Short path distillation under vacuum for the enrichment of natural substances

Description

[0001] The present invention relates to a process for the production, extraction and enrichment of dronabinol (Δ9-THC) as well as natural substances from plant extracts.

[0002] Cannabis (hemp), along with the genus Humulus (hops), belongs to the Cannabaceae family, although Humulus does not contain cannabinoids. Within the genus Cannabis, a botanical and chemotaxonomic differentiation occurs, namely into the species Cannabis sativa Linnaeus, Cannabis indica LAM, and Cannabis ruderalis, or into the "collective species" Cannabis sativa L., consisting of the subspecies Cannabis sativa ssp. sativa and ssp. indica. Furthermore, cannabis is divided into drug hemp and fiber hemp, with the distinction being made based on the quantitative ratio of the main cannabinoids cannabidiol (CBD) and Δ<-tetrahydrocannabinol (Δ<-THC) (INN: dronabinol). Fiber hemp (also: commercial hemp, industrial hemp) is mainly used for industrial fiber production and may have a maximum Δ 9< -THC content of 0.2% (e.g. Germany, etc.), while the drug type can have a Δ 9< -THC content of approximately 5-35% (marijuana, hashish).Cannabis sativa L. contains over 400 different compounds, of which more than 60 belong to the class of cannabinoids. The most important cannabinoids are listed below: Cannabigerol extract (CBG): Cannabigerol ((E)-CBG-C 5 ), cannabigerol monomethyl ether ((E)-CBGM-C 5 A), cannabigerolic acid A ((Z)-CBGA-C 5 A), cannabigerovarin ((E)-CBGV-C 3 ), cannabigerolic acid A ((E)-CBGA-C 5 A), cannabigerolic acid A monomethyl ether ((E)-CBGAM-C 5 A), cannabigerovaric acid A ((E)-CBGVA-C 3 A); Cannabichromene-arge (CBC): Cannabichromene (CBC-C 5 ), cannabichromenic acid A (CBCA-C 5 A), cannabichromevarin (CBCV-C 3 ), cannabichromevarinic acid A (CBCVA-C3 A); Cannabidiol oil (CBD): Cannabidiol (CBD-C 5 ), Cannabidiol monomethyl ether (CBDM-C 5 ), Cannabidiol-C4 (CBD-C 4 ), Cannabidivarin (CBDV-C 3 ), Cannabidiorcol (CBD-C 1 ), Cannabidiolic acid (CBDA-C 5 ), Cannabidivarinic acid (CBDVA-C 3 ); Cannabinodiol artige (CBND) : Cannabinodiol (CBND-C 5 ), cannabinodivarin (CBND-C 3 ); Tetrahydrocannabinol artige (THC):Δ9-Tetrahydrocannabinol (Δ9-THC-C 5 ), Δ9-Tetrahydrocannabinol-C4 (Δ9-THC-C 4 ), Δ9-Tetrahydrocannabivarin (Δ9-THCV-C 3 ), Δ9-Tetrahydrocannabiorcol (Δ9-THCO-C 9 Δ9-Tetrahydrocannabinolsäure (Δ9-THCA-C 5 A), Δ9-Tetrahydrocannabinolsäure B (Δ9-THCA-C 5 B), Δ9-Tetrahydrocannabinolsäure-C4 (Δ9-THCAins-C 4 A und / oderbi Ahydra BTevar Δ9 (Δ9-THCVA-C 3 A), Δ9-Tetrahydrocannabiorcolsäure (Δ9-THCOA-C 1 A und / oder B), (-)-Δ8-trans-(6aR,10aR)-Δ8-Tetrahydrocannabinol (Δ8-THC-C 5 ), (-)-Δ8-trans-(6aR,10aR)-Tetrahydrocannabinolsäure A (Δ8-THCA-C 5 A); (-)-(6aS,10aR)-Δ9-Tetrahydrocannabinol ((-)-cis-Δ9-THC-C 5 ); Cannabinol extract (CBN): Cannabinol CBN-C 5 , Cannabinol-C4 (CBN-C 4 ), Cannabivarin (CBN-C 3 ), Cannabinol-C2 (CBN-C 2 ), Cannabiorcol (CBN-C 1 ), Cannabinolsäure A (CBNA-C 5 A), Cannabinolmethylether (5CBNM ) Cannabitriol oil (CBT):(-)-(9R,10R)-trans-Cannabitriol ((-)-trans-CBT-C 5 ), (+)-(9S,10S)-Cannabitriol ((+)-trans-CBT-C 5 ), (±)-(9R,10S / 9S,10R)-Cannabitriol ((±)-cis-CBT-C 5 ), (-)-(9R,10R)-trans[10-O-Ethyl-cannabitriol] ((-)-trans-CBT-OEt-C 5 ), (±)-(9R,10R / 9S,10S)-Cannabitriol-C 3 ((±)-trans-CBT-C 3 ),8,9-Dihydroxy-Δ6a(10a) tetrahydrocannabinol (8,9-Di-OH-CBT-C 5 ), Cannabidiolsäure A (CBDA-C 5 9-OH-CBT-C5 ester), (-)-(6aR,9S,10S,10aR)-9,10-Dihydroxy-hexahydrocannabinol, Cannabiripsol Cannabiripsol-C5, (-)-6a,7,10a-Trihydroxy-Δ9-tetrahydrocannabinol ((-)-Cannabitetrol), 10-Oxo-Δ6a(10a) tetrahydrocannabinol (OTHC); Cannabielsoin-artige (CBE): (5aS, 6S, 9R, 9aR)- C 5 -Cannabielsoin (CBE-C 5 ), (5aS,6S,9R,9aR)-C 3 -Cannabielsoin (CBE-C 3 ), (5aS,6S,9R,9aR)-Cannabielsoinsäure A (CBEA-C 5 A), (5aS,6S,9R,9aR)-Cannabielsoinsäure B (CBEA-C 5 B), (5aS,6S,9R,9aR)-C3-Cannabielsoinsäure B (CBEA-C 3 B), Cannabiglendol-C3 (OH-iso-HHCV-C 3 ), Dehydrocannabifuran (DCBF-C 5 ), Cannabifuran (CBF-C 5 ); Isocannabinoids:(-)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabinol, (±)-Δ7-1,2-cis-(1R,3R,6S / 1S,3S,6R)-Isotetrahydrocannabivarin, (-)-Δ7-trans-(1R,3R,6R)-Isotetrahydrocannabivarin; Cannabicyclol-artige (CBL): (±)-(1aS,3aR,8bR,8cR)-cannabicyclol (CBL-C 5 ), (±)-(1aS,3aR,8bR,8cR)-cannabicyclolic acid A (CBLA-C 5 A), (±)-(1aS,3aR,8bR,8cR)-cannabicyclovarin (CBLV-C 3 ); Cannabicitran-artige (CBT): Cannabicitran (CBT-C 5 ); Cannabichromanon-artige (CBCN): Cannabichromanone (CBCN-C 5 ), cannabichromanone-C3 (CBCN-C 3 ), cannabicoumaronone (CBCON-C 5 ).

