Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-06-01
2002-03-19
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C530S324000
Reexamination Certificate
active
06358924
ABSTRACT:
BACKGROUND OF THE INVENTION
Formulations are presented that have improved storage characteristics. These formulations are particularly suitable for oral absorption of GLP-1 peptides that bind surfactants.
Administration of therapeutic peptides is often limited to parenteral routes rather than preferred oral administration due, e.g. to destruction of the peptides if ingested rather than injected. This is unfortunate because many peptides have proven clinically effective and could have more widespread use if easy to administer and acceptable to recipients. For example, GLP-1-like molecules possess anti-diabetic activity in human subjects suffering from Type II and, in some cases, even Type I diabetes. Treatment with GLP-1 elicits activity (increased insulin secretion and biosynthesis, reduced glucagon secretion, delayed gastric emptying) only at elevated glucose levels, and thus provides a potentially much safer therapy than insulin or sulfonylureas. Post-prandial and glucose levels in patients can be moved toward normal levels with proper GLP-1 therapy. There are also reports suggesting GLP-1-like molecules possess the ability to preserve and even restore pancreatic beta cell function in Type-II patients. On the other hand, to be effective as a treatment, GLP-1 formulations may have to be administered by injection at, or slightly before, each meal. This is the regimen used to administer insulin. For such a regimen, a multi-use solution formulation stored for long periods of time at refrigerated or ambient temperature is preferred. Such a formulation must contain a preservative with sufficient anti-microbial properties to prevent degradation and contamination of the solution. Unfortunately, preservatives tend to deleteriously affect the therapeutic agent, e.g. a peptide. For example, solutions of GLP-1 molecules undergo conformational changes in the presence of a preservative such as phenol. In the presence of the preservative meta-cresol (m-cresol), aqueous solutions of GLP-1 molecules that are near neutral pH turn hazy, and precipitation develops. What is needed therefore, are additives for formulations of peptides such as GLP-1 molecules that allow storage at refrigeration (about 4° C. or lower) and/or ambient temperatures while still preserving both solution clarity, compound integrity, and biological activity.
SUMMARY OF THE INVENTION
Methods and formulations of the present invention provide formulations for a. oral absorption of GLP-1 peptides that bind surfactants with high affinity; b. long term storage of formulations containing these peptides.
An aspect of the invention is a formulation comprising a GLP-1 peptide and a small quantity of a surfactant. Preferred surfactants include DSS (docusate sodium, CAS Registry Number [577-11-7]) and related substances; docusate calcium [CAS number 128-49-4], and docusate potassium [CAS number 7491-09-0]. Other surfactants include SDS (sodium dodecyl sulfate or sodium lauryl sulfate), sodium caprylate, sodium cholate, sodium deoxycholate, sodium taurocholate, and sodium glycocholate. Suitable agents also include zwitterionic (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3-cholamido-1-propyldimethylammonio-1-propane-sulfonate), cationic (cetylpyridinium chloride), non-ionic (Triton X-100, Dodecyl &bgr;-D-glucopyranoside), or polymeric (Tween-40, Tween-80, Brij-35) surfactants.
Peptides used in the formulations of the present invention include GLP-1 or GLP-1-like molecules. A preferred GLP-1-like molecule is Val
8
-GLP-1. Other suitable GLP-1-like molecules include the 2 native GLP-1 forms, position-8 analogs, and molecules containing a C-terminal acid.
The formulation is stable at a pH of about 6.5 to 9.0, more preferably at a pH of about 7 to 8. The formulation includes a preservative. Preferred preservatives include m-cresol, phenol, methylparaben, and benzyl alcohol. The formulation is stable during long term storage at 4° C. and ambient temperature. The formulation optionally includes an isotonicity agent, for example glycerin, or sodium chloride.
Another aspect of the invention is a method of treating a person having diabetes or other conditions in which the administration of a GLP-1-like molecule is indicated. The method includes obtaining a formulation of the present invention and administering a pharmacologically effective amount of the formulation to the person. Preferably an oral route is used to administer the formulation, although a parenteral route is also suitable.
DETAILED DESCRIPTION OF THE INVENTION
Methods and formulations of the present invention provide for a) the oral absorption of GLP-1 peptides that bind surfactants with high affinity; and b) long-term storage of preserved formulations containing these peptides. In an embodiment of the invention, a GLP-1/DSS complex is used to administer GLP-1 orally instead of parenterally. This aspect of the invention provides much greater convenience and compliance for diabetic patients and persons having other conditions in which treatment with a GLP-1-like molecule is indicated. This characteristic will make GLP-1 treatment more useful and widely available. Use of preservatives prevents microbial contamination and therefore allows multiple use from a single solution.
Several key observations suggest that a significant portion of a GLP-1 peptide in a formulation containing sodium docusate (DSS) will be absorbed orally:
a. DSS binds to GLP-1 with a high affinity;
b. DSS binding alters GLP-1 secondary structure; this altered structure may correspond to a membrane-transportable state as described by Milstein (1996). The DSS appears to be acting as a so-called carrier molecule.
c. After administration of the formulation into a body (subcutaneously) the GLP-1 peptide exhibits full biological activity; this suggests either that the GLP-1 in the formulation retains its receptor binding affinity or the GLP-1-DSS complex in the formulation can be disrupted, reforming the native GLP-1 in an alpha-helix structure; a CD study showed that a 2-day dialysis of a GLP-1-DSS mixture did not revert the GLP-1 back to its alpha-helix conformation.
d. Large quantities of DSS can be safely administered orally because it is already approved for use as a laxative in humans; some of the orally administered DSS is absorbed systemically.
The addition of an anionic surfactant sodium docusate (DSS), at a very low level (2:1 on a molar basis vs. peptide), also dramatically improved the solution stability of Val
8
-GLP-1(7-37)OH in a formulation that is isotonic, is at a near neutral pH (pH 7.8), and also contains a suitable preservative (m-cresol). This formulation provides an improved product that should meet antimicrobial-sterility standards throughout the world. Improvement in formulation stability is over a wide range of storage conditions, from about 2° C. to about 37° C., more preferably at about 4° to about 25° C.
In an embodiment, the formulation allows single or multi-use parenteral formulation of a GLP-1 analog to be prepared that is suitable for long-term storage. Also, because the DSS facilitates the GLP-1 existing in a soluble micelle or aggregated state, this formulation provides an improved prolonged time action after subcutaneous administration.
The anionic surfactant, sodium docusate (DSS) has a very high affinity for a GLP-1 compound, specifically Val
8
-GLP-1(7-37)OH and, upon binding to the peptide, the Val
8
-GLP-1 secondary structure is converted from mostly alpha-helix to mostly a beta sheet. A slightly larger form of Val
8
-GLP-1 with DSS molecule(s) bound to it was observed on size-exclusion chromatography (SEC) and the altered secondary structure was noted by circular dichroism experiments (CD).
A formulation containing DSS and Val
8
-GLP-1 injected subcutaneously into dogs showed insulinotropic-like activity comparable in potency to Val
8
-GLP-1 in a phosphate buffer solution (PBS formulation).
Preferred embodiments for a surfactant include DSS (docusate sodium, CAS Registry Number [577-11-7]) and related substances; docusate ca
Cox Gregory A.
Eli Lilly and Company
Russel Jeffrey E.
Stewart Mark J.
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