GB2463080A

GB2463080A - Pharmaceutical preparation

Info

Publication number: GB2463080A
Application number: GB0815972A
Authority: GB
Inventors: Nicholas John Larkins
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-09-02
Filing date: 2008-09-02
Publication date: 2010-03-03
Also published as: WO2010026375A1; GB0815972D0

Abstract

A composition comprising a catechin and one or more of the following;a gingkolide or metabolite thereof, a paeonol or metabolite thereof or a 2-hydroxy-4- methoxybenzaldehyde or metabolite thereof. The composition is of use in the treatment of arthritis, bowel disease, asthma, COPD, atherosclerosis, inflammation, hypertension, cancer or for the lowering of cholesterol.

Description

PHARMACEUTICAL PREPARATION

The present invention relates to compositions, for example, pharmaceutical compositions, for the treatment of disease.

Apocynin, (4-hydroxy-3-methoxyacetophenone, acetovanillone) is a methoxy-catechol. It is a natural organic compound which has been isolated from a variety of plant sources. Apocyniri is an efficient inhibitor of the multienzyme complex NADPH oxidase. Compositions for the treatment of disease which use apocynin as active agent are known.

The applicants have sought to develop pharmaceutical compositions which use a different active agent to apocynin (e.g. which show effective NADPH oxidase inhibition), while maintaining (or showing improved) pharmaceutical action. There is, for example, a need for compositions for the treatment of disease which have, for example, improved bioavailability (e.g. increased oral bioavailability) and/or pharmacokinetic profile. There is, for example, a need for compositions for the treatment of disease which have more readily available (or cheaper) active agents.

According to the invention in a first aspect there is provided a composition (for example a pharmaceutical composition) comprising: (i) a first component comprising a compound according to formula [I] or metabolite thereof: [I] I R1 wherein one of R1 or R2 is H and the other of R1 or R2 is C1 to C6 branched or straight chain alkyl; and (ii) a ginkgolide or metabolite thereof, a paeonol or metabolite thereof, or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.

The first component may comprise a compound according to formula [I] wherein R1 is CH3 and R2 is H, wherein the first component comprises 4-hydroxy-3-methoxybenzaldehyde, also known as vanillin.

The first component may comprise a metabolite of a compound according to formula [I] wherein R1 is CH3 and R2 is H, wherein the first component comprises a metabolite of vanillin. The metabolite of vanillin may be, for example, vanillyl alcohol, vanillic acid, vanilloyl glycine, catechol, 4-methylcatechol, guaiacol or 4-methylguaiacol.

The first component may comprise a compound according to formula [I] wherein R1 is H and R2 is CH3, wherein the first component comprises 3-hydroxy-4-methoxy-benzaldehyde, also known as isovanillin.

The first component may comprise a metabolite of isovanillin. The metabolite of isovanillin may be, for example, isovanillyl alcohol, isovanillic acid, vanillic acid, isovanilloyl glycine, catechol or 4-methylcatechol.

The first component may comprise the compound of formula [I] or a metabolite thereof which is present as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract (that is as a direct extract from a plant).

In this case, it may be referred to as a compound according to formula [I] or metabolite thereof, "in the natural form" or a natural compound" (e.g. "natural vanillin", "natural isovanillin", "natural vanillic acid" etc.). For example, if the compound according to formula [I] is vanillin which is present in the composition as an extract of the vanilla bean or vanilla extract" (which is a mixture of several hundred different compounds in addition to vanillin) this may be referred to as "natural vanillin". Alternatively or additionally, the first component may comprise a compound according to formula [I] in a purified or synthetic form, and this may be referred to as "isolated" compound according to formula [I]. For example, if the first component comprises a compound according to formula [I] which is in the form of synthetic vanillin, this compound may be referred to as isolated vanillin.

Synthetic vanillin may be made by methods well known in the art, e.g. from guaiacol or lignin.

