GB2463531A

GB2463531A - The extraction of pharmacological agents from medicinal herbs using subcritical water

Info

Publication number: GB2463531A
Application number: GB0817354A
Authority: GB
Inventors: Kenneth Davison; Gary William Wheatley
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-09-23
Filing date: 2008-09-23
Publication date: 2010-03-24
Anticipated expiration: 2028-09-23
Also published as: GB0817354D0; GB2463531B

Abstract

A method for preparing an extract containing pharmacologically active constituents from certain traditionally used medicinal herbs comprises extracting the botanical raw material with subcritical water and then removing the water to give a pharmaceutically acceptable extract. The extraction may be conducted at 200-230°C and/or 70-85 bar. The medicinal herb may be Schisandra chinensis (wu wei zu) berries, Scutellaria baicalensis (baikal skullcap), Astragalus membranaceus or Zingiber officinale (ginger). These sub-critical water extracts may be similar in composition to those extracts obtained by means of methanolic extraction. The extract may be formulated as a self emulsifying drug delivery system in order to improve the bioavailability of the active constituents: a formulation may comprise the extract, lauroyl macrogolglyceride and surfactant.

Description

A Method of Preparing Pharmacologically Active Extracts from Certain Medicinal Herbs in Traditional use in Asia Without the Use of an Organic Solvent.

FIELD OF THE INVENTION.

This invention relates to a method of producing an extract from certain herbs, used traditionally in Asia for their medicinal value, without the use of an organic solvent.

BACKGROUND TO THE INVENTION.

Higher plants are unsurpassed in their ability to produce biologically active molecules often of great complexity. These plant "secondary metabolites" have proven a fruitful source of new pharmaceuticals. Often the first use of these compounds as been in the form of traditional herbal medicines. However the structure of the active compounds is frequently so complex that synthetic chemistiy can provide no economically viable route to the molecule and this has to be isolated from the plant material.

Simple aqueous extraction of the biomass almost invariably results in a complex extract in which the target compound is diluted by a range of other unwanted phytochemicals derived from the plant, including proteins, sugars and other carbohydrates.

Extraction with a lower alcohol, typically ethanol or methanol, is traditionally a very popular means of obtaimng a pharmacologically active preparation from a medicinal herb. The use of an alcohol has the advantage over an aqueous extraction that the highly polar compounds such as carbohydrates, sugars and proteins (which generally are inactive and serve only to add bulk and dilute the concentration of the active compounds) are not extracted.

However the obvious disadvantages of the use of an alcohol in extraction is that it is flammable, necessitating expensive precautions during processing, and also the recovery of the organic solvent for disposal or for further purification and re-use is required. Methanol in addition is highly toxic, and residual levels must be rigorously limited in a pharmaceutical preparation. Indeed due to this high toxicity of methanol, it is frequently substituted by a mixture of the more polar water and the less polar ethanol to produce an extraction solvent of comparable polarity.

A more recent approach that has also successfully applied is the production of a high potency extract, standardised on the content of the active substance, using extraction with a subcritical fluid or liquefied gas, most commonly carbon dioxide. One drawback of LCO2 extraction is that the technique is limited to less polar compounds.

It will not extract the compounds most readily soluble in methanol or aqueous alcohol mixtures, including the important class of flavonoids and other polyphenolic compounds such as lignans. The importance of polyphenolic compounds as potential new drugs is increasingly being recognised; with anti-inflammatory activity, anti-bacterial activity and a wide range of activities related to suppression of tumour growth (including inhibition of angiogenesis and reversal of multidrug resistance) being well established.

A more recent example of a high pressure liquefied gas which is being evaluated as an extraction agent and which promises capabilities not exhibited by LCO2 is high pressure superheated water at >150°C. Importantly, it is capable of solubilising more polar compounds than LCO2 extraction. Subcritical water has the unique property that the polarity changes in a well established and predictable manner as temperature is increased; thus at 150°C subcritical water has a polarity equivalent to a 50:50 mixture of water and alcohol under normal conditions, and the polarity further decreases to a value equivalent to methanol alone at 230°C. It is this property that is the basis of this invention: by employing subcritical water it is found that extracts equivalent in composition to those produced by methanol can be obtained without the disadvantages resulting from the use of a toxic and flammable solvent.

The traditionally used medicinal herbs for which extraction with subcritical water is described in this invention all produce an extract with methanol that has been widely reported in the literature to contain flavonoid or other phenolic compounds which produce important pharmacological effects as follows: The metbanolic extract of Schisandra chinensis berries contains high levels of schisandrin and other related lignans that are known to be largely responsible for the strong anti-inflammatory and anti-cancer activity of the herb.

The methanolic extract of Scutellaria baicalensis root contains a range of flavonoids including baicalin, bacalein and wogonin that are now established as the principal active substance responsible for the anti-cancer and anti-inflammatory properties.