[0003] In addition to the cannabinoids mentioned above, their corresponding carboxylic acids are found in the raw drug. These carboxylic acids are biosynthetic precursors.

[0004] Cannabis preparations exert a variety of therapeutic effects, including antispastic, analgesic, antiemetic, neuroprotective, anti-inflammatory, and effects in psychiatric disorders (Grotenhermen F, Müller-Vahl K: The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 2012; 109(29-30): 495-501. DOI: 10.3238 / arztebl.2012.0495).

[0005] In Germany, a cannabis extract containing THC (dronabinol) and CBD in a 1:1 ratio (nabiximols) has been approved under pharmaceutical law since 2011 for the treatment of moderate to severe, therapy-resistant spasticity in multiple sclerosis (MS) as a sublingual spray (Sativex).

[0006] The following are the chemical structures of some cannabinoid active ingredients and the nomenclature of the two active ingredients of tetrahydrocannabinol, whose IUPAC names are (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol or Δ9-THC and (6aR-trans)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol or Δ8-THC.

[0007] For the purposes of the present invention, the term "tetrahydrocannabinol" or "THC" - unless otherwise stated - shall include all isomers, in particular double bond isomers.

[0008] THC can be produced synthetically (EP2314580B1).

[0009] DE 100 51 427 C1 (Müller) describes a THC-containing primary extract obtained from cannabis / hemp using CO2 extraction under supercritical or subcritical pressure and temperature conditions. This process is carried out using an SFC or SFE system ("supercritical fluid chromatography").

[0010] However, a suitable short-path distillation under vacuum for extracting high-purity THC from cannabis raw material is not described in the prior art. The prior art discloses the simple vacuum distillation of THC (WO 00 / 25127A1), and EP1051084B1 describes, for example, a steam distillation from hemp. US 2002 / 039795 describes a process for producing tetrahydrocannabinol by extracting plant material with a non-polar solvent followed by vacuum distillation.

[0011] WO2017055619A1 describes a short-path distillation for cannabidiol.

[0012] Therefore, the task is to provide an improved distillation for the extraction of THC, so that a THC-enriched extract, or even THC in high purity, is obtained.

[0013] The problem is solved by the patent claims.

[0014] Therefore, the invention relates to a method for extracting THC from cannabis plant material, wherein a short-path distillation is carried out in a vacuum (hereinafter: method according to the invention).

[0015] For the purposes of this invention, distillation refers to a thermal separation process for extracting evaporable liquids from a gas phase and separating them from substances that are difficult to evaporate, whereby a THC-containing extract is concentrated in the distillate. "Vacuum distillation" for the purposes of this invention means that the distillation takes place in a vacuum at 0.001 to 50 mbar, preferably 0.001 to 10 mbar, particularly preferably 0.001 to 1 mbar in the so-called fine vacuum range.

[0016] Furthermore, the evaporator temperature according to the invention is 120 to 240 degrees Celsius and preferably 150 to 230 degrees Celsius.

[0017] It is essential that the vacuum distillation process according to the invention is carried out by means of short-path distillation under vacuum. "Short-path distillation under vacuum" in the context of this invention means that the gas phase in the applied fine vacuum only has to travel a very short distance of preferably 10 cm, in particular 5 cm, in particular 2 cm, in particular 0.5 cm between the evaporator wall and the (internal) condenser. For example, a short-path evaporator can be used, which structurally corresponds to a conventional thin-film evaporator, but with the condenser integrated into the interior of the evaporator cylinder, so that the path the vapors have to travel to reach the condenser is very short, and pressures of 0.001 mbar can be achieved.

