Epinephrine Compositions And Containers

Patent No. US11207280 (titled "Epinephrine Compositions And Containers") was filed by Novaquest Co-Investment Fund X Lp on Mar 17, 2020.

’280 is related to the field of pharmaceutical formulations, specifically addressing the problem of stabilizing epinephrine in ready-to-administer injectable solutions. Epinephrine, a crucial drug for treating anaphylaxis and other emergencies, is known to degrade rapidly in aqueous solutions due to oxidation, racemization, and other factors. Existing formulations often require dilution prior to use, increasing the risk of dosage errors and contamination, or they contain antioxidants that can cause allergic reactions.

The underlying idea behind ’280 is to create a stable, ready-to-inject epinephrine formulation that avoids the drawbacks of prior solutions. This is achieved by carefully controlling several factors: using a low concentration of epinephrine (≤ 0.07 mg/ml), ensuring the epinephrine is primarily in the biologically active R-isomer form, maintaining a specific pH range (3.5–4.7), incorporating a metal ion chelator at a low concentration (1–50 μg/ml) to inhibit metal-catalyzed oxidation, and minimizing dissolved oxygen.

The claims of ’280 focus on both a method of producing and the resulting composition of a sterile, storage-stable, ready-to-inject epinephrine solution. Claim 1 specifically covers a method involving combining epinephrine, a metal ion chelator, and an aqueous carrier, adjusting the pH, packaging under inert gas, and then autoclaving to achieve sterility, while limiting the increase in the inactive S-isomer. Claim 10 covers the composition itself, emphasizing its antioxidant-free nature and the limits on total impurities and S-isomer content after storage.

In practice, the invention involves preparing an aqueous solution of epinephrine with a low concentration of a metal ion chelator like EDTA. The solution is carefully deoxygenated, the pH is adjusted to the specified range, and the formulation is packaged in a container under an inert atmosphere to minimize oxidation. A key step is the terminal sterilization via autoclaving, which ensures sterility without causing excessive degradation or racemization of the epinephrine. The resulting solution can be directly injected without prior dilution.

This approach differs from prior art in several ways. It avoids the use of traditional antioxidants, which can cause allergic reactions. The low concentration of epinephrine eliminates the need for dilution, reducing the risk of errors. The careful control of pH, oxygen levels, and the presence of a metal ion chelator at a low concentration synergistically contribute to the long-term stability of the formulation, even after sterilization and storage, as demonstrated by the low levels of impurities and S-isomer formation.

How does this patent fit in bigger picture?

Technical landscape at the time

In the late 2010s when ’280 was filed, epinephrine was typically marketed as a concentrated form for injection that required dilution prior to use. At a time when diluted epinephrine solutions were known to lack storage stability, epinephrine solutions deteriorated rapidly on exposure to air or light, with the rate of reaction increasing with increased pH, increased temperature, and in the presence of metal ions. When hardware or software constraints made long-term stability of diluted epinephrine solutions non-trivial, antioxidants were used to protect against auto-oxidation, but were associated with severe allergic reactions.

Novelty and Inventive Step

The examiner approved the claims because the prior art did not teach or suggest the claimed epinephrine composition comprising R-epinephrine in an amount of 0.07 mg/mL or less, and a metal ion chelator in an aqueous carrier, having a pH between 3.5-4.7; wherein the composition is substantially antioxidant-free, and the claimed method of preparing an epinephrine composition. The examiner also noted that the applicant provided evidence that the epinephrine formulation was much more storage stable compared to prior art formulations.

Claims

This patent contains 20 claims, of which claims 1 and 10 are independent. Independent claim 1 focuses on a method for producing a sterile and storage stable ready-to-inject epinephrine composition, while independent claim 10 focuses on the composition itself. The dependent claims generally narrow the scope of the independent claims by providing specific parameters, characteristics, or additional features related to the method or composition.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)	Support for Specification	Interpretation
Aqueous pharmaceutically acceptable carrier (Claim 1, Claim 10)	“For example, in one embodiment the antioxidant-free and storage stable ready-to-administer epinephrine composition includes an aqueous pharmaceutically acceptable carrier containing epinephrine such that epinephrine is present in the ready-to-administer epinephrine composition at a concentration of equal or less than about 0.07 mg/ml. With further respect to the aqueous pharmaceutically acceptable carrier, it is typically preferred that the carrier and/or the ready-to-administer epinephrine composition has a dissolved oxygen content of equal or less than about 5.0 ppm or equal or less than about 3.0 ppm or equal or less than about 2.5 ppm or equal or less than about 2.0 ppm or equal or less than about 1.5 ppm or equal or less than about 1.0 ppm O2 (typically during compounding and/or after 1 month of storage at 25° C.+/−2° C.).”	A water-based solution suitable for pharmaceutical use, acting as a vehicle for epinephrine.
Inert gas (Claim 1)	“To that end, the carrier and/or ready-to-administer epinephrine composition can be subjected to sparging with an inert gas (e.g., argon, helium, freons, nitrogen, etc.), vacuum stripping under agitation, storage under an inert gas headspace, storage in a polymeric container with metallized over-container that further includes an oxygen absorber/scavenger (e.g., metal-free oxygen scavenger (e.g., GLS100, Ageless®, Pharmakeep®, all commercially available from Mitsubishi Gas Chemical America)), and/or using an enzymatic systems that deplete a solution of dissolved oxygen (see e.g., U.S. Pat. No. 9,187,779).”	A non-reactive gas used to displace oxygen during packaging, preventing epinephrine degradation.
Metal ion chelator (Claim 1, Claim 10)	“Moreover, in further contemplated aspects, the ready-to-administer epinephrine composition will also include one or more chelating agents, and particularly metal ion chelators to slow down the baseline and metal ion-stimulated autoxidation of epinephrine. For example, suitable chelators include various bicarboxylic acids, tricarboxylic acids, and aminopolycarboxylic acids such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), and penta(carboxymethyl)diethylenetriamine (DTPA), and salts and hydrates thereof.”	A compound that binds to metal ions to inhibit their catalytic effect on epinephrine degradation.
Ready-to-inject epinephrine composition (Claim 1, Claim 10)	“The inventive subject matter is directed to antioxidant free sterilizable/autoclavable and ready-to-administer compositions containing an oxygen-sensitive drug, such as epinephrine, having improved stability and a physiologically acceptable pH. Advantageously, the compositions presented herein have excellent storage stability even over extended periods, and have suitably low concentrations of epinephrine that allows administration of the composition directly to a patient at a very low dosage rate (e.g., 0.05-2.0 mcg/kg/min) without prior dilution.”	A formulation of epinephrine in an aqueous carrier, suitable for direct administration without prior dilution.
Substantially antioxidant-free (Claim 10)	“It should further be appreciated that contemplated compositions are substantially free of antioxidants (i.e., do not include antioxidants in an amount effective to reduce degradation of total epinephrine by at least about 1% when stored over a period of at least three months at 25° C.+/−2° C.). Therefore, and viewed from a different perspective, antioxidant-free and storage stable ready-to-administer epinephrine composition will include antioxidants in an amount of equal or less than about 0.01 wt %, or equal or less than about 0.005 wt %, or equal or less than about 0.001 wt %, or equal or less than about 0.0005 wt %, or equal or less than about 0.0001 wt %.”	The composition contains a minimal amount of antioxidants, insufficient to significantly inhibit epinephrine degradation.

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US11207280

NOVAQUEST CO-INVESTMENT FUND X LP

Application Number: US16821785
Filing Date: Mar 17, 2020
Status: Granted
Expiry Date: Apr 18, 2039
External Links: Slate, USPTO, Google Patents

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