WO2023136785A1

WO2023136785A1 - Noscapine extraction from poppy (opium) capsules

Info

Publication number: WO2023136785A1
Application number: PCT/TR2022/050028
Authority: WO
Inventors: Ozan Fidan
Original assignee: Ozan Fidan
Priority date: 2022-01-17
Filing date: 2022-01-17
Publication date: 2023-07-20

Abstract

The invention relates to a standardized extraction method for obtaining noscapine from opium capsules.

Description

NOSCAPINE EXTRACTION FROM POPPY (OPIUM) CAPSULES

Technical Area

Background of the Invention

Papaver somniferum plant contains many alkaloids. While more oil is obtained from its seeds, its capsules contain alkaloids such as morphine, codeine, papaverine and noscapine. However, depending on the properties of the capsule, some capsules contain codeine, some capsules contain morphine, and some capsules contain noscapine. Generally, morphine and codeine are extracted from capsules, although noscapine is a non-narcotic alkaloid that is produced industrially on a limited scale. With the COVID-19 pandemic, there is a global demand for noscapine, the main indication of which is cough relief.

Chemical Formula 1

Noscapine (Chemical Formula 1) is a natural product found in opium, which can cross the blood-brain barrier and shows its effect on the central nervous system and suppresses cough. It is known to be used in cough suppressants in Japan and the Asian continent. Additionally, noscapine has been shown to reduce tumor growth in animal studies.

Noscapine is extracted from crude opium. In addition, raw opium may contain other substances such as morphine. Morphine is a controlled substance that is subject to government control in many places, the amount of crude opium available to a noscapine manufacturer may be limited by the amount of morphine in the raw opium.

Because of this limitation, noscapine manufacturers have turned to a blend of stems and capsules derived from the harvested opium poppy (Papaver somniferum) as an alternative source of noscapine. Depending on the particular type of poppy and the post-harvest processing of the poppy straw, the poppy straw may have a much higher noscapine content than the morphine content.

However, the poppy stem and pod may also contain a number of impurities such as papaverrubin compounds. Papaverrubine compounds can be irreversibly converted to red iminium salts under acidic conditions. In purified noscapine products, red iminium salts, when present, impart an undesirable reddish color to the noscapine product. There is a need to develop a method for separating noscapine from an opium source that may contain papaverrubins or other impurities that undergo irreversible color changes when exposed to acidic processing conditions.

As a solution to this problem, US8394814 has provided a method for obtaining noscapine from an opium source containing at least one impurity that undergoes an irreversible color change when exposed to a pH of less than about 5. According to the method, noscapine is soluble in a first solvent such as acetone, acetonitrile, which has a pH greater than about 5. By adding water as a second solvent to the reaction mixture, noscapine is recrystallized, separating it from the impurity causing the color change.

US4029797 relates to the preparation of a cough syrup that masks the characteristic unpleasant taste of noscapine.

Description of the Invention

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

Reference throughout this specification to "one aspect", "an aspect", "another aspect", "a particular aspect", "combinations thereof" means that a particular feature, structure or characteristic described in connection with the invention aspect is included in at least one aspect of the present invention. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more aspects.

The term "comprise(s)", or "comprising" is generally used in the sense of include(s)/including, that is to say, permitting the presence of one or more features or components. The terms "comprise(s)" and "comprising" also encompass the more restricted ones "consist(s)" and "consisting", respectively.

As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

The invention relates to the production of noscapine from opium capsules or opium capsules with stems. The process steps are given below. a) Opium capsules are weighed, b) It is passed through a 0, 1-5 mm sieve , it is converted micronized powder as much as possible, as a critical aspect of invention, c) As a pre-treatment before extraction, it is mixed with a high-speed ultrasonic or nonultrasonic mixer for 15 to 75 minutes, pH: 9.5 is adjusted with NaOH 1% solution, d) For each kg of the mass consisting of capsules rich in Noscapin, a solvent system containing Ethanol 80% and distilled water 20%between 4 and 8 liters, brought to a temperature of minimum 40°C and maximum 70°C, is added, preferably the temperature is 50-55°C, e) Extraction is carried out in the period of 1 hour to 6 hours, preferably the extraction time is 2 hours, f) After the ethanol is evaporated in the extraction system, the remaining aqueous phase is brought to a temperature between 40° C and 50° C before being filtered, filtered with the help of cellulose-containing or cartridge filters, g) Acetonitrile is added into the obtained aqueous solution (Acetonitrile comprising solvent system as acetonitrile 80%and distilled water 20%) and the extraction is carried out at a temperature of 50°C to 70°C, preferably at 50-55°C for a minimum of 1 hour and a maximum of 3 hours, h) After the extraction process, a sufficient amount of minimum 0.01%, maximum 1% activated carbon is added to the extraction system by mixing, i) Acetonitrile solution with activated carbon is taken into a separate glass or steel reactor for crystallization after filtration, j) Temperature of Acetonitrile 80% Water 20% extraction solvent is increased to 50° C, distilled water is added to the system within a minimum of 1 hour and a maximum of 24 hours, and concentration rate of extraction solvent system is changed to Acetonitril %20 and Water 80% concentration. Simultaneously in a minimum of 1 hour and a maximum of 24 hours, temperature of the extraction solvent system is decreased to minimum 2° C maximum 15 ° C with the help of a cooling system (with the help of chillers or cooled glass reactors), after 12 hours or 24 hours, the precipitated solution is filtered at a temperature not exceeding 8 ° C to obtain raw noscapine, k) The filtered acetonitrile- water solution is centrifuged at minimum 1000 G and maximum 5000 G by industrial centrifuge, precipitated noscapine is added to the crude noscapine crystals precipitated in the previous step, l) Raw noscapine is dried in an oven or industrial powder dryers with a moisture content of around 0.1% or 0.5%, m) The dried raw noscapine which looks slightly yellow to greenish color is washed with acetone solution or methanol solution in order to reduce the amount of impurity thanks to the washing process, another aspect of invention n) Noscapin obtained after washing is dried at 30° C (minimum) , 80° C (maximum) so that the moisture content is adjusted to the pharmacopoeial limits. The pharmacopoeial noscapine obtained is 99% to 101% pure, and noscapine is obtained with a total impurity of less than 0.50% and each impurity less than 0.2%, in accordance with the limits of the noscapine monograph available in the European Pharmacopoeia.