The methanolic extract of Astragalus membranaceus root contains polyphenolic compounds thought to be responsible for the anti-cancer and anti-microbial properties.

The methanolicextract of Zingiber officinale (ginger) root contains the gingerol and shogaol compounds known to exhibit the anti-inflammatory and anti-cancer activities.

Thus as the subcritical water extract of the herbs as described in this invention are demonstrated to exhibit a composition essentially similar to that of the corresponding methanolic extract then it can be expected that these extracts will exhibit comparable pharmacological properties to these and to the compound contained therein.

A problem limiting the use of flavonoids and related polyphenolic compounds in therapeutic situations in which systemic treatment rather than local application is required is poor water solubility. This is largely responsible for the low circulating plasma levels after a single oral dose and results in the majority of the dose being excreted without absorption.

Hence this invention also describes self emulsif'ing formulations that increase the water solubility of these compounds, thus increasing their oral bioavailability and therapeutic efficacy.

SUMMARY OF THE INVENTION.

Example 1.

The extraction apparatus consists of: * Two suitable stainless steel vessels capable of resisting high temperature and pressure connected by stainless steel tubing, the first to act as a reservoir in which subcritical water is produced prior to introduction to the second extraction vessel. These are contained in a thermostatted oven.

* The first reservoir is connected via an inlet valve to a high pressure pump outside the thermostatted oven.

* The extraction vessel is also connected via an outlet valve to a stainless steel receiver vessel outside the thermostatted oven but maintained at approximately 90°C.

* A valve from the receiver vessel allows the solution that accumulates to be transferred to a suitable storage vessel.

A schematic representation of a suitable arrangement of the extraction apparatus is provided as Figure 1.

Coarsely ground Schisandra chinensis berry botanical raw material is packed into the stainless steel extraction vessel. The extraction vessel is then filled with deionised water (equivalent to approximately four times the mass of botanical raw material employed) and the temperature and pressure of the extraction vessel gradually raised to respectively 230°C and 85 bar. The extraction vessel is then held at these conditions for up to 15 minutes before the resulting solution is forced from the vessel by passing a second quantity of subcritical water into the system to continue the extraction. In all four portions of subcritical water are used to extract the botanical raw material in the manner described above.

Alternatively the same extraction may be achieved in a dynamic mode by passing the same quantity of subcritical water maintained at 23 0°C and 85 bar through the botanical raw material packed in the extraction vessel over the course of approximately 1 hour.

The extract is isolated from the solution resulting from the extraction by removing the water by evaporation, the final stages of which are preferably carried out under reduced pressure.

Alternatively the extract may be isolated from the solution resulting from the extraction by removing the water by the process of either freeze drying or spray drying.

A TLC fingerprint representative of the extract (also termed a botanical drug substance) produced in this example is given in Figure 2.

Example 2.

A method as described in example 1 wherein the botanical raw material is ground Scutelarria baicalensis root. In addition to the method described in example 1, ii is surprisingly found that as the volume of the solution resulting from the extraction is reduced in volume (typically to about � of the original volume) that a precipitate forms. When this precipitate is recovered by filtration it is found that it is comprised -4 of essentially a mixture of three closely related polyphenolic compounds also present in the methanolic extract. The remaining filtrate is found to contain negligible levels of polyphenolic compounds.

A TLC fingerprint representative of the extracts produced in this example is given in Figure 3.

Example 3.

A method as described in example I wherein the botanical raw material is ground Astragalus membranaceus root.

A TLC fingerprint representative of the extract produced in this example is given in Figure 4.

Example 4.

A method as described in example 1 wherein the botanical raw material is ground Zingiber officinale root.

A TLC fingerprint representative of the extract produced in this example is given in Figure 5.

While the preferred embodiments of the invention have been described above, it will be recognised and understood that various modifications may be made therein, and the appended claims are intended to cover all such modifications which may fall within the spirit and scope of the invention.

Example 5.

A Self Emusifying Drug Delivery System (SEDDS) formulation for oral administration of the extracts containing the poorly water soluble polyphenols can be prepared as follows: Extract (selected from the extracts produced in Examples 1-4) 15% w/w Lauroyl macrogoiglycerides EP (e.g Gelucire 44/14) 65-85% w/w Surfacant (e.g Cremophor RH4O or Labrafac) 0-20% w/w The extract is dispersed with stirring in the molten lauroyl macrogoiglycendes at 70- 80°C. The surfactant is then added and stirring continued for a furtherS minutes.

Using suitable automatic or manual equipment the molten mixture is then dispensed into two piece hard shell gel capsules that are then sealed.