The applicants have found that compositions according to the invention which include a compound of formula (I) or metabolite thereof may show similar or improved effect when compared to a composition which includes apocynin.

Further, compositions which include vanillin may show improved toxicity (e.g. reduced side effects at high doses) and/or may be less expensive to produce (because of the wide availability of vanillin as vanilla extract).

According to the present invention in a further aspect there is provided a composition (for example, a pharmaceutical composition) comprising: a catechin; and one or more of a ginkgolide or metabolite thereof; a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.

For the purposes of the present application, the term catechin means a polyphenolic antioxidant plant metabolite which belongs to the family of flavonoids (flavan-3-ols). For the purposes of the present application, the term catechin includes catechin, epicatechin, gallocatechin, epigallocatechin, and the gallates. In one example, the catechin is epicatechin. A preferred epicatechin is (-)-epicatechin.

The catechin (e.g. epicatechin) may be present as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract. If this is the case, it may be referred to as catechin [or epicatechin] "in the natural form" or "natural catechin" (e.g. "natural epicatechin", "natural (-)-epicatechin' etc.). The catechin may be natural catechin in the form of an extract of Camel/ia sinenisis or Theobroma cacao. The catechin may be present as an extract from, for example, white tea, green tea, black tea, Oclon tea. Alternatively or additionally, the catechin (e.g. epicatechin) may be used in the composition or preparation in a purified or synthetic form, and this may be referred to as "isolated catechin" or "isolated epicatechin".

Compositions which include catechins may show improved toxicity (e.g. reduced side effects at high doses) and/or may be less expensive to produce (because of the wide availability of e.g. natural catechins in certain teas etc.).

In an example of this aspect of the invention the catechin is (-)-epicatechin, either in the isolated form, the natural form, or both. The (-)-epicatechin may provide improved bioavailability over [and/or reduce side effects of], for example, natural forms of apocynin (e.g. Picrorhiza kurroa) because it is believed to act as a "prodrug" of apocynin-like metabolites, being metabolised in the liver to form these active species.

According to the present invention in a further aspect there is provided a composition (for example, a pharmaceutical composition) comprising: a derivative or metabolite of apocynin; and one or more of a gingkolide or metabolite thereof; a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof. The metabolite of apocynin may be, for example, demethylated apocynin; a three ring-hydroxylated metabolite of apocynin; the para-methoxy derivative (acetoisovanillone); the dimethoxy-hydroxy derivative; a 1-phenylethanol derivative formed by ketone reduction of aceteovanillone; and a 1-phenylethanol derivative formed by ketone reduction of 3,4- dihydroxyacetophenone. The derivative of apocynin may be, for example, a 4-nitroguaiacol (2-methoxy-.4-nitrophenol) or 4-cyanoguaiacol.

The applicants have found that compositions according to the invention which include: a compound of formula (I) or metabolite thereof; a catechin; or a derivative or metabolite of apocynin; may show similar or improved effect when compared to a composition which includes a (pharmaceutically) equivalent amount of apocynin.

At least 0.05% by weight of the composition may be the compound of formula (I) or metabolite thereof; the catechin or the derivative or metabolite of apocynin. The composition may include the compound of formula (I) or metabolite thereof; the catechin; or the derivative or metabolite of apocynin in an amount which is at least 1% by weight of the total composition. For example, at least 5% by weight (for example, at least 10%, 15%, 20%, 25% or 30% by weight) of the composition may be the compound of formula (I) or metabolite thereof; the catechin; or the derivative or metabolite of apocynin.

Compositions of the invention may comprise a ginkgolide or metabolite thereof.

By ginkgolide is understood all of the natural ginkgolides obtained from the Ginkgo biloba tree, as well as synthetic ginkgolides and their derivatives.

