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Kytogenics Pharmaceuticals, Inc.

Kytogenics Drug Delivery

TIJO Platform

Based on preliminary early results from our pre-clinical studies another major area of interest for Kytogenics is the development of unique drug delivery systems based on the TIJO technology.

Interstitial Cystitis

Kytogenics is using the TIJO Technology as a component in formulations for urinary tract and gastrointestinal disorders which can be treated by the instillation of TIJO. An anti-inflammatory drug has also been incorporated in the TIJO formulations. The Interstitial Cystitis product is a sterile formulation comprising TIJO polymer with the anti-inflammatory agent 5ASA in a 50 ml container. The product is constituted with water and instilled into the bladder. Pre-clinical data in rats, for Interstitial Cystitis showed very promising results, with up to a 75% improvement over the control. Specifically, five measures of inflammation were investigated, blood vessel vasodilation, edema, cell infiltration, epithelial damage and TNF release. The improvement on these five measures when using a 3% TIJO formulation was as high as 58%, 77%, 88%, 88%, and 76% respectively.

A second experiment was performed to determine the effect of the S-NOCC + 5ASA treatment on the disease itself with the disease parameter chosen being urinary frequency.  All animals (non-treated controls as well as treated) were placed in metabolic cages overnight which were equipped with a screen floor and a urine collection device.  Continuous recording of the weight of the urine collection allowed identification of timing and volume of each void.  Figure 1 is a histogram of the level of disease in the treated vs. non-treated animals.  An improvement of over 70% was obtained in the reduction of urinary frequency.

Figure 1

Resolution of Urinary Frequency In a Rat Model of Interstitial
Cystitis
Kytogenics Urinary figure

Inflammatory Bowel Disease (IBD)

Trinitrobenzenesulfonic acid was used to produce a rat inflammatory IBD model which was reliable and reproducible.   The same formulation (3% SNOCC + 5ASA) that was used in IC  was also  used to treat IBD and was compared to a control group that did not receive any treatment agent and to Rowasa which is a commercially available product currently widely used as a therapeutic treatment of IBD in the USA.  In this pilot study, the effect of the treatments on the median lesion size and percentage of animals with severe lesions were determined.  The results are shown in Figure 2 and it is obvious that the sNOCC formulation gave substantially better results than the untreated control and it was 100% better than the Rowasa commercial product.

Figure 2

Reduction in Median  Lesion Size in a Rat Model of Inflammatory
Bowel Disease
Kytogenics Lesion Size

Oral Delivery of Peptides and Proteins

The delivery of proteins and peptides by oral administration has been considered the "Holy Grail" of drug delivery for a number of years. The very limited bioavailability of proteins and peptides is due to the extremely low permeability of these materials across the mucosal epithelia that line the intestinal tract. The intestinal epithelium is characterized by 'tight junctions' between the individual cells of the lining. For a number of years, researchers have been evaluating different compounds for their ability to open the tight junctions and allow hydrophilic compounds such as proteins to permeate the epithelial barrier and enter the blood stream. Such compounds have been labeled as permeability enhancers.

Kytogenics has collaborated with the Center for Drug Research at Leiden University and Dalhousie University to evaluate NOCC and its derivatives to enhance the delivery of peptides, proteins and other drugs (i.e. hydrophilic macromolecules) across mucosal epithelia.

Intestinal and nasal mucosa are characterized by a lining of epithelial cells having its "tight junctions" that physiologically connect the enterocytes apically. TIJO and TIJO derivatives were employed to disrupt or open these tight junctions and, thereby, allow hydrophilic macromolecules to permeate through the epithelial barrier and be absorbed systemically. Permeation involved a paracellular pathway not an intracellular pathway. Initially, a number of derivatives of TIJO and TIJO itself were screened for their ability to "open" the tight junctions between differentiated epithelial cells that had formed a continuous layer in an in-vitro model. It was found that their low molecular weight modified TIJO derivatives were the most effective. The same in-vitro model was then used to study the influence of modified TIJO on the permeation of a sugar, a 4000 molecular weight dextran and heparin. The effectiveness of modified TIJO was comparable to or exceeded that of the positive controls (which were compounds described in published reports as being effective permeation enhancers).

The permeability of a low molecular weight heparin (blood thinner) was also studied in vivo following implantation of a mixture of heparin and TIJO into the intestinal tract of rats. The level of heparin found in collected blood samples well exceeded the therapeutic dosage for the six hour duration of the experiment. Both formulations of the TIJO technologies that were used increased the absorption of the LMWH above the ant-thrombotic level (0.2 Anti-XaU/ml). The LMWH values were between 2.5 and 4.5 Anti-XaU/ml throughout the six hour experiment. In addition, the enhancement ratio (measured from the total amount of drug delivered from the permeation enhancer into the blood compared to a buffer solution) exceeded the ratios published for other delivery agents, and it was 10 to 20-fold higher than the control formulation that did not use TIJO. Work on the oral delivery of macromolecules was initiated at Dalhousie University using large animals (pigs), which have intestinal tracts more similar to that of humans. The work will be continued when the financing is secured.