Cortecs Presents Phase I Oral Insulin Trial Data At Controlled Release Symposium In Stockholm; Planning Phase IIA European Trial In 3rd Quarter.

LONDON--(BUSINESS WIRE)--June 30, 1997--Cortecs International ("Cortecs") (NASDAQ:DLVRY/LSE:COR/ASX:CRI) the U.K. based pharmaceutical company, today announced that its Phase I trial of its Macrulin(TM) oral insulin formulation was presented during the Controlled Release Society 24th International Symposium on Controlled Release of Bioactive Materials held in Stockholm, 15-19th June.

The report confirmed and expanded the preliminary data on the Macrulin(TM) Phase I trial announced last November.

The challenge set by the trial was the avoidance of intestinal digestion of Macrulin(TM) and its passage through the bloodstream to the liver. The trial included six healthy subjects who received Macrulin(TM) or oral placebo via a tube passing through the mouth into the upper intestine. Each subject was studied twice, once receiving placebo and once receiving a commercially viable dose of Macrulin(TM) in randomised order. The subjects were simultaneously administered a glucose solution intravenously. Blood samples were collected before starting the experiment and at timed intervals afterwards and assayed for insulin and reduction of C-peptide and glucose levels.

The results showed that after administration of Macrulin(TM) the subjects' C-peptide response reduced, insulin levels in the blood increased and there was an increase in the disappearance rate of blood glucose thus successfully meeting the trial challenge. The C-peptide, which is a measure of the body's own insulin production was reduced by more than 40% over a period of four hours.

Commenting Dr. Michael Flynn, President of Cortecs International said: "These results are encouraging and we are planning a Phase IIa Macrulin(TM) trial in diabetics using encapsulated Macrulin(TM) during the third quarter this year. These results and the success of our Macritonin(TM) oral calcitonin Phase III European trial in May, have broad implications for the potential oral delivery of other peptide and protein molecules coming from the biotech industry."

Cortecs is a British-based company quoted on the London Stock Exchange, the Australian Stock Exchange and on Nasdaq. The Company specializes in the development of new oral pharmaceutical delivery systems, new oral mucosal vaccines and point-of-care rapid diagnostics which provide the opportunity to advance the management of serious diseases such as:

- OSTEOPOROSIS

- Macritonin(tm) - An oral calcitonin therapy for the prevention of bone breakdown. Analysis of European Phase III trial nearing completion.

- Osteosal(tm) - A rapid doctors' office test in development to detect increased bone breakdown indicating the risk of osteoporosis and also to monitor the adequacy of osteoporosis therapy.

- DIABETES

- Macrulin(tm) - An oral formulation of insulin. Preparing for European Phase II trials.

- Glycosal(tm) - Rapid doctors' office tests in development to assist in the management and identification of diabetes.

- Neurulin - A topical product to treat diabetic neuropathy. In Phase II trials. * INFECTIOUS DISEASE

- Pseudostat(tm) - Oral therapeutic vaccine to prevent and treat lung infection with Pseudomonas aeruginosa in cystic fibrosis and chronic bronchitis. In Phase II trials.

- Flustat(tm) - An oral vaccine against influenza in Phase I trials.

- Helisal(tm) - A rapid doctors' office whole blood test for the detection of H. pylori. Launched.

- A 'One-step' whole blood test for H. pylori. Launched in the UK.

- Further rapid tests in development including saliva test and for the coccoid form of H. pylori.

- Ulsastat(tm) - Oral therapeutic vaccine in development to stimulate immunity against H. pylori.

- CANCER

- Cellcom - A novel class of molecules to inhibit signaling pathways within cancer cells and to control their unrelenting growth.

- NPC Test - A rapid test to assist in diagnosing nasopharyngeal cancer.

Cortecs also markets a range of ethical and OTC medicines and diagnostic products in the UK.

"Safe Harbor" Statement under the US Private Securities Litigation Reform Act of 1995: Some or all of the statements in this document that relate to future plans, expectations, events, performances and the like are forward-looking statements, as defined in the US Private Securities Litigation Reform Act of 1995. Actual results of events could differ materially from those described in the forward looking statements due to a variety of factors, including those set forth in the Company's filings with the US Securities and Exchange Commission.

Press releases and other Cortecs International information are available on the Cortecs International web site: http://www.cortecs.com.

-- The abstract presented at Stockholm follows --

Presented to Controlled Release Society 24th International Symposium on Controlled Release of Bioactive Materials, Stockholm, Sweden, 15-19 June 1997.

External Delivery of Insulin in Normal Humans

Using an Oil-based Macrosol Formulation

New RRC, Littlewood GM, Cripps D, Kirby CJ, Guard P and Flynn MJ.

Cortecs International Ltd., The Old Blue School,

Lower Square, Isleworth, Mddlesex TW7 6RL, United Kindgom

Introduction

Using previously described Macrosol(tm) technology (1) bovine insulin has been formulated as a solution in medium chain monoglycerides, in the absence of an acqueous phase. This oil formulation has been administered enterally at a dose of 300iu/subject to normal human volunteers. Blood samples were taken at intervals and levels of glucose, insulin and C-peptide were measured and compared with those from the same subjects receiving a placebo formulation as a two-way cross-over.