[0018] A suitable thin-film evaporator within the meaning of this invention has a substantially cylindrical, steam-heated inner wall, onto which a thin layer of a primary extract is applied by means of rotating distribution elements. The motor-driven distribution elements are required to apply and distribute the mixture, which rapidly evaporates on the plates.

[0019] In another embodiment, a wiper system accelerates the evaporation process by keeping the thin layer (product film) turbulent and optimizing heat transfer and mass transfer. The lower-boiling fractions of the incoming raw material or crude extract evaporate directly from the product film within a short time. The required residence time of the product on the heated evaporator inner wall is thus minimal. Thanks to the short residence time, low evaporation temperature, and the immediate subsequent cooling of the concentrate, thermal damage and stress to the cannabinoids, especially THC, are minimized. A particularly advantageous feature is that the incoming crude extract can be applied without the need for additional solvent.

[0020] However, according to the invention, a short-path evaporator or a correspondingly adapted thin-film evaporator in a vacuum device is preferred.

[0021] Furthermore, it is preferred that the process according to the invention for short-path distillation under vacuum is carried out with at least one additional column or separation column. A suitable column according to the invention is, for example, a DN 60 column (ø50 mm, L = 360 cm) with a vacuum jacket and TI nozzles made of borosilicate or stainless steel. The column can have conventional trays as well as packing or compartments, so that preferably at least 10 separation stages are achieved. Such separation columns according to the invention are available, for example, from VTA Verfahrenstechnische Anlagen GmbH & Co. KG, Niederwinkling (DE) or UIC GmbH, Alzenau-Hörstein. In a further embodiment, the length of the column is at least 2.50 m, preferably 2.70 m or more than 3 m.

[0022] In a further preferred embodiment of the invention, the short-path distillation under vacuum can be combined with an additional column distillation. In particular, a short-path evaporator or a suitably adapted thin-film evaporator can be equipped with a separation column. For the purposes of this invention, a column distillation is also a suitable rectification under vacuum, even under reflux, which preferably has 10 separation stages. The rectification allows for the reliable separation of CBD and enrichment of THC to more than 80%.

[0023] It is further preferred that the short-path distillation according to the invention be carried out in a vacuum with a coupled or connected column distillation or a coupled or connected separation column at a pressure of 0.001 to 50 mbar, preferably 0.001 to 10 mbar, in particular 0.001 to 1 mbar. It is further preferred that the temperature is 120 to 240 degrees Celsius, in particular 150 to 230 degrees Celsius. In a preferred embodiment, the pressure is 5-10 mbar and the temperature is 200 to 230 degrees Celsius. This allows for safe THC enrichment, while other cannabinoids are completely depleted.

[0024] It is further particularly preferred that the short-path distillation under vacuum according to the invention be combined with a centrifugal partition chromatography (CPC) process, either in series upstream or downstream. In particular, the short-path distillation under vacuum can be coupled or combined with a CPC process.

[0025] Therefore, in a further object, the invention relates to a method for the separation and / or purification of natural substances from plant extracts, in particular cannabinoids from a cannabis extract.

[0026] To achieve this object, a process for the separation and / or purification of natural substances from plant extracts, in particular cannabinoids from a cannabis extract, is carried out, comprising at least one liquid-liquid partition chromatography step, wherein a solvent is kept stationary by centrifugal force with a second immiscible liquid phase in the mobile phase and a short-path distillation in a vacuum is carried out upstream or downstream, wherein one or more fractions or one or more pure substances are separated.

[0027] The CPC process can be used for the extraction and enrichment of plant compounds from plant extracts on analytical, semi-preparative, and preparative scales. CPC is a liquid-liquid chromatography method that typically uses a two-phase solvent system.

[0028] The CPC process enables the virtually loss-free separation of highly complex substance mixtures from crude extracts. Manufacturers of such centrifugal partition chromatographs for CPC include Kromaton Sarl (Annonay, FR) and Armen Instrument Sas (Saint-Avé, FR).

[0029] As with common liquid-liquid chromatography methods, such as high-speed countercurrent chromatography (HSCCC), the CPC process uses a two-phase solvent mixture. Either the upper or lower phase can be used as the stationary phase. Unlike HSCCC, however, CPC does not use a capillary coil, but rather a rotor equipped with several hundred separation chambers. In these chambers, arranged directly one after the other, the substances contained in the plant extract are distributed between the mobile and stationary phases.

[0030] The system is set into rapid rotation (up to 2,500 rpm) during the separation process. This not only retains the desired phase in the CPC rotor, depending on the flow direction, but also accelerates the separation of the two phases through centrifugal force. This allows for high flow rates and, consequently, the throughput of large amounts of substance in a short time, thus enabling preparative applications of this separation technique.

[0031] It is further particularly preferred that the short-path distillation under vacuum according to the invention be combined with a sequential centrifugal partition chromatography (sCPC) process, either in series upstream or downstream. In particular, the short-path distillation under vacuum can be coupled or combined with an sCPC process.

[0032] To achieve the above-mentioned object, a process for the separation and / or purification of natural substances from plant extracts, in particular cannabinoids from a cannabis extract, is carried out, comprising at least one liquid-liquid partition chromatography step, wherein a continuous change of the stationary phase to the mobile phase and vice versa takes place and a short-path distillation in a vacuum is carried out upstream or downstream, wherein one or more fractions or one or more pure substances are separated.