Example 6a

A cream formulation for topical application of the extracts can be prepared as follows: Extract (selected from the extracts produced in Examples 1-4) 2% w/w Cetostearyl alcohol EP 7% wlw Macrogol cetostearyl ether (e.g Cremophor A6/A25) 3% w/w Liquid paraffin EP 12% wlw Parabens (e.g. Nipastat) 0.2% w/w Deionised water 67.8% w/w Propylene Glycol EP 8% w/w The extract is dispersed in the propylene glycol at 70-80°C with stirring. All other ingredients except the water are mixed at 80°C and then added with stirring to the water that was heated separately to 80°C. The dispersion of extraGt in propylene glycol is then added to this mixture maintained at 70-80°C with stirring. The formulation is then filled into tubes.

Example 6b

A hydroalcoholic gel formulation for topical application of the extracts can be prepared as follows: Extract (selected from the extracts produced in Examples 1-4) 2% w/w Ethanol EP 44% w/w Carbomer (e.g. carbopol 980 NF) 3% w/w Deionised water 51% w/w Sodium hydroxide (a qs to neutralise The extract is dissolved in the ethanol at 50-60°C with stirring. The carbomer is then added slowly to the water with rapid stirring. The extract solution is then added to the aqueous carbomer whilst stirring. The resulting mixture is then neutralised by slowly adding aqueous sodium hydroxide to produce a smooth semi-solid.

The formulation is then filled into tubes.

Claims

CLAIMS1. A method of preparing an extract containing pharmacologically active constituents from certain traditionally used medicinal herbs comprising reduction of the particle size of the botanical raw material as appropriate, extracting the botanical raw material with subcritical water, and then removing the water from the resulting solution to produce a pharmaceutically acceptable extract.
2. The method according to claim 1-6 wherein the extraction is earned out at a temperature in the range 150-260°C, and most preferably in the range 200-230°C.
3. The method according to claim 1-6 wherein the extraction is carried out at a pressure in the range 15-100 bar sufficient to maintain the water in the liquid phase, and most preferably at 70-85 bar
4. The method according to claims 1-6 wherein the medicinal herb is selected from the group consisting of the traditionally used parts of Schisandra chinensis (Wu Wei Zu) berries, Scutellaria baicalensis (baikal skullcap), Astragalus membranaceus and Zingiber officinale (ginger).
5. The method according to claim 1-6 wherein the water is removed to yield the extract by evaporation.
6. The method according to claim 1-6 wherein the water is removed to yield the extract by freeze drying or spray drying.
7. The method according to any preceding claim wherein the extraction of Schisandra chinensis berries, produces an extract with a TLC fingerprint substantially as illustrated in Figure 2, which is essentially similar to the corresponding methanolic extract and exhibiting a significant spot attributable to schisandrin.
8. The method according to any preceding claim wherein the extraction of Scutellaria baicalensis root produces an extract with a TLC fingerprint substantially as illustrated in Figure 3, which is essentially similar to the corresponding methanolic extract and exhibiting a significant spot attributable to baicalin and related flavonoids.
9. The method according to any preceding claim wherein the extraction of Astragalus membranaceus root produces an extract with a TLC fingerprint substantially as illustrated in Figure 4, which is essentially similar to the corresponding methanolic extract.
10. The method according to any preceding claim wherein the extraction of ginger root produces an extract with a TLC fingerprint substantially as illustrated in Figure 5, which is essentially similar to the corresponding methanolic extract and exhibiting a significant spot attributable to 6-shogaol and to 6-gingerol.
11. The use of a botanical drug as claimed in any of the preceding claims that consist essentially of botanical drug substances.
12. The use of a botanical drug as claimed in claim 11 further comprising excipients.
13. The use of a botanical drUg as claimed in claim 11 wherein the botanical drugs substances comprise total extracts derived from the botanical raw materials.
14. The use of a botanical drug as claimed in claim 11 wherein the botanical drugs substances comprise more refined fractions derived from the total extracts of the botanical raw materials.
15. The use of a botanical drug as claimed in claim 11 wherein the botanical drugs substances are standardised extracts.
16. The method according to any preceding claim wherein the pharmacologically active extract is formulated in a self emulsifying drug delivery system to improve the oral bioavailability of the active constituents.
17. The method according to claim 16 wherein the self emulsifying drug delivery system is based on the formulation described in Example 5.
18. The method according to claim 16-17 wherein the pharmacologically active extract is selected from the list of the subcritical water extracts of Schisandra chinensis (Wu Wei Zu berries), Scutellaria baicalensis (baikal skullcap), Astragalus membranaceus and Zingiber officinale (ginger).
19. The method according to any preceding claim wherein the pharmacologically active extract is formulated in a topical vehicle formulated to increase bioavailability of the active constituents.
20. The method according to claim 19 wherein the topical vehicle is based on the formulation described in Example 6.
21. The method according to claim 19-20 wherein the pharmacologically active extract is the subcritical water extract of Schisandra chinensis (Wu Wei Zu berries), Scutellaria baicalensis (baikal skullcap), Astragalus membranaceus and Zingiber officinale (ginger).L