Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-09-01
2002-08-06
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S805000, C530S399000
Reexamination Certificate
active
06429195
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel compositions useful for the sustained-release of bioactive proteins. More particularly, the present invention provides a superior aqueous sustained release injectable formulation of bovine growth hormone releasing factor. Also provided are methods of using these novel compositions for the sustained or prolonged release of bovine growth hormone releasing factor.
With the advent of genetic engineering, the large-scale availability of many bioactive peptides and proteins has been achieved. However, the administration of these recombinantly produced peptides and proteins presents a unique set of problems. In many cases the maintenance of the biological effect of these proteins requires long-term administration. Since daily administration of these agents is inconvenient, sustained or prolonged release is preferred.
For numerous reasons, the art has long focused on the use of biocompatible oils as vehicles to achieve the sustained release of many drugs, including proteins and specifically somatotropins. Among the patents directed to this technology are U.S. Pat. No. 5,013,713 to Mitchell and U.S. Pat. No. 4,977,140 to Ferguson et al. Mitchell reports that prolonged parenteral release of bovine somatotropin (bSt;BGH) at desirably effective levels can be achieved using substantially non-aqueous compositions comprising at least about 10% by weight of a biologically active somatotropin and, as a continuous phase of the composition, a biocompatible oil such as corn oil. Ferguson et al. report that the injection of a sustained release formulation comprising bSt, wax and an oil increases daily milk production in a cow for an extended period of time.
Those skilled in the art have also directed their attention to achieving the sustained release of other growth enhancing proteins such as growth hormone releasing factor. Specifically, U.S. Pat. No. 5,352,662 to Brooks et al. reports an injectable, extended release formulation which includes a growth hormone or a growth hormone releasing factor in a carrier including a biocompatible hydrophobic vehicle and an amount of polyglycerol ester effective to extend release of the proteins in the animal.
The above patents illustrate the art's emphasis on the use of non-aqueous delivery systems for the prolonged release of growth hormones and growth hormone releasing factors. Recently, the art has taught the use of an aqueous formulation to achieve the prolonged release of bSt. International Patent Application No. PCT/US95/00023 teaches the prolonged parenteral release into the circulatory system of a cow of a bioactive bSt. This is achieved by using novel compositions in which the bSt is present in an aqueous liquid at a dose of at least about 150 mg and at a concentration of at least about 50 mg/ml. The disclosed aqueous bSt formulation reportedly provides for the sustained release of bSt into the circulatory system of the animal for greater than 3 days.
Prior to this teaching, however, the art studiously avoided using aqueous systems for the sustained delivery of proteins, especially somatotropins. The reason for this behavior was the general view that proteins are highly unstable when exposed to aqueous environments for long periods of time. (Pitt,
Int. J. Pharmaceutics
59:173-196 (1990)). As different proteins behave differently in aqueous environments (bSt comprises 191 amino acids whereas growth hormone releasing factors comprises 44 amino acids), the general view of the art that proteins are highly unstable when exposed to aqueous environments for long periods of time remains uncontradicted for growth hormone releasing factor.
INFORMATION DISCLOSURE
Mariette et al.,
Journal of Controlled Release
, 24:237-246 (1993) report that release of GRF29NH
2
analog (comprised of the first 29 amino acids of human GRF44NH
2
) from a compression molded matrix designed to form a percolating network of entrapped peptide particles depended much more on the solubility characteristics of the peptide than on the diffusion through the matrix or through the channels or on the morphology of the matrix itself. The authors report that controlled release was achieved in salt-containing media by using sink conditions generated by a continuous flow of GRF29NH
2
-free aqueous media. The authors note that the GRF29NH
2
hGRF analog is also poorly soluble in plasma, but that phenomena in plasma appear rather complex and the peptide seemed to interact with serum proteins. The authors concluded by noting that further work was needed to better understand these interactions.
Carmona et al.,
Spectrochimica Acta
, 51A(5):929-938 (1995) report that while the backbone of GRF29NH
2
is unordered in the solid state, some intermolecular beta-sheet aggregation is observed in aqueous solutions. They further report that their spectroscopic data indicate that the non-aggregated GRF29NH
2
analog exists as an ensemble of conformers in aqueous solution, that this peptide can undergo conformational changes on modification of the environment, and that such conformational flexibility of hGRF may be important for its clearance from circulation.
Pitt,
Int. J. Pharmaceutics
59:173-196 (1990), reports on the difficulties in developing parenteral sustained release delivery systems for proteins such as the somatotropins which are highly unstable in aqueous environments at high protein concentrations.
U.S. Pat. No. 5,013,713 to Mitchell issued May 7, 1991, discloses a method for achieving prolonged release of a biologically active somatotropin into the circulatory system of an animal by the parenteral administration to the animal of a substantially non-aqueous composition of at least about 10% by weight of a biologically active somatotropin and, as a continuous phase of the composition, a biocompatible oil. Mitchell emphasizes that his composition should be non-aqueous in order not to accelerate release.
U.S. Pat. No. 4,977,140 to Ferguson et al. issued Dec. 11, 1990, discloses a method for obtaining 28 days of increased daily milk production from a dairy cow by injecting into the cow 2 to 10 grams of a formulation comprising 10-25% bovine somatotropin suspended in a carrier that comprises 8-20% of a wax and 80-92% of an oil. Ferguson et al. do not consider the question of whether aqueous formulations can be used as a prolonged release vehicles.
U.S. Pat. No. 5,352,662 to Brooks et al. issued Oct. 4, 1994, discloses an injectable, extended release formulation which includes a growth hormone or a growth hormone releasing factor in a carrier including a biocompatible hydrophobic vehicle and an amount of polyglycerol ester effective to extend release of the proteins in the animal. Brooks et al. do not consider the question of whether aqueous formulations can be used as a prolonged release vehicles.
International Application No. PCT/US95/00023 teaches the prolonged parenteral release into the circulatory system of a cow of a bioactive bSt using an aqueous formulation. This is achieved by using novel compositions in which the bSt is present in an aqueous liquid at a dose of at least about 150 mg and at a concentration of at least about 50 mg/ml. The disclosed aqueous bSt formulation reportedly provides for the sustained release of bSt into the circulatory system of the animal for greater than 3 days. The reference reveals nothing about whether an aqueous delivery system be used to achieve the prolonged release of growth hormone releasing factors.
SUMMARY OF THE INVENTION
The present invention discovered that substantially aqueous growth hormone releasing factor compositions can be used to achieve the prolonged release of a biologically active growth hormone releasing factor into the circulatory system of an animal by the parenteral administration to the animal of the substantially aqueous growth hormone releasing factor composition. The compositions comprise at least about 50 mg of a biologically active growth hormone releasing factor in an aqueous carrier at a concentration of at least about 20 mg/ml. The aqueous growth hormone releasi
Caputo James F.
Foster Todd P.
Hageman Michael J.
Moseley William M.
Cawley, Jr. Thomas A.
Darnley , Jr. James D.
Delacroix-Muirheid C.
Jones Dwayne C.
Pharmacia & Upjohn Company
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