Case Study 3:

NCE bioavailability enhancement using a SMEDDS formulation

Objectives

Company B (undisclosed) engaged Tillotts Services for the development of a lipid based oral formulation with the objective of improving the oral bioavailability of their active “Compound X”.

Class IHigh Solubility

High Permeability5%

Class IILow Solubility

High Permeability70%

Hig

hPe

rmea

bilit

y

High Solubility Low Solubility

Low

Perm

eabi

lity

Formulation

Class IIIHigh Solubility

Low Permeability5%

Class IVLow Solubility

Low Permeability20%

Figure 1. Biopharmaceutical Classification System

Background

Today around 70% of new chemical entities entering drug discovery and development programs exhibit poor aqueous solubility and high lipophilicity. These are classified as Class II compounds according to the Biopharmaceutical Classification System (Figure I). In such cases, the development of a lipid self dispersing formulation is driven by the desire to increase, and/or make reproducible, the oral bioavailability of these molecules. Compound X is a small molecule (M <600) with a low aqueous solubility in acidic media (0.1 M HCl), and in media with more physiological pH’s (up to ca. pH 7.2). Since the lipophilicity of the active is rather high with a CLogP>3, it is classified as a Class II compound.

r

Formulation Development Strategy

The formulation development strategy was agreed with our customer in order to deliver a superior and stable drug product with increased oral bioavailability, this included:

Development of Self Micro-emulsifying Drug Delivery Systems (SMEDDS)

Solubility in excipients with different hydrophobic lipophilic balance (HLB) values

Microemulsion development (pseudo ternary phase diagrams)

Dispersion/Precipitation tests in aqueous media

In vitro dissolution of hard gelatine capsules

Dissolution Parameters

500 ml media, paddle method, 75 rpm, 37°C, 6 hours

Media: Fasted State Simulated Intestinal Fluid (FaSSIF)

Formulation tested

Conventional capsules (powder filled)

Oily formulation capsules

SMEDDS capsules

In vivo Pharmacokinetic (PK) study in beagle dogs

Results and Discussion

Table 1 summarises the kinetic solubility of Compound X in a set of galenical excipients having different HLB values. While the solubility of the active in co-solvents was rather low, the compound showed high solubility in oily excipients as well as in most of the non-ionic surfactants investigated. Based on these results, three lipid formulations were developed for the compound; one as a pure oily formulation (active dissolved in an oil) and two as SMEDDS that were developed using pseudo ternary phase diagrams. The dissolution of these formulations were investigated in vitro using fasted state simulated intestinal fluid (FaSSIF) as biorelevant media. FaSSIF was selected due to a previous finding indicating that conventional oral forms of the active did show lower oral exposure in fasted vs. fed state in the dog. This result was hypothetically attributed to the low solubility of the compound as well as the solubilising properties of the mixed micelles formed after digestion of lipids in fed state.

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Table 1. Solubility of Compound X in galenical excipients

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Excipient

PEG 400

Ethanol

Sesame oil

Labrafac lipophyle WL 1349

Labrafac PG

Labrafil M-1944 CS

Labrafil M-2125 CS

Lauroglycol FCC

Lauroglycol 90

Plurol oleique CC

Labrasol

Gelucire 44/14

Solutol HS 15

Cremophor EL

Tween 80

Cremophor RH 40

Chemical denomination

Polyethylene glycol 400

EtOH

Sesame oil

Medium chain triglycerides-MCT

Propylene glycol dicaprylocaprate

Oleoyl polyoxylglycerides

Linoleoyl polyoxylglycerides

Propylene glycol monolaurate (Type I)

Propylene glycol monolaurate (Type II)

Polyglyceryl-3 dioleate

Caprylocaproyl polyoxyglycerides

Lauroyl polyoxyglycerides

Macrogol 15 Hydroxystearate

Polyethylene glycol-35 castor oil

Polyoxyethylene sorbitan monoleate

PEG-40 Hydrogenated Castor Oil

Type

Co-solvent

Co-solvent

Oil

Oil

Oil

Co-surfactant

Co-surfactant

Co-Surfactant

Co-Surfactant

Co-surfactant

Surfactant

Surfactant

Surfactant

Surfactant

Surfactant

Surfactant

H.L.B

-

-

1 - 2

1

2

4

4

5

5

6

14

14

14

14

15

14-16

Solubility

S < 25

S < 10

S > 100

S > 100

50 > S > 25

S > 100

S > 100

50 > S > 25

50 > S > 25

100 > S > 50

S > 100

S > 100

S > 100

S > 100

100 > S > 50

S > 100

(mg/mL)

Figure 2 represents the in vitro dissolution behaviour of the lipid based formulations as well as conventional solid form capsules (control) of Compound X. An erratic release was observed with the conventional capsules probably due to the low intrinsic aqueous solubility of the active. An improved dissolution profile was observed with the simple oily solution. This may have been driven by an in situ emulsification and solubilisation process by the sodium taurocholate and lecithin from the media together with the oily excipient of the formulation. However, it only led to 20% of dissolved compound and a trend to precipitation was observed over time. The most promising results were obtained with the SMEDDS formulations 1 and 2, respectively. In the case of the SMEDDS-1, almost 100% of the active was kept dissolved along the dissolution test. The PK results obtained after the oral administration to fasted dogs of either conventional capsules or capsules containing the SMEDDS-1 are summarized in Figure 3. More than two fold increase in Cmax and the same for the overall oral exposure was observed in the dogs that were dosed with the SMEDDS-1. These results perfectly correlate with the in vitro findings suggesting that the improved solubility may have led to the improved oral exposure in vivo.

Conclusions

The SMEDDS developed showed a significant increase of dissolution of the active in a bio-relevant media (FaSSIF).

Two fold increase of oral exposure was observed in dogs with SMEDDS-1 capsules.

Long term physical and chemical stability of the lipid based formulations under investigation.

% D

isso

lved

0 1 2 3 4 5 6Time (hours)

010

20

30

40

50

60

70

80

90

100

Pure Oil-caps Conventional caps

SMEDDS 2-capsSMEDDS 1-caps

0

5

10

15

20

25

Plas

ma

conc

entr

atio

n (n

g/m

L) (i

n 00

0’s)

SMEDDS-capsules

Conventional caps (Powder)

0 5 10 15 20 25 30Time (hours)

% D

isso

lved

0 1 2 3 4 5 6Time (hours)

010

20

30

40

50

60

70

80

90

100

Pure Oil-caps Conventional caps

SMEDDS 2-capsSMEDDS 1-caps

0

5

10

15

20

25

Plas

ma

conc

entr

atio

n (n

g/m

L) (i

n 00

0’s)

SMEDDS-capsules

Conventional caps (Powder)

0 5 10 15 20 25 30Time (hours)

Figure 2. in vitro dissolution behaviour Figure 3. Oral PK Results

For further information on how Tillotts Services can help with your formulation development options, clinical drug product supply or commercial liquid-fill manufacture, please contact us at: E: services@tillotts.com or W: www.tillotts.com

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w.tillotts.com

Copyright © Tillotts Pharma AG 2012