The ginkgolide may be present as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract. If this is the case, it may be referred to as ginkgolide "in the natural form" or "natural ginkgolide". The ginkgolide may be a natural ginkgolide in the form of ginkgo biloba; or extract or component thereof. The ginkgo biloba may be in concentrated standard form, such as is well known in the art. For example, the ginkgo biloba may be a concentrated extract which is equivalent to four times the concentration of ginkgo biloba in the natural form, such as ginkgo biloba tablets sold by MediHerb of Australia (500 mg tablets containing ginkgo biloba concentrated extract equivalent to 2.Og dry leaf ginkgo biloba standardised to contain 22-26% ginkgo flavone glycosides). The component of ginkgo biloba may be, for example, one of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J or ginkgolide M. Alternatively or additionally, the ginkgolide may be used in the composition or preparation in a purified or synthetic form, and this may be referred to as "isolated ginkgolide". The (isolated) ginkgolide may be, for example, one (or more) of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J or ginkgolide M. The composition may include ginkgolide (e..g ginkgolide A, ginkgo biloba; or extract or component thereof) in an amount which is at least 1% by weight of the total composition. For example, at least 5% by weight of the composition may be ginkgolide, for example, at least 10%, 15%, 20%, 25% or 30% by weight of the composition may be ginkgolide.

Compositions according to the invention may comprise paeonol or metabolite thereof. Paeonol is 2-hydroxy-4-methoxy-acetophenone and is shown by the following formula:

I COCH3

HO OCH3

It may be found in plant substances and plant extracts. For example paeonol may be found in Paeonia suifruticosa, Paeonia lactiflora, Paeonia veitchii, Paeonia obovata, Glycyrrhiza glabra, Cynanchum paniculatum, Picrorrhiza kurroa, Picrorrhiza scrophularliflora, Rheum palmatum (rhizome) and Scutellaria baicalensis (root).

The compositions and preparations of the invention may include "isolated" paeonol, that is paeonol which has been synthesised or paeonol which has been extracted from plants and purified. Alternatively or additionally, paeonol may be present in preparations according to the invention as direct extracts from plants (i.e. as part of an unresolved mixture of compounds in the form of an unpurified plant or root extract). These will be referred to a paeonol "in the natural form" or "natural paeonol". For example, paeonol present in preparations according to the invention in the form of Paeonia suffruticosa or extract thereof will be referred to as "natural paeonol". The terms paeonol "in the natural form" or "natural paeonol" include glycosides of paeonol such as those found in the plant species in which paeonol is found. Such glycosides include paeonin, paeonolide and paeonoside,

for example.

Compositions according to the invention may comprise paeonol rnetabolites.

These include compounds which are formed by the metabolism of paeonol.

Paeonol rnetabolites include 2, 4-dihydroxyacetophenone-5-O-sulfate, resacetophenone-2-O-sulfate, 2-hydroxy-4-methoxyacetophenone-5-O-sulfate, paeonol-2-O-sulfate, and resacetophenone.

The composition may include paeonol or metabolite thereof (e. .g paeonol, Paeonia suifruticosa or extract thereof) in an amount which is at least 1% by weight of the total composition. For example, at least 5% by weight of the composition may be paeonol or metabolite thereof, for example, at least 10%, 15%, 20%, 25% or 30% by weight of the composition may be paeonol or metabolite thereof.

A preferred composition comprises a compound of formula (I) or metabolite thereof; a catechin; or a derivative or metabolite of apocynin; and paeonol (or metabolite thereof) wherein the ratio (by weight) of the compound of formula (I) or metabolite thereof; the catechin; or the derivative or metabolite of apocynin; to the paeonol is between about I to 100 and about 100 to 1, preferably between about 1 to 10 and I to 30, more preferably between about 1 to I and 1 to 20, more preferably between about 1 to 2 and ito 10.

The composition may further comprise Picrorrhiza kurroa.

The composition may further comprise a gingerol (e.g. 6-gingerol), or a natural source of gingerols such as Zingiber Officinale or extract thereof.

The composition according to the invention further may further comprise L-glutamine.