Materials and Methods

Reagents Insulin (CD Pharmaceuticals UK), sodium urso-deoxycholate (Erregierre, Italy), polysorbate 80 (Surfachem UK) and Akoline MCM0 Karlshamns, Sweden) were co-dispersed using a Cortecs proprietary process, resulting in a clear solution of insulin in the oil phase. The concentration of insulin was 200iu/g of oil, and the oil phase comprised Akoline and polysorbate 80 in a 9:1 ratio (wt:wt).

Dosing The study was performed at Hammersmith Medicines Research Ltd., Central Middlesex Hospital, London, UK. 1.5g of Macrosol(tm) insulin formulation was dispensed in 3ml of PBS and administered to individual subjects via a naso-jejunal catheter which reached into the jejunem. Immediately before the intra-jejunal dose, glucose was administered i.v. at a level of 500mg/kg body weight. Six subject were employed in the study, and each received both active and placebo as a two-way cross-over on successive days. Blood samples were taken at intervals and assayed for insulin and C-peptide by RIA and for glucose using the YSI model 32AM glucose analyser.

Results

In an attempt to circumvent the homeostatic mechanisms in the normal subject, each volunteer was subjected to a glucose challenge, which gave, in addition to a sharp rise in blood glucose concentration, sharp rises also in insulin and C-peptide levels. All of these levels fell back to baseline after two to three hours. The AUCs for each of these parameters are shown in Table 1.

Table 1. Area under the curve for blood parameters after administration of Macrosol(tm) insulin or placebo via the jejunum. -0-

------------------------------------------------------------
                         Insulin     Glucose     C-Peptide
                        -------     -------     --------
Period in minutes          0-20       0-150        0-240

Placebo                     857         326          638
Active                     1127         215          397

s.c. of mean difference     320          70          214

Ratio (A/P)                1.32        0.66         0.62
-----------------------------------------------------------

In five out of the six subjects studied, insulin levels were higher at ten minutes after administration of the active formulation, than after receiving placebo (Figure 1). At this time exogenous insulin may be expected to be entering the bloodstream, while endogenous insulin is starting to decrease.

Figure 1. Plasma insulin levels in individual subjects ten minutes after receiving a glucose challenge, followed by Macrosol(tm) insulin formulation, or placebo, i.j.

Discussion

Because of the strong homeostatic response operating in normal human subjects effects of exogenous insulin on glucose may be small. Even after administration of hypoglycaemic agents such as tolbutamide, little change in blood glucose levels is seen (2). Feedback mechanisms act to inhibit secretion of endogenous insulin from the pancreas, so that overall blood insulin levels measured by RIA (which distinguishes poorly between the two types) do not reflect the total quantity of insulin absorbed. This lack of correspondence is further accentuated by the fact that after enteral administration, a substantial proportion of insulin going directly to the liver will be removed from circulation. In the current study, however, increases in total insulin were observed over the first twenty minutes in five out of six subjects receiving the insulin in Macrosol(tm), at later times, in response to this, the suppression of endogenous secretion of insulin was indicated by the marked reduction in C-peptide (a breakdown product of pro-insulin) in the blood. A small reduction in glucose was also observed, presenting a consistent picture of insulin, C-peptide and glucose changes in accord with those to be expected after administration of exogenous insulin.

Data has been presented elsewhere (3) showing that effective delivery of insulin can be achieved intra-jejunally in animals using Cortecs' Macrosol formulation incorporating medium chain mono-glycerides. Those studies suggest that enterally-delivered insulin passes rapidly across the gut and enters the liver via the hepatic portal vein and will come into contact to a much lesser extent with peripheral tissues than insulin delivered parenterally. Consequently, it may be hoped that oral administration will correct metabolic abnormalities in Type II diabetics more effectively, and reduce the side-effects such as obesity and hypoglycaemia seen with conventional therapy. The detection of changes in insulin, C-peptide and glucose concentrations in normal human subjects is very encouraging, and the study is being followed up with further trials in healthy volunteers and type II diabetics, using encapsulated Macrosol(tm) formulations administered orally.

References

1. New RRC & Kirby CJ. (1997) in Advances in Drug Delivery Reviews 25:1 Elsevier. "Oil formulations for administration to the gastro-intestinal tract."

2. Saad MF, Anderson RL, Laws A et al. (1994) Diabetes 43 p1114. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance."

3. New RRC, Gay CL, Kirby CJ et al. (1996) Proceed Intern Symp Control Rel Bioact Mater 23 p545-6. "Use of an oil-phase carrier - Macrosol(tm) - for intestinal delivery of peptides in large animals."

CONTACT: Dr. Michael Flynn, President

Cortecs International

011-44-181-847-2013

or

John Barrington-Carver, External Affairs

Cortecs International

011-44-181-758-0505

or

Zena Bates/Lisa Baderoon

Buchanan Communications

011-44-171-489-1441

or

John P. Kehoe/Van Negris

Kehoe, White, Savage & Company, Inc

212/888-1616

or

Dr. Geoffrey Brandon

Brandon Harris

011-44-171-407-6854