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Process for Manufacturing Stable Epinephrine

a manufacturing process and stable technology, applied in the direction of granular delivery, organic active ingredients, pill delivery, etc., can solve the problems of acidic solutions, irritating, and adding significantly to the cost of the product, and mildly acidic ph epinephrine is notoriously vulnerable to oxidative degradation

Inactive Publication Date: 2020-09-24
HARC THERAPEUTICS AG
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The solid-state epinephrine formulation at pH 8.5 demonstrates remarkable stability and resistance to oxidation, reducing undesirable impurities like epinephrine sulfonate and total impurities, making it suitable for various dosage forms without the need for expensive delivery devices or acidic conditions.

Problems solved by technology

Further, epinephrine at mildly-acidic pH is notoriously vulnerable to oxidative degradation to epinephrine sulfonate, an undesirable contaminant.
Such acidic solutions, however, may be irritating.
Such devices add significantly to the expense of the product.
Such devices also greatly increase the number of potential failure modes, a risk which Failure Mode, Effects And Criticality Analysis (FMECA) attempts to reduce.
Further, in certain usage environments liquid solution formulations may be unsuitable or unstable.

Method used

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  • Process for Manufacturing Stable Epinephrine
  • Process for Manufacturing Stable Epinephrine
  • Process for Manufacturing Stable Epinephrine

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0022]To test the effect of increased acidity on epinephrine stability, I had prepared epinephrine dissolved in aqueous solvent to make a solution containing 3.33% (w / w) epinephrine in solution, with the pH adjusted to pH 6 for some of my samples and pH 5 for my other samples. I number these samples / 1A and / 2A respectively. I had my samples assayed when made, and again after one month storage under normal storage conditions and in accelerated condition, and again after two months storage under normal and accelerated conditions. Results for normal storage conditions are show in Table 1.

TABLE 125° C. / 60% RH ResultsEpinephrine in SolutionMonths012Epinephrine Assay (% label claim) / 1A95.996.296.8 / 2A100.098.099.2Sodium Metabisulfite (% label claim) / 1A50.442.045.0 / 2A19.713.315.4Epinephrine sulfonate (% NPA) / 1A4.465.917.75 / 2A1.511.322.00Limit151515Total Unknown Impurities (% NPA) / 1A0.17ND0.14 / 2A0.120.540.18Limit111Total Impurities (% NPA) / 1A4.635.917.89 / 2A1.631.862.18Limit161616

[0023]The d...

example 2

[0027]In Example 2, no acid / base is added, thus providing a mixture with a pH of about 7. In contrast to Example 1, which employed acidic pH and thus produced true solutions of epinephrine dissolved in solvent, Example 2 uses a neutral pH. The epinephrine thus does not dissolve. Rather, it remains in solid state, suspended (not dissolved) in the solvent system. Sample number / 1 used 3.33% (w / w) epinephrine (as used in Example 1). Sample number / 2 used 13.33% (w / w) epinephrine. I designate these samples as sample numbers / 1 and / 2, and provide the formulae for each in Table 3.

TABLE 3Sample Number / 1 / 2Material% w / wmg% w / wmgPurified water87.32%130.9878.22%117.33Gelatin (EP / USP / JP)4.80%7.204.30%6.45(Fish HMW)Mannitol (EP / USP)3.84%5.763.44%5.16Sodium metabisulfite0.30%0.450.30%0.45(Ph Eur)Disodium EDTA (Ph Eur)0.05%0.080.05%0.08Epinephrine3.33%5.0013.33%20.00Sucralose micronized NF0.35%0.530.35%0.53NaOH0.00%0.000.00%0.00Total100.00%150.00100.00%150.00

[0028]Sample numbers / 1 and / 2 were not ...

example 3

[0033]In Example 3, I used the same general formula as in Example 2, but specified adding sodium hydroxide to increase the pH of the suspension to 8.5. As with Example 2, I compared 3.33% and 13.33% (w / w) epinephrine. I provide the formulae for Sample numbers / 3 and / 4 in Table 7.

TABLE 7Sample Number / 3 / 4Material% w / wmg% w / wmgPurified water84.75%127.1375.71%113.56Gelatin (EP / USP / JP)4.80%7.204.30%6.45(Fish HMW)Mannitol (EP / USP)3.84%5.763.44%5.16Sodium metabisulfite0.30%0.450.30%0.45(Ph Eur)Disodium EDTA (Ph Eur)0.05%0.080.05%0.08Epinephrine3.33%5.0013.33%20.00Sucralose micronized NF0.35%0.530.35%0.53NaOH2.57%3.852.51%3.77Total100.00%150.00100.00%150.00

[0034]Sample numbers / 3 and / 4 were basic pH. I thus had these samples assayed to determine whether the epinephrine dissolved into solution and if so, by what amount. I provide these data in Table 8.

TABLE 8Epinephrine at pH 8.5 Remains In Solid StateSuspension Assay Testing% ofMinimum StoppageEpinephrine(Min 30)TheoreticalEpinephrineDissol...

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Abstract

Epinephrine formulated in aqueous solvent at a basic pH of about 8.5 remains in solid state. My data show that epinephrine formulated at a pH of about 8.5 is surprisingly resistant to oxidation. I here teach how to formulate solid-state epinephrine in basic solution, and how to use solid-state epinephrine to make pharmaceutical dosage forms.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of U.S. patent application Ser. No. 16 / 355941 filed 18 Mar. 2019, the contents of which are here incorporated by reference.STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT.[0002]None.THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.[0003]HARC Therapeutics AG (Switzerland) and Catalent UK Swindon Zydis Ltd. (United Kingdom).REFERENCE TO SEQUENCE LISTING.[0004]None.STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.[0005]None.BACKGROUND[0006]Epinephrine, also known as 4-[(1 R)-1-Hydroxy-2-(methylamino)ethyl]-1, 2-benzenediol, is the active principle of the adrenal medulla and an endogenous catecholamine which acts directly on both alpha and beta adrenergic receptors. When used in pharmaceutical compositions, epinephrine can act as a non-selective alpha and beta adrenergic agonist and can work rapidly to improve breathing, stimulate the heart, raise dropping blood...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/137A61K9/16A61K9/20
CPCA61K9/1611A61K9/2063A61K9/2009A61K9/2018A61K9/19A61K9/2095A61K9/1658A61K9/1623A61K31/137
Inventor CHISHOLM, ROBERT
Owner HARC THERAPEUTICS AG
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