Claims

1. A process for obtaining noscapine from opium capsules or a mixture of stem and capsule, comprising the steps of; a) Weighing the opium capsules, sifting them with a 0,1-5 mm sieve, turning them into micronized powder as much as possible, b) Mixing for 15 to 75 minutes with a high-speed ultrasonic or non-ultrasonic mixer as a pretreatment before extraction, adjusting to pH: 9.5 with NaOH 1% solution, c) The addition of a solvent system containing Ethanol 80% and distilled 20% water between 4 and 8 liters per kg of mass, brought to a temperature of minimum 40°C and maximum 70°C, preferably 50-55°C, d) Extracting for 1 hour to 6 hours, preferably 2 hours, e) After the ethanol is evaporated in the extraction system, the remaining aqueous phase is brought to a temperature between 40° C and 50° C before filtering, filtered with the help of cellulose-containing or cartridge filters, f) Adding 80% acetonitrile to the obtained aqueous solution, containing 20% distilled water, and extraction between 50°C and 70°C, preferably at 50-55°C for a minimum of 1 hour and a maximum of 3 hours, g) Adding a sufficient amount of minimum 0.01%, maximum 1% activated carbon to the extraction system after the extraction process, h) Transfer the acetonitrile solution with activated carbon into a separate glass or steel reactor for the crystallization process after filtration, i) Heating the solution to 50°C, adding distilled water to the system within a minimum of 1 hour and a maximum of 24 hours, bringing 20% acetonitrile to 80% water concentration, simultaneously cooling the solution system to 2-15°C within a minimum of 1 hour and a maximum of 24 hours, filtering the crude noscapine solution, which precipitated after 12 hours or 24 hours, at a temperature not exceeding 8°C, j) Centrifugation of the filtered acetonitrile-water solution at a minimum of 1000 G and a maximum of 5000 G, adding the precipitated noscapine to the crude noscapine crystals precipitated in the previous step, k) Drying the raw noscapine moisture content of 0.1% to 0.5% in an oven or industrial powder dryers, l) Washing the dried raw noscapine with acetone solution or methanol solution, m) Drying between 30° C- 80° C.

2. A process for obtaining noscapine according to claim 1, comprising the steps of; a) Weighing the opium capsules, sifting them with a 0,1-5 mm sieve, turning them into micronized powder as much as possible, b) Mixing for 15 to 75 minutes with a high-speed ultrasonic or non-ultrasonic mixer as a pretreatment before extraction, adjusting to pH: 9.5 with NaOH 1% solution, c) The addition of a solvent system containing Ethanol 80% and distilled water 20% between

4 and 8 liters per kg of mass, brought to a minimum temperature of 50-55°C, d) 2 hours of extraction, e) After the ethanol is evaporated in the extraction system, the remaining aqueous phase is brought to a temperature between 40° C and 50° C before filtering, filtered with the help of cellulose-containing or cartridge filters, f) Adding 80% acetonitrile to the obtained aqueous solution containing 20% distilled water, extraction at 50-55°C for a minimum of 1 hour and a maximum of 3 hours, g) Adding a sufficient amount of minimum 0.01%, maximum 1% activated carbon to the extraction system after the extraction process,

4 h) Transfer the acetonitrile/water solution with activated carbon into a separate glass or steel reactor for the crystallization process after filtration, i) Heating the solution to 50°C, adding distilled water to the system within a minimum of 1 hour and a maximum of 24 hours, bringing 20% acetonitrile to 80% water concentration, simultaneously cooling the solution system to 2-15°C within a minimum of 1 hour and a maximum of 24 hours, Filtering the crude noscapine solution, which precipitated after 12 hours or 24 hours, at a temperature not exceeding 8°C, j) Centrifugation of the filtered acetonitrile-water solution at a minimum of 1000 G and a maximum of 5000 G, adding the precipitated noscapine to the crude noscapine crystals precipitated in the previous step, k) Drying the raw noscapine moisture content of 0.1% to 0.5% in an oven or industrial powder dryers, l) Washing the dried raw noscapine with acetone solution or methanol solution, m) Drying between 30° C- 80° C.

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