[0033] A characteristic of sCPC is the continuous switching of the stationary phase to the mobile phase and vice versa. This means that the denser or less dense phase can be selected as the mobile phase, and this selection can be changed during a separation. The substances to be separated are moved in a liquid-liquid centrifugal column at different velocities in the two phases of different densities due to a different partition coefficient.

[0034] An sCPC apparatus comprises at least one rotor with numerous round metal plates containing, for example, over a thousand separation chambers connected in series (also called rotor chambers, forming a rotating separation column). With the aid of a pump, a mobile liquid phase (continuously) flows through the stationary liquid phase in the rotor. The rotor is accelerated to approximately 1,000 rpm or more, so that centrifugal force causes the separation of the two liquid phases due to the density differences in the individual chambers. Once the liquid mobile phase is in equilibrium with the liquid stationary phase, the sample or substance mixture can be injected into the rotor.

[0035] Separation occurs based on different adsorption in the mobile or stationary phase, or on the respective partition coefficient (K) of a substance between the mobile and stationary phases. The substances are moved through the individual separation chambers to the rotor outlet and fractionated. The characteristic alternating switching between stationary and mobile phases is achieved by controlling the pumps used via valves at a selectable frequency. The corresponding solvent is pumped into the respective controlled phase at a selectable time period ("duration of pumping"), at each end of a rotor, so that the pumps are arranged in opposite directions.

[0036] The sample or substance mixture is preferably fed into the rotor as an intermediate. In another embodiment, two or more rotors can be coupled.

[0037] The rotor chambers are preferably filled with an upper and a lower liquid phase in a 50 / 50 (volume) ratio. The substance mixture is continuously pumped between the two rotating separation columns at a defined flow rate, and the separation occurs cyclically and staggered, with the upper phase serving as the mobile phase in a first step ("ascending") and the lower phase serving as the mobile phase in a second step ("descending").

[0038] Depending on the concentration and the different distribution coefficients of the substances in the mixture, the separation takes place into two product streams.

[0039] Suitable equipment and devices can be obtained from Armen Technologies (France) under the name "True Moving Bed CPC".

[0040] The sCPC process can be used for the extraction and enrichment of plant compounds from plant extracts on analytical, semi-preparative, and preparative scales. sCPC is a liquid-liquid chromatography method that typically uses a two-phase solvent system.

[0041] The following genera are preferred for the plant extracts according to the invention: Equiseti, Juglandis, Millefolii, Quercus, Taraxac, Althaeae, Matricariae, Centaurium, Levisticum, Rosmarinus, Angelica, Artemisia, Astragalus, Leonurus, Salvia, Saposhnikovia, Scutellaria, Siegesbeckia, Armoracia, Capsi, Echina, Echina, Echinaceae Galphimia, Hedera, Melia, Olea, Pelargonium, Phytolacca, Primula, Salix, Thymus, Vitex, Vitis, Rumicis, Verbena,Sambucus, Gentiana, Cannabis, Silybum.

[0042] The following species are preferred for the plant extracts according to the invention: Equiseti grass (horsetail herb), Juglandis folium (walnut leaves), Millefolii herba (yarrow herb), Quercus cortex (oak bark), Peanut herb (Dandelion herb), Althaeae radix (marshmallow root) and Matricariae flos (or Flos chamomillae (chamomile flowers)), Centaurium erythraea (Tausendgüldenkraut), Levisticum officinale (Liebstöckel), Rosmarinus officinalis (Rosmarin), Angelica dahurica (Siberian Engelwurz, PinYin Name: Baizhi), Angelica sinensis (Chinese Angelika, PinYin Name: Danggusia scopariate), Armisia scopariate (Besen-Beifuß, PinYin Name: Yinchen), Astragalus membranaceus (var. Mongolicus) (Traganthwurzel, Chin.: Huang-Qi), Leonurus japonicus (Löwenohr, Chin.: T'uei ), Salvia miltiorrhiza (Rotwurzel-Salbei, Chin.: Savaria dipos). (Siler, PinYin Name: Fangfeng), Scutellaria baicalensis (Baikal-Helmkraut, Banzhilian), Siegesbeckia pubescens (Himmlisches Kraut, PinYin Name: Xixianciao), Armoracia rusticana (Meerettich), Capsicum sp.(Paprika), Cistus incanus (Echiliaceastroa), Z (Sunflower), Echinacea purpurea (Sunflower), Galphimia glauca, Hedera helix (Efeu), Melia toosendan (Chinesische Holunderfruchte, Chin.: Chuan Lian Zi), Olea europaea (Olive), Pelargonium sp.(Pelagornia), Phytolacca americana (Pokeweed), Primula veris (Cowslip), Salix sp. (Willow), Thymus L. (Thyme), Vitex agnus castus (Chasteberry), Vitis vinifera (Noble Grapevine). Rumicis herba (Sorrel herb), Verbena officinalis (Verbena),Sambucus black (Black elderberry), Gentiana lutea (Yellow Gentian), Cannabis sativa (Hemp), Silybum marianum (Milk thistle).

[0043] Mixtures of the above genera and / or species are also encompassed by the invention.

[0044] The above species and genera are particularly rich in healing natural substances and are described as medicinal plants, such as in the products based on plant extracts from Bionorica SE (e.g., Bronchipret ®< , Imupret ®< , Sinupret ®< ). Furthermore, such plants exhibit common characteristic substance classes, such as flavonoids, polyphenols, etc.

[0045] In a preferred embodiment, the plant extract is obtained from a first solvent, such as alcohols, ethanol, water, hydrocarbons, heptane or mixtures thereof, and the soluble components are used.

