[e-drug] Heat stable oxytocin? (3)

["Richard Prankerd" <Richard.Prankerd@vcp.monash.edu.au>]

E-DRUG: Heat stable oxytocin? (3)
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[If you are interested to follow up a research project with Richard please contact him directly at
Richard Prankerd <Richard.Prankerd@vcp.monash.edu.au>  ]

Heat stable oxytocin - is it possible?

Oxytocin is a nonapeptide, of which 6 of the 9 amino acids form a
relatively stable ring system that includes a disulfide bond. The
current formulation of oxytocin is an aqueous injectable form, which
indicates that the peptide is relatively stable, provided that storage
is at refrigeration conditions.

In principle, such products can be heat stabilized to a significant
extent by developing a freeze-dried (lyophilized) formulation. However,
the drawbacks to this proposition are the following:

1. the cost of developing the formulation will be considerable, as it is
unlikely that the present solution formulation can be stabilized merely
by freeze-drying without the addition of further stabilizers, such as
mannitol or other polyhydric alcohols, which will ensure that the
freeze-dried product can be reconstituted for use in the field;

2. the cost of manufacture of the new lyophilized formulation will be
substantially higher than the present injectable solution. Typically,
the all up cost of a lyophilized injectable formulation is five times
the cost of the same drug in a non-lyophilized injectable formulation;

3. the adminstration of the lyophilized formulation will require a
preliminary reconstitution step using sterile water for injection. This
must be done under aseptic conditions, which may present further
difficulties in third world settings. In addition, the reconstitution
step also have costs that must be covered.

Alternatives to lyophilization of a sterile injectable aqueous
formulation are few. It would certainly be possible to design a more
stable peptidomimetic form of oxytocin, in which the labile peptide
bonds are exchanged chemically for more stable bonds with similar
electronic and steric attributes. However, this would be a completely
new drug and therefore hugely expensive. 

Most Likely Solution Approach:
There have been a very small number of small molecule drugs that are
heat labile in aqueous solution, and which have been adequately
stabilized by partial or complete replacement of the injection vehicle
with less reactive, water miscible and pharmacologically acceptable
solvents, such as ethanol or propylene glycol. These cosolvent systems
have had some measure of success with drugs such as diazepam and
phenytoin sodium (for both of which a solubility problem is also of
concern) and with pentobarbitone sodium, where shelf-life was improved
quite significantly by such a change in solvent system. However, the use
of cosolvent mixtures (such as the classic 40% propylene glycol, 10%
ethanol, 50% water originally developed for pentobarbitone sodium), also
has issues. Chiefly, these are toxicological, as propylene glycol has
some specific cardiotoxicity, as well as more general intoxicant
properties similar to ethanol. Further, there is the difficulty that is
exemplified best with phenytoin sodium, in that the dissolved active may
precipitate on direct injection into the blood stream. These issues have
resulted in at least one drug (phenytoin) being redesigned so that it is
directly and freely soluble in water. 

For oxytocin, the problems of propylene glycol as a cosolvent might be
reasonably expected to be minimal, as: (i) it is normally administered
clinically by addition to isotonic saline or dextrose infusion, and so
the pharmacological effects of the very small dose of propylene glycol
would be highly diluted; (ii) the oxytocin is already sufficiently water
soluble that precipitation would not occur; (iii) the total dose of
propylene glycol would be very limited, as the administration of
oxytocin is a single acute event, not chronic.

Having said all that, it would still be a significant effort to develop
an oxytocin formulation in such a cosolvent mixture. In the opinion of
this writer, it would be worthwhile to set up a small research project
along these lines, and he would be interested in some follow up with
interested parties. However, he has no funding for such a project, and
would need some laboratory assistance to perform the work. If an
interested NGO wishes to become involved in this potential project,
please contact the writer directly.

Rgds
Richard

Richard J. Prankerd, PhD
Senior Lecturer
Victorian College of Pharmacy, Monash University
381 Royal Pde., Parkville VIC 3052

Phone: 	INT+613-9903-9003
Phax:   	INT+613-9903-9583
Email:	richard.prankerd@vcp.monash.edu.au