Sincalide formulations

Details Sincalide formulations Sincalide formulations

2002-08-16

2004-10-12

Page, Thurman K. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C514S001600, C514S018700, C514S019300, C514S951000

Reexamination Certificate

active

06803046

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to pharmaceutically acceptable formulations of sincalide.
BACKGROUND OF THE INVENTION
KINEVAC® (Sincalide for Injection, USP) is a cholecystopancreatic-gastrointestinal hormone peptide for parenteral administration. The active pharmaceutical ingredient, 1-De(5-oxo-L-glutamine-5-L-proline)-2-de-L-methioninecaerulein or “sincalide” (CAS# 25126-32-3), is a synthetically prepared C-terminal octapeptide of cholecystokinin (CCK-8), with the following amino acid sequence: A sp-Tyr(SO
3
H)-Met-Gly-Trp-Met-Asp-Phe-NH
2
.
KINEVAC® was first introduced in 1976, and was finished as a sterile, nonpyrogenic, lyophilized white powder in a 5-mL (nominal) glass vial to contain: 5 &mgr;g sincalide with 45 mg sodium chloride to provide tonicity; sodium hydroxide or hydrochloric acid may have been added for pH adjustment (pH 5.5-6.5). The type I glass vial was sealed under a nitrogen headspace with a Tompkins B0849 closure. This two-ingredient formulation was incorporated into the U.S. Pharmacopea/National Formulary, USP 24, NF 19, Jan. 1, 2000.
Since its introduction, various drawbacks in the manufacturing and analysis of KINEVAC® have been identified. For example, the two-ingredient formulation suffers from potency variability. This variability was exacerbated by the fact that the formulation was analyzed using a guinea pig gallbladder contraction bioassay for potency of both sincalide and KINEVAC®. This bioassay was unable to distinguish between bioactivity of sincalide and bioactivity of sincalide degradants. Accordingly, a 20% overage of sincalide was required in previous sincalide formulations to compensate for the limitations of the bioassay. Thus, there is a need for sincalide formulations having improved and consistent potency as established by a sincalide specific assay such as HPLC.
SUMMARY OF THE INVENTION
The present invention satisfies the need for improved sincalide formulations by providing formulations that eliminate the need for a 20% overage of sincalide. The sincalide formulations of the invention are also purer than prior art formulations, and have fewer degradants and more consistent potency. In addition, the purity of these formulations, may be assessed by HPLC, thus eliminating the need for the bioassay of the prior art formulations.
The present invention provides sincalide formulations adapted for administration by injection. These sincalide formulations are characterized by improved stability and may be prepared as a relatively large volume batch (≈100 L).
In one aspect, the invention features sincalide formulations that include an effective amount of sincalide, a bulking agent/tonicity adjuster, one or more stabilizers, a surfactant, a chelator, and a buffer. The invention also features kits and methods for preparing improved sincalide formulations, as well as methods for treating, preventing, and diagnosing gall bladder-related disorders using sincalide formulations.
The formulations of the invention preferably have a pH between 6.0 and 8.0. Suitable buffers include, but are not limited to, phosphate, citrate, sulfosalicylate, borate, acetate and amino acid buffers. Phosphate buffers, such as dibasic potassium phosphate, are preferred.
In various embodiments of the invention, the surfactant is a nonionic surfactant, preferably a polysorbate, such as polysorbate 20 or polysorbate 80; the chelator is pentetic acid (DTPA); and the stabilizer is an antioxidant and/or amino acid. In a particularly desirable embodiment of the invention, the formulation includes a plurality of stabilizers, preferably L-arginine monohydrochloride, L-methionine, L-lysine monohydrochloride, and sodium metabisulfite.
Suitable bulking agents/tonicity adjusters include, but are not limited to, mannitol, lactose, sodium chloride, maltose, sucrose, PEG's, cyclodextrins, dextran, polysucrose (Ficoll), and polyvinylpyrrolidine (PVP). D-Mannitol is a preferred bulking agent/tonicity adjuster.
In a particularly preferred embodiment, the reconstituted formulation includes 0.0008 to 0.0012 mg/mL active ingredient (i.e., sincalide); 20.0 to 50.0 mg/mL mannitol, 2.0 to 7.0 mg/mL arginine; 0.2 to 1.0 mg/mL methionine; 2.0 to 30.0 mg/mL lysine; 0.002 to 0.012 mg/mL sodium metabisulfite; 0.000001 to 0.003 mg/mL polysorbate 20, 0.1 to 3.0 mg/mL pentetic acid (DTPA); and 5.4 to 12.0 mg/mL potassium phosphate (dibasic). In, a more preferred embodiment, the reconstituted formulation includes about 0.001 mg/mL sincalide; about 34 mg/mL D-mannitol, about 6 mg/mL L-arginine monohydrochloride; about 0.8 mg/mL L-methionine; about 3 mg/mL L-lysine monohydrochloride; about 0.008 mg/mL sodium metabisulfite; less than about 0.01 mg/mL polysorbate 20, about 0.4 mg/mL pentetic acid (DTPA); and about 1.8 mg/mL potassium phosphate (dibasic).
The kits of the invention may, for example, include the various components of the formulation as a mixture in powder form, along with a container (e.g., a vial) to hold the powder mixture and a physiologically acceptable fluid for reconstitution of the formulation, The components of the formulation may be present in the kit either in the powder mixture or in the fluid portion. Kits of the invention may also include all components in a liquid mixture or some components in a liquid form and some in the form of a powder.
The formulations of the invention have improved stability and potency compared to previous sincalide formulations, and are useful as diagnostic aids for imaging the hepatobiliary system of a patient. When used as a diagnostic aid, the sincalide formulations may, for example, be co-administered with a radiopharmaceutical agent having rapid hepatic uptake, such as
99m
Tc-mebrofenin, or similar hepatobiliary imaging agents, to assist in the diagnosis of gallbladder diseases and related disorders. Additionally, the formulations may be administered before and/or after diagnostic imaging (including for example, magnetic resonance imaging, scintigraphic imaging, ultrasound imaging, etc.)
The sincalide formulations of the invention may also be administered to patients receiving total parenteral nutrition (TPN), in order to treat and/or prevent TPN-related disorders.


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