[0046] For example, classes of substances from plant extracts such as alkaloids, bitter substances, anthocyanins, anthraquinones, coumarins, flavonoids, glucosinolates, lactones, lignans, lipids, cannabinoids, phenols, polyphenols, saponins, terpenes, xanthones can be enriched or depleted in the fractions in the aforementioned processes and can be separated.

[0047] Such fractions and pure substances can be obtained particularly advantageously in high purity and yield in the aforementioned processes.

[0048] Solvents used in liquid-liquid partition chromatography can be found, for example, in Skalicka- Woźniak K, Garrard I, A comprehensive classification of solvent systems used for natural product purifications in countercurrent and centrifugal partition chromatography, Nat Prod Rep. 2015 Nov;32(11):1556-61.

[0049] Examples of suitable solvents according to the invention from which two-phase solvent systems (mobile phase / stationary phase) for plant extracts can be provided are: a.) Hydrocarbons such as n-hexane, cyclohexane, isohexane, heptane, isooctane; b.) Ethers such as t-butyl methyl ether, petroleum ether, diethyl ether; c.) Halogenated solvents such as chloroform, dichloromethane, benzotrifluoride, dichloroethane, carbon tetrachloride, trichloroethane; d.) Water-soluble alcohols such as butanol, methanol, ethanol, isopropanol; e.) Water-soluble esters such as ethyl acetate, isopropyl acetate; f.) Acetonitrile, toluene.

[0050] Suitable two-phase solvent systems can be prepared from these aforementioned solvents, preferably those such as: n-heptane / acetonitrile n-heptane / ethyl acetate / acetonitrile; n-heptane / ethyl acetate / t-butyl methyl ether / acetonitrile; n-heptane / ethyl acetate / methanol / water; n-heptane / ethanol / water.

[0051] According to the invention, a process is therefore provided for the separation and / or purification of natural substances from plant extracts, in particular cannabinoids from a cannabis extract, in particular THC from cannabis plant material, wherein a short-path distillation in a vacuum is coupled with a CPC process and / or sCPC or is connected upstream or downstream.

[0052] For example, the CPC process comprises at least one liquid-liquid partition chromatography step, or the use of a centrifugal partition chromatograph for liquid-liquid partition chromatography for the extraction of, for example, THC, wherein preferably a solvent is selected from hexane, cyclohexane, heptane, n-heptane, iso-heptane, octane, n-octane, iso-octane, which is held stationary by centrifugal force and a second immiscible liquid phase can be pumped through as the mobile phase.

[0053] For example, the sCPC process comprises at least one liquid-liquid partition chromatography step for the extraction of, for example, THC, wherein preferably a solvent is selected from hexane, cyclohexane, heptane, n-heptane, iso-heptane, octane, n-octane, iso-octane, wherein a continuous change of the stationary phase to the mobile phase and vice versa takes place.

[0054] The density and viscosity of hexane, cyclohexane, n-heptane, and iso-octane are higher than the density / viscosity of n-hexane, resulting in a more stable two-phase system compared to a second mobile phase such as acetonitrile, allowing for better retention of the stationary phase and consequently achieving increased separation efficiency; for example, with purity for THC of over 95 wt.%, even 99 wt.%.

[0055] In a further embodiment, one or more short-path distillations in a vacuum can be carried out upstream or downstream, so that, for example, a purity for THC of more than 99.0 wt.%, in particular greater than 99.7 wt.%, can be achieved.

[0056] Short-path distillation is carried out under vacuum on a first primary extract containing at least 15% by weight of THC or the desired cannabinoid. Therefore, in a first step, the cannabis plant material is cut, crushed, and subjected to a first extraction, for example, a CO2 extraction, as described in DE 100 51 427 C1. Alternatively, extraction with an alkane, propane, butane, pentane, hexane, heptane, alcohol, methanol, ethanol, propanol, isopropanol, water, and other liquid and gaseous solvents, or column chromatography, can also be performed, thus obtaining a primary extract containing at least 15% by weight of THC, which is used for further short-path distillation under vacuum (supra). However, CO2 extraction is preferred. The preferred cannabis plant material is drug hemp (Cannabis sativa).

[0057] Furthermore, the carboxylic acids of the cannabinoids, especially tetrahydrocannabinolcarboxylic acids and cannabidiolcarboxylic acid, can be decarboxylated in the primary extract. Decarboxylation occurs by heating at 120°C under vacuum, preferably at 100-200 mbar. Continuous decarboxylation is also possible using short-path distillation in the degassing stage, preferably at 120°C and 1 mbar.

[0058] Therefore, the invention also relates to a THC-containing extract obtainable by a process according to the invention.

[0059] In a further embodiment according to the process of the invention, an extract with the following composition could be obtained after a short path distillation in vacuum: Delta9-THC Gew. % 92,04 CBC Gew. % 0,83 CBG Gew. % 1,51 CBN Gew. % 0,73 VUX Gew. % 0,00

[0060] Therefore, the process according to the invention allows an enrichment of THC of more than 90% by weight, in particular 92% by weight as well as 95% by weight or more, with advantageous depletion of other cannabinoids and impurities that are difficult to separate.

[0061] Furthermore, the low-boiling fraction based on THC [wt.%] is 5 and the high-boiling fraction based on THC [wt.%] is 3. This means that the process according to the invention advantageously made it possible to selectively separate almost all substances that boil before and after THC.

