IP Verse

Epinephrine Compositions And Containers

Patent No. US12133837 (titled "Epinephrine Compositions And Containers") was filed by Novaquest Co-Investment Fund Ix Lp on Nov 15, 2021.

What is this patent about?

’837 is related to the field of pharmaceutical formulations, specifically addressing the challenge of creating a stable, ready-to-administer epinephrine solution. Epinephrine, a crucial medication for treating severe allergic reactions and other emergencies, is known to degrade rapidly in aqueous solutions, especially when diluted. Existing solutions often require dilution prior to use, increasing the risk of dosage errors and contamination, and have a short shelf life, necessitating frequent preparation and disposal.

The underlying idea behind ’837 is to formulate a low-concentration epinephrine solution that remains stable over an extended period without the need for antioxidants, which can themselves cause allergic reactions. This is achieved by carefully controlling several factors: maintaining a mildly acidic pH, using a metal ion chelator to prevent degradation catalyzed by metal ions, minimizing dissolved oxygen, and packaging the solution in a way that protects it from light and oxygen exposure. The low concentration allows for direct administration without prior dilution, reducing the risk of errors.

The claims of ’837 focus on a sterile, storage-stable, ready-to-inject epinephrine composition. The key elements include an aqueous carrier, epinephrine at a concentration of 0.07 mg/ml or less with a high percentage of the R-isomer, a pH between 3.0 and 4.7, a tonicity agent, and a metal ion chelator (bicarboxylic, tricarboxylic, or aminopolycarboxylic acid) at a concentration between 1 and 50 μg/ml. The composition must maintain a total impurities concentration of 0.3% or less after one month of storage at 25°C. A related claim covers a method of producing such a composition, including autoclaving for sterilization.

In practice, the invention involves carefully preparing an aqueous solution of epinephrine with a low concentration of a metal ion chelator like EDTA. The pH is adjusted to a mildly acidic range, and dissolved oxygen is minimized through techniques like sparging with inert gas. The solution is then packaged in a polymeric container under an inert atmosphere, and the entire package is sterilized via autoclaving. This process ensures that the epinephrine remains stable, with minimal degradation and isomerization, even after prolonged storage.

The differentiation from prior approaches lies in the combination of factors that contribute to stability without relying on traditional antioxidants. Previous attempts to stabilize epinephrine often involved antioxidants, which can cause allergic reactions, or complexing agents, which can complicate manufacturing and potentially reduce bioavailability. ’837 achieves stability through a synergistic effect of low epinephrine concentration, controlled pH, metal ion chelation , minimal dissolved oxygen, and appropriate packaging, resulting in a ready-to-inject solution with an extended shelf life and reduced risk of administration errors. The use of autoclaving for sterilization is also a key differentiator, ensuring sterility without significant degradation of the epinephrine.

How does this patent fit in bigger picture?

Technical landscape at the time

In the late 2010s when ’837 was filed, at a time when sterile pharmaceutical solutions were typically manufactured using aseptic processing or terminal sterilization techniques. When dealing with oxygen-sensitive drugs, it was common practice to minimize oxygen exposure through inert gas purging and specialized packaging. When formulating such drugs, maintaining stability and preventing degradation during storage and administration were non-trivial challenges.

Novelty and Inventive Step

The examiner approved the application because the claimed epinephrine composition and its method of preparation were not taught or suggested by the prior art. While Sanghvi taught stable epinephrine compositions with a tonicity agent and a metal complexing agent, the examiner found that the claimed composition, with its specific concentration of epinephrine (equal to or less than 0.07 mg/mL), high R-isomer content (at least 90 mol%), metal ion chelator concentration (1-50 µg/mL), pH (3.0-4.7), and low total impurities (equal to or less than 0.3% after one month at 25°C), exhibited unexpected purity and stability compared to Sanghvi's compositions.

Claims

This patent contains 17 claims, with claims 1 and 10 being independent. Claim 1 focuses on a sterile, storage-stable, ready-to-inject epinephrine composition, while claim 10 focuses on a method of producing such a composition. The dependent claims generally specify further details, limitations, or features of either the composition or the method.

Key Claim Terms New

Definitions of key terms used in the patent claims.

Term (Source)Support for SpecificationInterpretation
Aqueous pharmaceutically acceptable carrier
(Claim 1, Claim 10)		“In one aspect of the inventive subject matter, the inventors contemplate an antioxidant-free and storage stable ready-to-administer composition containing an oxygen-sensitive drug, for example, an epinephrine composition that includes an aqueous pharmaceutically acceptable carrier containing epinephrine. Most typically, the aqueous pharmaceutically acceptable carrier is water for injection, and may further comprise a buffer (e.g., buffer is present in a concentration of between about 1 mM and about 25 mM, buffer may be an acetate buffer, a citrate buffer, a phosphate buffer, a tartrate buffer, and a borate buffer).”A water-based medium suitable for pharmaceutical use, in which epinephrine is dissolved or suspended.
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, preventing them from catalyzing the degradation of epinephrine. The chelator is a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid.
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, with a tonicity agent and a metal ion chelator, that is stable during storage and can be administered directly to a patient without prior dilution.
Tonicity agent
(Claim 1, Claim 10)		“Contemplated compositions may also include a tonicity agent (e.g., sodium chloride, glycerol, thioglycerol, mannitol, lactose, and dextrose). With respect to suitable tonicity agents, pharmaceutically acceptable salts are generally preferred to adjust/increase tonicity. For example, NaCl may be employed at a concentration of at least about 0.6 wt %, or at least about 0.7 wt %, or at least about 0.8 wt %, or at least about 0.9 wt %.”A substance added to the composition to adjust its osmotic pressure to be compatible with physiological fluids.
Total impurities concentration
(Claim 1, Claim 10)		“In further preferred aspects, the ready-to-administer epinephrine composition has, after storage of at least one month, total impurities of equal or less than about 0.7% and equal or less than about 2% S-isomer content. For example, certain ready-to-administer epinephrine composition had, after storage of at least one month at not less than 25° C., total impurities of equal or less than about 0.5% and equal or less than about 1% S-isomer content, or had, after storage of at least one month at 25° C.+/−2° C., total impurities of equal or less than about 0.2% and equal or less than about 1.5% S-isomer content.”The combined amount of all degradation products and other unwanted substances present in the epinephrine composition, expressed as a percentage.

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US12133837

NOVAQUEST CO-INVESTMENT FUND IX LP
Application Number
US17526786
Filing Date
Nov 15, 2021
Status
Granted
Expiry Date
Sep 23, 2039
External Links
Slate, USPTO, Google Patents