Preferably the composition according to the invention further comprises a filler.

Preferred fillers include at least one flavonoid, preferably a mixture of one or more flavonoids.

The compositions may be used as pharmaceutical compositions, for the treatment of disease in humans, or veterinary compositions, for the treatment of non-human animals.

The compositions may further comprise additional components such as pharmaceutically conventional carriers, diluents, flavourings, emulsifiers and stabilisers. They may comprise additional components (for example carriers or diluents) which are "conventional" in herbal remedies. The pharmaceutical or veterinary composition may further comprise, for example, one or more of the following: [1] an agent to enhance the immune system, for example lactoferrin which has antiviral antibacterial and antioxidant effects; [2] a natural source of vitamins such as bee pollen; [3] a source, for example a natural source, of vitamins, minerals and amino acids, for example chlorella; [4] a source of trace elements, for example, chromium and/or vanadium and/or copper and/or zinc and/or manganese; and/or [5] taste masking agents, for example yoghurt, fruit juice, honey and syrup.

Compositions according to the invention may be useful for treatment of arthritis (including osteoarthritis, rheumatoid arthritis), bowel disease, asthma, COPD (congestive obstructive pulmonary disease), atherosclerosis, inflammation, hypertension, or cancer, or for lowering cholesterol.

The compositions may be suitable for oral administration, The methods of formulation of the compositions for oral administration are well known in the art.

For example, the composition for administration may be prepared using a pharmaceutically acceptable carrier in a form suitable for administration. Such a carrier can be prepared as a tablet, a pill, a sugar-coated agent, a capsule, a liquid, a gel, a syrup, a slurry, a suspension, etc. The carrier may be a herbal binder such as Glycyrrhiza glabra or one or more pharmaceutically acceptable carriers such as liposomes, lactose, trehalose, sucrose, mannitol, xylitol, crystalline cellulose, chitosan, calcium carbonate, talc, titanium oxide, or silica (silicon oxide) or the like.

The composition may be obtained, for example, by combining the active ingredients with a solid excipient, pulverizing the mixture (if necessary) and inserting into a capsule, for example, a soft sealed capsule consisting of a gelatin capsule, gelatin and coating (e.g., glycerol or sorbitol) or a capsule composition suitable for vegetarians. In the soft capsule, the composition may be dissolved or suspended in an appropriate liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol, with or without a stabilizer.

The formulation (composition or preparation) may also be in the form of a standardised liquid extract. Standardised liquid extracts may in some circumstances have advantages when compared to the solid dose forms (tablets

I

and hard shell capsules). They may involve minimal processing during manufacture during manufacture and may reflect the true spectrum of the original herb (or plant etc.), in a compact and convenient form. There is also the possibility of superior bioavailability as the preparation is already in the liquid form. The prescribed dose may then be easily diluted (water, fruit juice, adding ice etc.) so as to minimise the experience of any unpleasant taste thus increasing the likelihood of patient compliance.

It will be appreciated that the preparations are suitable for other means of administration, for example mucosal delivery routes (for example rectal, nasal, vaginal) and also topical administration. The methods of formulation of the compositions for use in these methods are well known in the art.

According to the present invention in a further aspect there is provided a method of treatment of arthritis (including osteoarthritis, rheumatoid arthritis), bowel disease, asthma, COPO (congestive obstructive pulmonary disease), atherosclerosis, inflammation, hypertension, or cancer, or a method of lowering cholesterol in a patient, in need thereof, comprising a step of administering to the patient a composition (for example a pharmaceutical composition) comprising: (i) a first component selected from (a) a compound according to formula [I] or metabolite thereof: [I] I R1 wherein one of R1 or R2 is H and the other of R1 or R2 is C1 to 06 branched or straight chain alkyl; (b) a catechin; or (c) a derivative or metabolite of apocynin; and; a second component comprising a ginkgolide or metabolite thereof, a

I

paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.