[0062] Therefore, the invention also relates to a THC-containing extract obtainable by a process according to the invention having a high boiling point content of less than 53 wt.% based on THC and a low boiling point content of less than 5 wt.% based on THC.

[0063] Furthermore, an exemplary starting composition was used for the process according to the invention as follows: Delta9-THC Gew. % 78 CBC Gew. % 0,69 CBG Gew. % 1,36 CBN Gew. % 0,62

[0064] The process according to the invention particularly advantageously allows for a significant reduction in the low-boiling and high-boiling fractions compared to the starting material used. This results in an extract with specific properties such as advantageous residue-free vaporization, which is particularly suitable for the inhalation of THC in medical applications, especially for a pharmaceutical. The residue-free vaporization of THC is achieved particularly at 0.001 to 1 mbar. Furthermore, the temperature is 120 to 240 degrees Celsius, in particular 150 to 230 degrees Celsius, in particular 180-200 degrees Celsius.

[0065] This extract is particularly advantageous for CPC or sCPC, as the loading can be increased by a factor of 5 compared to a non-distilled extract.

[0066] The obtained fractions, pure substances, extracts can be the subject of a galenic or pharmaceutical composition.

[0067] The galenic preparation of a pharmaceutical composition or agent according to the invention, in particular a medicament (drug), can be carried out in a conventional manner. Suitable solid or liquid galenic preparation forms include, for example, granules, powders, coated tablets, tablets, (micro)capsules, hard capsules, suppositories, syrups, juices, suspensions, or emulsions. Conventional excipients such as carriers, disintegrants, binding agents, coating agents, swelling agents, lubricants, flavorings, sweeteners, and solubilizers are used in their production. Excipients include magnesium stearate, sodium chloride, magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and mono- or polyhydric alcohols, for example glycerol.

[0068] Furthermore, further detergents and surfactants may be provided as auxiliaries and additives, as explained below for a cosmetic composition.

[0069] Emulsions are generally understood to be heterogeneous systems consisting of two liquids that are immiscible or only partially miscible with each other, which are usually referred to as phases. In an emulsion, one of the two liquids is dispersed in the other liquid in the form of extremely fine droplets. If the two liquids are water and oil, and oil droplets are finely dispersed in the water, the emulsion is an oil-in-water emulsion (O / W emulsion). The basic character of an O / W emulsion is determined by the water. A water-in-oil emulsion (W / O emulsion) applies the opposite principle, with the basic character being determined by the oil. Mixed systems such as water-in-oil-in-water emulsions (W / O / W emulsions) and oil-in-water-in-oil emulsions (O / W / O emulsions) are also known. All of the emulsions mentioned are suitable for the invention.

[0070] The anhydrous systems suitable according to the invention include pure oil preparations such as skin oils. Also usable are pastes containing the preparation according to the invention, which are characterized by the fact that they consist of the same or similar components as an emulsion, but are essentially anhydrous. Within the context of the present invention, the terms oil phase and lipid phase are used synonymously. In a further preferred embodiment, the preparation according to the invention can contain an emulsifier as a further component. In a very preferred embodiment, this emulsifier can be an O / W emulsifier.

[0071] Emulsifiers can advantageously be selected from the group of non-ionic, anionic, cationic or amphoteric emulsifiers.

[0072] Various emulsifiers from the groups of partial fatty acid esters, fatty alcohols, sterols, polyethylene glycols such as ethoxylated fatty acids, ethoxylated fatty alcohols and ethoxylated sorbitan esters, sugar emulsifiers, polyglycerol emulsifiers or silicone emulsifiers can be used as non-ionic emulsifiers.

[0073] Various emulsifiers from the soap groups, e.g. sodium stearate, fatty alcohol sulfates, mono-, di- and trialkyl phosphoric acid esters and their ethoxylates, fatty acid lactate esters, fatty acid citrate esters or fatty acid citroglycerol esters, can be used as anionic emulsifiers.

[0074] Quaternary ammonium compounds with a long-chain aliphatic residue, e.g. distearyldimonium chloride, can be used as cationic emulsifiers.

[0075] Among the amphoteric emulsifiers, various emulsifiers from the groups of alkylamininoalkanecarboxylic acids, betaines, sulfobetaines or imidazoline derivatives can be used.

[0076] According to the invention, naturally occurring emulsifiers are preferred, including, for example, beeswax, wool wax, lecithin, and sterols, among others, which can also be used in the production of a preparation according to the invention. In a preferred formulation of the preparation according to the invention, O / W emulsifiers can be selected from the group of plant protein hydrolysates and their derivatives.

[0077] For the purposes of the present invention, substances selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids and / or alkenecarboxylic acids with a chain length of 3 - 30 carbon atoms and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 - 30 carbon atoms and from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 to 30 carbon atoms can also advantageously be included as additives.Such esterols can then advantageously be selected from the group of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate as well as synthetic, semi-synthetic and natural mixtures of such esters, such as jojoba oil.

[0078] Furthermore, the oil phase can advantageously be selected from the group of branched and unbranched hydrocarbons and waxes, dialkyl ethers, saturated or unsaturated, branched or unbranched alcohols, and fatty acid triglycerides, namely triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkanecarboxylic acids with a chain length of 8-24 carbon atoms, in particular 12-18 carbon atoms. The fatty acid triglycerides can advantageously be selected, for example, from the group of synthetic, semi-synthetic, and natural oils.

