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Equidyne systems, inc

Technical Report TR-01-001, Equidyne Systems, Inc. Retention of structural/potency characteristics of Lantus Insulin, AKA Authored by:
Vision Biotechnology Consulting
315 S. Coast Hwy. 101, Suite U, PMB144
Encinitas, CA 92024
Phone/FAX: 760-634-2999
Technical Report TR-01-001, Equidyne Systems, Inc. This document contains information that is privileged or confidential and may not
be disclosed unless such disclosure is required by Federal or State law or
regulations. This information may be disclosed only to those persons involved in
the study who have a need to know, but all such persons must be required not to
further disseminate this information to others. These restrictions on disclosure
will apply equally to all future information supplied to you which is indicated as
privileged or confidential.

Technical Report TR-01-001, Equidyne Systems, Inc. I. INTRODUCTION AND PURPOSE
The Equidyne Systems, Inc. Injex device is an FDA-approved (for sub-cutaneous
injections) needle-free delivery device which utilizes a mechanical pressure technology
to propel 0.05-0.3 ml of solution through a 0.006” orifice under a pressure of ~3000 psi.
Previously, trials have been performed by various pharmaceutical companies and
Equidyne to determine whether compounds wil be ‘sheared’, inactivated, or otherwise
damaged due to the pressure of injection. The previous studies performed by Equidyne
(Protocols EquA-001 and EquA-003) demonstrated no detectable effect on various
insulins including Humalog, Humulin-R, Humulin L, Humulin U, NPH, Iletin, Velosulin,
and Novolin, as well as model compounds spanning a molecular weight range of 700 to
~1 million daltons.
Since that time, Lantus® insulin (Aventis Pharmaceuticals, Inc.) has been approved by
the Food and Drug Administration (FDA) for the treatment of adults and children with
type I diabetes mellitus, and adults with type 2 diabetes who require long-acting insulin
for control of hyperglycemia. This new insulin is produced by recombinant DNA
technology and differs from endogenous insulin by three amino acids: asparagine is
substituted for a glycine residue at position A21 of the A-chain and two arginine residues
are added at positions B31 and B32 of the B chain. Lantus is of interest as the
molecular structure causes a precipitation in the subcutaneous tissue after injection.
This precipitation delays absorption, the pharmacokinetic outcome of which is a long
distribution and elimination phase with no pronounced peak.
The present study was designed to determine whether this new insulin retains its
molecular structure and/or potency post-injection with the Injex™ needle-free delivery
device. Comparisons to delivery via a standard syringe as well as a control retention
were performed.
The methods, observations, results, and conclusions in this report are applicable to
evaluation of molecular damage to Lantus insulin as a result of injection via the Injex in
comparison to a control and a standard needle syringe.

RIA: radioimmunoassay based on competitive inhibition of labeled substrate vs. native substrate for binding by a monoclonal or polyclonal antibody.
This study was performed, managed, and analyzed by Mark J. Sarno, Scientific
Consultant to Equidyne Systems and Founding Partner, Vision Biotechnology

Reports: EquA-003 (TR105) and EquA-001
Technical Report TR-01-001, Equidyne Systems, Inc. VI. EQUIPMENT, MATERIALS, AND METHODS

The study is designed as an in-vitro test using an immunometric method to indicate
Equidyne Injex 0.3 ml injector, reset box, appropriately sized ampules, and small vial
adapters were required for this study. In addition, Becton-Dickinson 0.5 ml syringes and
28 gauge needles were required.
A. Materials
Lantus insulin (insulin glargine or HOE901) was obtained courtesy of Aventis
Pharmaceuticals. Lot H007 (exp. 4/2002) was used for this study. The nominal
concentration (label claim) was 100 Units/milliliter (U/ml). The material is supplied as a
clear solution with no visible contaminants.

B. Measurement method
Lantus insulin samples were measured by radioimmunoassay (RIA). The assay
utilizes guinea pig antiserum specific for insulin as the primary antibody and
radioiodinated recombinant human insulin as tracer. A second antibody specific for
guinea pig immunoglobulin is used to precipitate immune complexes. Each sample was
tested in duplicates. Testing was performed by the Esoterix unit of Endocrine Sciences
(Calabasas, CA). All samples required dilutions in order to achieve concentrations
within the quantitative linear range of the assay (0-60 µU/ml)
C. Test injections
For each delivery method 6 deliveries were performed, i.e. 0.3 ml was delivered 3
times into two Type I glass receptacles by a Becton-Dickinson 0.5 ml syringe fitted with a
28 gauge needle, and another 6 aliquots of 0.3 ml were delivered into two Type I glass
receptacles by the Injex 0.3 ml injector. A pre-delivery retention was kept as a control.
The Injex and syringe test aliquots were then compared to the retention control using the
immunoassay method described above.
D. Statistical methods
Standard statistical methods were employed to compare the results (U/ml) from the
Injex, syringe, and control solutions. Means and standard deviations (SD) are reported.
Additionally, insulin values from the Injex, syringe, and control were compared
parametrically using the Students-t test. Differences between delivery methods and vs.
the control are reported. P<0.05 was considered significant.

Table 1 displays the results from the immunoassay analysis. Means and standard
deviations (SD) are reported for the Injex device, the syringe, and the control retention.
Technical Report TR-01-001, Equidyne Systems, Inc. TABLE 1: Immunoassay results by injection device, or control
Device/Control Mean
p vs. Control

This new insulin had not been previously tested in the insulin radioimmunoassay. The
results suggest that the antibody utilized in this assay is only 50% cross-reactive as the
expected result for the control was ~100 U/ml. However, the results are internally
consistent, i.e. the actual results from the Injex and the syringe are being compared to
the actual results for the control, not the expected concentration.
Thus, the results demonstrate no loss in Lantus insulin potency after injection by either
the Injex device or the syringe in comparison to the control. The results of the Students
t-test are not significant, i.e. p>0.05.

This in-vitro study demonstrates complete retention of molecular identity of Lantus
insulin injected via the Injex. The immunoreactivity was retained, thus suggesting that
epitope moieties were maintained intact despite the high pressures of injection utilized
by the Injex methodology. It is a logical extension that if epitopes are maintained intact,
that the overall primary and secondary structure of the molecule is likely intact. To
explain further, molecular epitopes for peptide/protein molecules are generally on the
order of tens of amino acids. Since Lantus insulin is a dipeptide on the order of 50
amino acids, it is unlikely that any shearing can have occurred.
Further, protein epitopes are generally required to be in a three dimensional
conformation consistent with the original antigen used to produce and select antibodies.
Since there is no loss of immunoreactivity in this study (compared to the control), the
three dimensional conformation (tertiary structure) of the molecule is also maintained
after injection. It is therefore logical to conclude that structural damage (cleavage of the
disulfide bonds or unwinding of the tertiary structure) has not occurred as a result of
Respectfully submitted,
Mark J. Sarno Vision Biotechnology Consulting


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