According to the present invention in a further aspect there is provided a composition for the treatment of cancer, osteoporosis or hypertension comprising: a first component selected from (a) a compound according to formula [I] or metabolite thereof: [I] I wherein one of R1 or R2 is H and the other of R1 or R2 is C1 to C6 branched or straight chain alkyl; (b) a catechin; (c) a derivative or metabolite of apocynin; or (d) apocynin; and a second component comprising a ginkgolide or metabolite thereof, a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.

The present invention in a further aspect also provides compositions as disclosed and defined herein for use in the manufacture of medicaments for the treatment of disease.

The present invention will now be described in detail with reference to illustrative

examples.

Example I

The following preparation is suitable for the treatment of inflammation in adult humans. This mix packs into a type 0' capsule (650mg in total) and is taken (based on a human of body weight 60 to 80kg) at a rate of two such capsules twice per day: am and pm. In exceptional cases the dose may be increased at the beginning of treatment, (e.g. doubled for the first 1 to 3 days).

I

EXAMPLE I

L-glutamine 50mg Glucosamine 50mg Moutan cortex (Paeonia suifruticosa) 100mg Paeonol (isolated) 350mg (-)-epicatechin (isolated) 100mg

Example 2

EXAMPLE 2

L-glutamine 50mg Glucosaniine 50mg Moutan cortex (Paeonia suifruticosa) 100mg Paeonol (isolated) 350mg van I Ii n (isolated) 100mg

-

Examples 3 to 6

The dose of the following Examples 3, 4, 5 and 6 for adults and mature children for the the treatment of asthma or reduction of excessive mucous production is 1,000 mg (two 500 mg capsules) in the morning and 1,000 mg (two 500 mg capsules) in the evening.

EXAMPLE 3

Lecithin 100mg Zingiber Officinale (standardised to contain a minimum of 5% gingerols) 180 mg 234 mg Ginkgo biloba (standardised to contain 24% ginkgo flavone glycosides) Picrorrhiza kurroa 324 mg vanilli n (isolated) 162 mg The mixture of Example 3 was divided and prepared in a form suitable for dosing, for example, in a capsule form for oral dose.

EXAMPLE 4

Lecithin 110mg 60mg Ginkgolide A Sodium carbonate (filler) 650 mg va ni lii n (isolated) 180 mg The mixture of Example 4 was divided and prepared in a form suitable for dosing, for example, in a capsule form for oral dose.

EXAMPLE 5

Lecithin 100mg Zingiber Officinale (standardised to contain a minimum of 5% gingerols) 180 mg 234 mg Ginkgo biloba (standardised to contain 24% ginkgo flavone glycosides)

I

Picrorrhiza kurroa 324 mg (-)-epicatechin (isolated) 162 mg The mixture of Examples 5 was divided and prepared in a form suitable for dosing, for example, in a capsule form for oral dose.

EXAMPLE 6

Lecithin 110mg 60mg Ginkgolide A Sodium carbonate (filler) 650 mg (-.)-epicatech in (isolated) 180 mg The mixture of Examples 6 was divided and prepared in a form suitable for dosing, for example, in a capsule form for oral dose.

Example 5

Inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with osteoporosis. The applicants have shown that paeonol inhibits matrix metalloproteinase enzymes (MMP) activity and lL-13 production. NADPH oxidase assembly inhibitors inhibit the onset of the inflammatory cascade. This indicates that compositions according to the invention may find use in the treatment of osteoporosis.

In vitro observations suggest that paeonol has the potential to be explored for use as an effective antitumor agent for human hepatocellular carcinoma (HCC).

NADPH oxidase might be a potential target for the treatment of pancreatic fibrosis. This indicates that compositions according to the invention may find use in the treatment of cancer.