[0079] In particular, antioxidants and / or radical scavengers can be added to the preparations according to the invention as adjuvants or additives. Such antioxidants are advantageously selected from the group of lipophilic systems, for example: natural and synthetic tocopherols, nordihydroguaiaretic acid, coniferyl benzoate, butylhydroxyanisole, butylhydroxytolul, gallic acid esters, and various antioxidant plant extracts. Among the hydrophilic systems, inorganic sulfur compounds, sodium hydrogen sulfite, cysteine, or ascorbic acid are particularly advantageous.

[0080] The following examples serve to further explain the invention, but do not limit the invention to these examples. Example 1: 1.1 Short path distillation V9001

[0081] Cannabis extract (50-95% Cannabis sativa) was used as the starting material. The starting material was previously heated to 80°C in an oil bath and transferred to the heated dropping funnel of the short-path distillation. The amount used was 103.3 g. The temperature in the dosing vessel was 70°C. The stirrer speed was 400 rpm, and the temperature in the evaporator was 180°C. The extract was introduced at a rate of 180 ml / h - 200 ml / h, and the pressure in the entire apparatus was 1.2 * 10-1 mbar. The distillation lasted a total of 35 minutes. 79.53 g of distillate and 58.15 g of residue were obtained, corresponding to a ratio of approximately 75 / 25. In addition, a distillate formed in the cold trap during the distillation. The amount of distillate was approximately 3 ml. A hot air dryer was needed to convert the resulting residue into a flowable form. The distillate, which was subsequently used, had a bright yellow color. 1.2 Short path distillation V9002

[0082] 137.51 g of cannabis extract 50-95% Ch. 0000106433 was used. The temperature in the dosing vessel was 70°C, and in the evaporator, 165°C. The speed was set at 400 rpm as before. The entire distillation took approximately 45 minutes. 90.4 g of distillate were obtained, leaving 61.31 g of residue. A distillate volume of approximately 3 ml was formed in the cold trap. The cut ratio was 65 / 35. The distillate, which was subsequently used, had a bright yellow color. 1.3 Preparation of stock solution V9001

[0083] The distillate from the short-path distillation served as the starting material for the stock solution. The same concentration was used for the stock solution as in the FCPC system, i.e., 0.1 g / ml. The distillate from V9001 was dissolved in a water bath at 80°C and then transferred to a 1000 ml round-bottom flask. The sample weight was 62.26 g. The 1000 ml round-bottom flask was then dissolved again in a water bath at 80°C and added to 622 ml of heptane FCPC and dissolved.

[0084] The results are presented in Table 1. Example 2:

[0085] Comparative test of a THC-containing cannabis extract with and without short-path vacuum distillation (short path: 2-5 cm) Information in wt.% without KWD with KWD D9 THC 97,53 98,90 Impurity A 0,00 0,05 Impurity B 0,12 0,00 Impurity C 0,09 0,08 Impurity D 0,32 0,24 Impurity E 0,05 0,06 CBD 0,00 0,00 CBN 0,05 0,10 CBC 0,64 0,62 Exo-THC <0,05 <0,05 D8-THC 0,00 0,00 Other contaminants 1,30 <0,05

[0086] Contamination can be significantly minimized.

