preconcentrate

Water

III. Lipid based formulationsFrom Preconcentrate to the Microemulsion


III. Lipid-based formulationsCyclosporine A

Cyclic petide (containing 11 aminoacids)

Lipophilic, low aqueous solubility (< 0.004% w/v)

Higher solubility in lipids (olive oil >4%) and ethanol (~10%)

Cyclosporine A


III. Lipid based formulationsCyclosporine vs. Sandimmun ® vs. Sandimmun Neoral ®

Prior to dilution with water

Diluted with water

Cyclosporine drug substance

Sandimmun® SandimmunNeoral®


III. Lipid based formulationsSandimmun ® vs. Sandimmune Neoral ® - Pharmacokinetic data

• Sandimmun®: Adsorption is dependent on digestion of the lipid-formulation solubilization depends on individual physiological state in the GIT (e.g. food

intake, bile flow) high inter- and intra-subject variability

Concentration-time profiles following single oral administration of 300 mgSandimmun® to 24 volunteers

J.M. Kovarik et al., Journal of Pharmaceutical Sciences, 83 (3), 1994

0

200

400

600

800

1000

1200

1400

1600

0 2 4 6 8Time (h)

Con

cent

ratio

n (n

g/m

l) Sandimmun®

0

200

400

600

800

1000

1200

1400

1600

0.0 2.0 4.0 6.0 8.0Time (h)

Con

cent

ratio

n (n

g/m

l)

Concentration-time profiles following single oral administration of 180 mgSandimmun Neoral® to 24 volunteers

Sandimmun Neoral®

• Sandimmun Neoral®: Spontaneous formation of the microemulsion in the GIT without the need of endogenous compounds like bile salts / phospholipids

significant reduction of dose as well as inter-, and intra-subject variability


III. Lipid based formulationsLipid digestion models for in-vitro assessment lipid-based formulations

Sek L et al. , J. Pharm. Pharmacol., 2002, 54:29-41Porter CJH et al. , Nature Reviews | Drug Discovery, 2007, 6:231-248

Undispersed oil phasecontaining drug (D)

Aqueous phasecontaining drug solubilized in micellarand vesicular structures,

Pellet phasecontaining precipitated drug and insoluble (calcium) soaps of FA


III. Lipid based formulationsIn vitro digestion test to evaluate solubilization pattern after digestion

0

200

400

600

800

1000

1200

1400

1600

0 2 4 6 8Time (h)

Con

cent

ratio

n (n

g/m

l)

0

200

400

600

800

1000

1200

1400

1600

0.0 2.0 4.0 6.0 8.0Time (h)

Con

cent

ratio

n (n

g/m

l)

Sandimmun Neoral®Sandimmun®

0

10

20

30

40

50

60

70

80

90

100

% in aqueous phase % in pellet phase

Digestion phases%

mod

el P

WSD

FastedFed

Digestion phases

0

10

20

30

40

50

60

70

80

90

100

% in undigested phase % in aqueous phase % in pellet phase

% m

odel

PWS

D

FastedFed

Similar solubilization pattern in Similar solubilization pattern in fasted and fed statefasted and fed state

Digestion needed to release and Digestion needed to release and maintain drug in the aequous solutionmaintain drug in the aequous solution

Ref: Taillardat A. et al. Am. Pharm Rev 2007 10(6):40-46


Examples

Improved oral bioavailability of a weakly basic drug

pH-modified Formulations


IV. pH-modified FormulationsImproved bioavailability of weakly basic drugs by modulating the micro-pH

Gastrointestinal pH is influenced by several factors (e.g. food, age) intra-, intersubject variability

Stomach (fasted): pH 1-2

Intestine (fasted): pH 5-6

pH-modified Formulation: Incorporation of acids to improve dissolution of weakly basic drugs

pH2 3 4 5 6 7 8

Dip

yrid

amol

e so

lubi

lity

[mg/

ml]

0

10

20

30

40N

N

N

NN

N N

N

CH2OH

CH2OH

CH2OH

CH2OH

Dipyridamole:Solubility pH=2.72 36.64 mg/ml

pH=6.80 0.0031 mg/ml


0 60 120 180 240 300 3600

20

40

60

80

100 FA CA SA AA no acid

Dru

g re

leas

e [%

]

Time [min]

28.611.64.2Ascorbic acid (AA)

7.75.64.2Succinic acid (SA)

59.26.44.83.1Citric acid(CA)

0.614.43.0Fumaric acid (FA)

SolubilitypKa3pKa2pKa1Acid type

28.611.64.2Ascorbic acid (AA)

7.75.64.2Succinic acid (SA)

59.26.44.83.1Citric acid(CA)

0.614.43.0Fumaric acid (FA)

SolubilitypKa3pKa2pKa1Acid type

Acidic strength and solubility of the acids have an impact on drug release

(Ref. Siepe S. et.al. PhD-thesis 2005)

Dissolution in phosphate buffer pH 6.8, SDS 0.1%

IV. pH-modified FormulationsEffect of different pH-modifier (20%) on release rate of Dypyridamol tablets

Fumaric acid selected due to most favourable phys.-chem. properties


Optimal drug to pH-modifier ratio (1:1)

Monolytic tablet (d=10mm) Minitablets (d=2mm)

0 60 120 180 240 300 3600

20

40

60

80

100

Dru

g re

leas

e [%

]

Time [min]

FA 20% FA 40% Without acid

0 30 60 90 120 150 1800

20

40

60

80

100

Dru

g re

leas

e [%

]

Time [min]

Without acid FA 20%

0 1 2 3 4 5 6 70

20

40

60

80

Solu

bilit

y [g

/l]

pH

Solubility profile NVS05

Dissolution rate: minitablets > monolytic tablets


IV. pH-modified FormulationsDissolution rate of NVS05 (20%) pH-modified tablets (monolytic-, mini-tablets)

Dissolution rate in phosphate buffer pH 6.8, SDS 0.1%


IV. pH modified FormulationsIn-vivo study in fasted, gastric-acidity controlled beagle dogs (n=6)

Plasma level

A A-FA B B-FA0

20

40

60

80

100

CV

[%]

Formulation

Minitab

lets w

ith F

A

Minitab

lets w

ithou

t FA

Table

ts with

FA

Tablet

s with

out F

A

A A-FA B B-FA0

20

40

60

80

100

CV

[%]

Formulation

Minitab

lets w

ith F

A

Minitab

lets w

ithou

t FA

Table

ts with

FA

Tablet

s with

out F

A

AUC0-24h Variability

The incorporation of an acidic ph-modifier improved oral bioavailability of a weakly basic drug (exposure, variability)

0 2 4 6 8 10 12 140

50

100

150

200

250

300

NV

R1

plas

ma

conc

entra

tion

[ng/

ml]

Time [h]

Tablet without FA Tablets with FA Minitablet without FA Minitablet with FA

NV

S5

Intersubject variability of multiparticulates < monolytic tablet



Several formulation approaches are available to improve the dissolution rate of poorly water soluble compoundsTo identify the most appropriate formulation principles the drug substance properties, the pharmacological dose (range) and physiological state have to be considered In-vitro and in-silico tools should be fully utilized to select the most appropriate technology / formulation variantToday in-vivo studies for a final proof of concept are still needed

Summary


Dieter BeckerJean CuineAnke DiederichBruno GalliMichael JuhnkeMartin Mueller-ZsigmondyStefanie SiepeAgnes TaillardatCarsten Timpe

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