NADPH oxidases have recently been shown to contribute to the pathogenesis of hypertension. Paeonol inhibits MMP activity and IL-113 production. Paeonol upregulates the anti-inflammatory cytokine IL-b. This indicates that compositions according to the invention which include paeonol plus NADPH inhibitor (e.g. vanillin) may find use in the treatment of hypertension.

Claims

SClaims 1. A composition comprising: a catechin; and one or more of a gingkolide or metabolite thereof; a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.
2. A composition according to claim 1 wherein the catechin is selected from catechin, epicatechin, gallocatechin, epigallocatechin, and the gallates.
3. A composition according to claim 1 or 2 wherein the catechin is (-)-epicatechin
4. A composition according to any preceding claim wherein the catechin is natural catechin in the form of an extract of Camel/ia sinenisis or Theobroma cacao.
5. A composition comprising: (i) a first component comprising a compound according to formula [I] or metabolite thereof: []Rwherein one of R1 or R2 is H and the other of R1 or R2 is C to C6 branched or straight chain alkyl; and (ii) a ginkgolide or metabolite thereof, a paeonol or metabolite thereof, or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.
6. A composition according to claim 5 wherein the first component comprises a compound according to formula [I] wherein R1 is CH3 and R2 is H, or a metabolite thereof.
7. A composition according to claim 5 or 6 wherein the metabolite is vanillyl alcohol, vanillic acid, vanilloyl glycine, catechol, 4-methylcatechol, guaiacol or 4-methylguaiacol.
8. A composition according to claim 5 wherein the first component comprises a compound according to formula [I] wherein R1 is H and R2 is CH3 or metabolite thereof.
9. A composition according to claim 5 or 8 wherein the metabolite is isovanillyl alcohol, isovanillic acid, vanillic acid, isovanilloyl glycine, catechol or 4-methylcatechol.
10. A composition comprising: a derivative or metabolite of apocynin; and one or more of a gingkolide or metabolite thereof; a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.
11. A composition according to claim 10 wherein the metabolite of apocynin is demethylated apocynin; a three ring-hydroxylated metabolite of apocynin; the para-methoxy derivative (acetoisovanillone); the dimethoxy-hydroxy derivative; a 1-phenylethanol derivative formed by ketone reduction of aceteovanillone; or a 1- phenylethanol derivative formed by ketone reduction of 3,4-dihydroxyacetophenone.
12. A composition according to claim 10 wherein the derivative of apocynin is 4-nitroguaiacol (2-methoxy-4-nitrophenol) or 4-cyanoguaiacol.
13. A composition according to any preceding claim for the treatment of arthritis (including osteoarthritis, rheumatoid arthritis), bowel disease, asthma, COPD (congestive obstructive pulmonary disease), atherosclerosis, inflammation, hypertension, or cancer, or for lowering cholesterol.
14. A method of treatment of arthritis (including osteoarthritis, rheumatoid arthritis), bowel disease, asthma, COPD (congestive obstructive pulmonary disease), atherosclerosis, inflammation, hypertension, or cancer, or a method of lowering cholesterol in a patient, in need thereof, comprising a step of administering to the patient a composition (for example a pharmaceutical composition) comprising: a first component selected from (a) a compound according to formula [I] or metabolite thereof: T R1 R2 wherein one of R1 or R2 is H and the other of R1 or R2 is C1 to C6 branched or straight chain alkyl; (b) a catechin; or(c) a derivative or metabolite of apocynin; and a second component comprising a ginkgolide or metabolite thereof, a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.
15. A composition for the treatment of cancer, osteoporosis or hypertension comprising: a first component selected from (a) a compound according to formula [I] or metabolite thereof: [I] I R1Swherein one of R1 or R2 is H and the other of R1 or R2 is C1 to C6 branched or straight chain alkyl; (b) a catechin; (c) a derivative or metabolite of apocynin; or (d) apocynin; and a second component comprising a ginkgolide or metabolite thereof, a paeonol or metabolite thereof; or 2-hydroxy-4-methoxybenzaldehyde or metabolite thereof.