[0087] The Figures 1 and 2 show a cross-section of suitable systems for short-path vacuum distillation with the following reference symbols: 1 Wiper motor 2 Evaporator 3 (Internal) condenser 4 Distillate discharge 5 Residue discharge Table 1 Test No. info V9001 V9001 V9001 V9002 V90 02 V9002 V9005 V90 65 V9005 V9006 V90 06 Designation NTHC KDL 1 Week 46, 2016 start - End start - End start - End start - Feed, from protocol Cannabis extract 50-95% Ch-B: 0000106433 Date dd.mm.yy 16.11.20 16.11.20 16.11.20 17.11.20 17.11.20 13.01.20 13.01.20 13.01.20 yy 16 16 16 16 16 17 17 17 time hh:mm 13:50 14:00 14:25 09:43 10:30 10:47 11:30 11:30 Dosing vessel °C 70 70 70 70 70 70 70 70 evaporator °C 180 180 180 165 165 195 195 215 vacuum mbar 0,17-0,18 0,12 0,12 0,12 0,12 0,17-0,18 0,17-0,18 - speed rpm 400 400 400 400 400 400 400 400 Feed, discontinued ml / h 180-200 180-200 200 180-200 180-200 180 180 - Feed, protocol g / h - - - - - - - - Distillation time min 35 47 43 Feed calculated g / h 177 176 136 m (reactant, start) g 800,26 692,85 527,00 m (reactant, after removal) g 696,96 555,34 429,27 m (reactant, consumed), Feed F g 103,30 137,51 215,529 97,73 m (distillate) + m (flask) g 127,39 138,56 126,93 m (distillate flask) Tara g 47,86 48,14 49,28 m (distillate) Distillate D g 79,53 90,42 77,65 m (residue) + m (piston) g 58,15 61,31 54,02 m (residue flask) Tara g 47,77 48,11 47,77 m (residue) Residue R g 23,77 47,09 6,25 m (cold trap) Cold trap K g m (cold trap / feed) K / F % Cutting ratio D / R D / R according to protocol % 75 / 25 65 / 35 Cutting ratio D / F calculated % 77 66 79 Analytics Mass fraction [%] Attempt V9001 V9001 V9001 V9002 V90 02 V9002 V9005 V90 05 V9005 V9006 V90 06 Electricity F D R F D R F D R F D CBD % 1,36 1,67 0,52 1,36 1,51 0,67 1,36 1,36 CBN % 0,62 0,81 0,21 0,62 0,73 0,27 0,62 0,62 D9-THC % 78,84 88,73 16,54 78,84 92,04 18,78 78,84 85,00 6,76 78,84 81,40 D8-THC % 0,08 0,13 0,04 0,08 0,02 0,04 0,08 0,08 CBC % 0,69 0,85 0,11 0,69 0,83 0,14 0,69 0,69 VU74 at RT 74 % 0,00 0,00 0,46 0,00 0,00 0,91 0,00 0,00 VU77 at RT 77 % 0,00 0,00 0,53 0,00 0,00 1,09 0,00 0,00 Vux at RT ~150 % 0,20 0,00 0,20 0,20 0,00 1,33 0,20 0,20 Evaluation Absolute mass [g] Attempt V9001 V9001 V9001 V9002 V90 02 V9002 V9005 V90 05 V9005 V9006 V90 06 Electricity F D R F D R F D R F D CBD g 1,40 1,32 0,12 1,87 1,37 0,32 1,33 0,00 0,00 1,60 0,00 CBN g 0,64 0,65 0,05 0,85 0,66 0,13 0,60 0,00 0,00 0,73 0,00 D9-THC g 81,44 70,57 3,93 108,41 83,2 3 8,85 77,04 66,6 0 0,42 92,87 81,0 5 D8-THC g 0,09 0,10 0,01 0,11 0,02 0,02 0,08 0,00 0,00 0,10 0,00 CBC g 0,72 0,68 0,03 0,96 0,75 0,07 0,68 0,00 0,00 0,82 0,00 VU74 at RT 74 g 0,00 0,00 0,11 0,00 0,00 0,43 0,00 0,00 0,00 0,00 0,00 VU77 at RT 77 g 0,00 0,00 0,13 0,00 0,00 0,52 0,00 0,00 0,00 0,00 0,00 Vux at RT ~150 g 0,21 0,00 0,05 0,28 0,00 0,63 0,20 0,00 0,00 0,24 0,00 Yield in distillate Enrichment [%] Attempt V9001 V90 02 V90 05 V90 06 Electricity D D D D CBD VU % 94,42 73,1 6 0,00 0,00 CBN VU % 100,00 78,1 7 0,00 0,00 D9-THC Product % 86,65 76,7 7 85,6 7 87,2 7 D8-THC VU % 100,00 16,7 5 0,00 0,00 CBC VU % 94,60 78,1 4 0,00 0,00 VU74 at RT 74 VU % - - - - VU77 at RT 77 VU % - - - - Vux at RT ∼150 VU % 0,00 0,00 0,00 0,00 Mass balance D9-THC SHOULD = 0 g 6,9 16,3 10,6 11,6 Mass balance D9-THC Deviation in % % 8,5 15,1 13,8 12,5 Summary of D9-THC in feed (Educt) V9001 V90 02 V90 05 V90 06 w (D9-THC) Feed w(D9-THC) % 78,8 78,8 78,8 78,8 Summary of D9-THC in the product V9001 V90 02 V90 05 V90 06 Aspect ratio D / F % 77,6 65,8 79,5 84,5 w (D9-THC) product w(D9-THC) % 88,7 92,0 85,0 81,4 Yield D9-THC m(D9,D) / m(D9,F) % 86,7 76,8 85,7 87,3 % = wt. %

Claims

1. A process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof, characterised in that a short-path vacuum distillation is carried out to obtain a tetrahydrocannabinol-enriched extract in which other cannabinoids are depleted, wherein the short path vacuum distillation is carried out at a pressure of 0.1 to 5.0 ×103 Pa (0.001 to 50 mbar) and a temperature of 120 to 240 degrees Celsius, and wherein the short path vacuum distillation is carried out on a first primary extract containing at least 15% by weight of tetrahydrocannabinol.

2. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to claim 1, characterised in that the short-path vacuum distillation is carried out by means of a short-path evaporator.

3. The process for extracting tetrahydrocannabinol from cannabis plant material or an extract thereof according to claim 1 or claim 2, characterised in that the short path is 10 cm, in particular 5 cm, in particular 2 cm, in particular 0.5 cm between the evaporator wall and the condenser.

4. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to one of the preceding claims, characterised in that the short-path vacuum distillation is carried out by means of an additional column or separation column.

5. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to claim 4, characterised in that the length of the separation column is at least 2.50 m.

6. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to any of the preceding claims, wherein the short-path vacuum distillation is carried out at a pressure of 0.1 to 1 ×102 Pa (0.001 to 1 mbar).

7. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to any one of the preceding claims, wherein the short-path vacuum distillation is carried out at a temperature of 150 to 230 degrees Celsius.

8. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to any one of the preceding claims, characterised in that one or more of the short-path vacuum distillations is preceded by at least one liquid-liquid partition chromatography step.

9. The process for the extraction of tetrahydrocannabinol from cannabis plant material or an extract thereof according to claim 8, wherein at least i.) a continuous change of the stationary phase to the mobile phase and vice versa takes place and / or ii.) a solvent is kept stationary by centrifugal force with a second immiscible liquid phase in the mobile phase.