Figure 1 CCK –gastrin antagonists.

Figure 2 Chemical structure of CCK2 gastrin antagonist PNB-001, a potent anti-inflammatory analgesic.

Figure 3 Docking of CCK antagonist PNB-001 into the CCK2 receptor.

Figure 4 Dose range of PNB-001 in the tail immersion test by PO administration using rats.

Figure 5 5a. PK analysis of PNB-001 in rats by oral administration. 5b. Linear pharmacokinetics of PNB001 in rats in the active dose range.

Figure 6PNB001 50 mg tablets versus 50 mg capsules.

Figure 7 Dissolution profiles of the two formulations under investigation formulated into tablet or capsule solid forms dissolved in either de-ionised water or phosphate buffer (pH 6.8) media.

Figure 8 Responses to CCK-5 in the absence and presence of PNB-001, using the rat duodenum assay; CCK-5, CCK-5 +10 nM PNB-001, CCK-5 +30 nMPNB-001, CCK-5 + 100 nM PNB-001; N = 2 for each data point.

Figure 9 The inhibitory concentration-response curves of PNB-001 and L-365,260 (standard) for DSS stimulated contractions using the rat duodenum.

Lactam

X=

R=

CCK1
[mM]

CCK2
[mM]

PNB-001

H

Phenylethyl-

>10

0.022±0.002

Lorglumide

0.17±0.01

>10

L-356,260

0.25±0.01

0.003±0.001

Table1 CCK binding affinity expressed in IC50 in micromolar using iodinated hot CCK8 as radioligands with cortex and pancreatic membranes; N=3.

Material

Function

F1(g)

F2(g)

PNB001

Drug

1.6

1.6

Crospovidone

Disintegrant

Corn Starch

Disintegrant/
binder

Wheat Starch

Disintegrant/
binder

4.32

4.32

Icing Sugar

Diluent

5.616

4.32

 

Diluent/
binder

4.32

5.616

 

Lubricant

0.144

0.144

Table2 Various placebo batches and test formulations (F1 and F2) under investigation.

Product

Disintegration (min)

Formulation 1

42.1 ± 2.8

Formulation 2

 12.2 ± 0.4

Table3 Disintegration times of various placebo batches and test formulations under investigation (mean ± SD, n = 3).

Formulation

Dosage form

Dissolution medium

DE (%)

MDT (min)

MDR (%min-1)

f2

Formulation 1

Tablet

Water

4.65±0.79

1.64±0.07

2.14±0.79

76.2

Buffer

6.95±0.34

0.58±0.08

4.00±0.07

Capsule

Water

3.47±0.56

0.87±0.12

2.29±0.74

91.6

Buffer

2.88±0.96

1.63±0.41

1.17±0.34

Formulation 2

Tablet

Water

8.32±0.43

1.19±0.11

4.46±0.41

86.1

Buffer

7.38±0.26

0.39±0.12

4.40±0.05

Capsule

Water

2.15±0.62

1.49±0.28

0.95±0.28

91.1

Buffer

3.17±0.51

1.71±0.30

1.34±0.05

Table4 Dissolution efficiency (DE), mean dissolution time (MDT) and mean dissolution rate (MDR) (mean ± SD, n = 3) for the two formulations under investigation formulated in a tablet or capsule solid form dissolved in either water or buffer (pH 6.8) media.