WO1990007331A1

WO1990007331A1 - Anti-inflammatory liniment

Info

Publication number: WO1990007331A1
Application number: PCT/AU1989/000555
Authority: WO
Inventors: Noel James Went; Arthur George Bolt; Michael Whitehouse
Original assignee: Noel James Went; Arthur George Bolt
Priority date: 1988-12-23
Filing date: 1989-12-28
Publication date: 1990-07-12
Also published as: AU629286B2; AU4830290A

Abstract

A composition for topical application to the skin adjacent a locus of inflammation includes an oil, being linseed oil or a substantially equivalent oil thereto, or an effective amount of a component thereof, as the primary pain relieving agent. The composition also includes a thinner or solvent therefor which assists in moving the said agent through the skin to said locus. The thinner may have a synergistic effect on the activity of the agent. A method for the relief of inflammation by using the aforementioned composition is also provided.

Description

ANTI-INFLAMMATORY LINIMENT

FIELD OF INVENTION

The present invention relates to compositions for topical application for the relief of pain, in particular pain arising from inflammation of the joints, such as arthritic pain, and pain arising from headaches, such as migraine.

BACKGROUND ART

Pain arising from inflammation, particularly in the joints, in mammals, particularly humans, arises for a wide variety of reasons including over-exercising of the joints, physical injury, rheumatism and arthritis. A number of parenteral and topical compositions exist which are alleged to either cure or relieve the pain arising out of these causes of inflammation.

For example, aspirin is a commonly used antiinflammatory drug, taken orally for the relief of pain.

Cortisone and its analogs is also considered to be an antiinflammatory drug and may be used both in parenterally administered or topically administered formulations. In particular cortisone has several undesirable side effects which limit its application.

There also exist a number of pain relieving creams for topical applications to the joint. However, these usually provide only temporary alleviation of the pain. DISCLOSURE OF INVENTION

The present invention results from a discovery by the present inventors that a composition containing linseed oil when applied topically to an inflamed region reduced the inflammation and pain resulting therefrom. It was also discovered that the linseed oil had to be dispersed in an appropriate solvent or thinner medium for the antiinflammatory and analgesic affects of the composition to be noted. Some of the preferred thinners clearly displayed a synergistic effect on the activity of the linseed oil.

According to the invention, there is provided a

composition for topical application to the skin adjacent a locus of inflammation, said composition comprising an oil, being linseed oil or a substantially equivalent oil thereto, or an effective amount of a component thereof, and a thinner therefor which assists in moving said oil or component through the skin to said locus.

According to another embodiment of the invention, there is provided a method for the relief of inflammation,

particularly of the joints, said method comprising topically applying to the skin adjacent a locus of inflammation a composition comprising an oil being linseed oil, or a

substantially equivalent oil thereto or an effective amount of a component thereof, dissolved in a thinner therefor, which thinner assists in moving said oil or component thereof through the skin to the locus. Preferably the composition of the present invention comprises about 80% by volume of linseed oil and the

remaining % by volume thinner. The composition may also contain an antioxident, such as wheatgerm oil or Vitamin E to increase its shelf life.

In tests described later in the specification,

compositions which comprise linseed oil and a thinner, thethinner being preferably selected from one or more members of the group comprising mineral or distilled turpentine, methyl, ethyl and isopropyl salicylate esters, eucalyptol (also known as cineole), tea tree oil (also known as ateol) and oil of wintergreen were shown to exhibit what could be described as synergism between the two components and were shown to exhibit an anti-inflammatory affect which is surprising in light of present knowledge. Without being bound to theory, it is considered that the linseed oil contains one or more active ingredients such as alpha and gamma-linolenic acid which have a primary anti-inflammatory effect. Linseed oil has a very hign proportion of alpha and gamma-linolenic acid.

Therefore, as used throughout this specification, the term "linseed oil" also embraces the chemical equivalents thereof and components thereof and thus will include the primary constituents such as alpha and gamma-linolenic acids, or any other constituents shown by experimentation to be active in the relief of inflammation.

Distilled turpentine is an essential oil which is distilled from turpentine, an oily substance derived from pine cones, which contain several terpenes such as pinene and diapentene. The use of the term "distilled turpentine" herein embraces various turpentine oils such as gum

turpentine and wood turpentines as well as the major

constituents thereof and the synthetic analogs.

The use of the term "mineral turpentine" includes any of a number of narrow boiling fractions of the petroleum with boiling points in the order of about 200°F to 300°F.

The above mentioned salicylate esters (particulary methyl salicylate) also have a mild analgesic effect on their own and so may enhance the pain relief primarily attributable to linseed oil.

Linseed oil itself is available in different forms, these being primarily cold pressed edible, boiled and

pigmented oils, with each being effective in the present invention.

In one form of the invention, the composition includes a propellant for application to the skin as an aerosol sprayon. The choice of propellant will be readily apparent to those skilled in the art.

DESCRIPTION OF PREFERRED EMBODIMENTS

In order that the invention may be more readily

understood and put into practical effect, reference will now be made to the following examples.

Example 1

Initial tests on the composition of the present

invention were conducted in the following manner. Four formulations were used: L1, L2, L3 and L4.

Theseformulations were as follows (all percentages are expressed by volume:

L1 : 50% mineral turpentine

35% linseed oil

10% methyl salicylate

5% eucalyptus oil.

L2: 25% gum turpentine

25% mineral turpentine

35% linseed oil

10% methyl salicylate

5% eucalyptus oil.

L3: 50% mineral turpentine

35% corn oil

10% methyl salicylate

5% eucalyptus oil.

L4: 50% corn oil

35% linseed oil

10% methyl salicylate

5% eucalyptus oil.

Five groups, each of four Dark Agouti rats were used. Groups 1 to 4 challenged on day one with Freund's complete adjuvant, composed of 500 micrograms delipidated, heat killed Mycobacterium tuberculosis (human) dispersed in 50

microliters squalane by injection into the tail base. Group five was used as a control and was not subjected to the pretreatment step. Chronic polyarthritis develops in the rats in all limbs and along the tail after about 12 days.

Treatment with the compositions was begun on day 12 for four days and daily scores of arthritis parameters were taken from the beginning of treatment to day 19. Treatment was by rubbing the limb joints with a 0.5ml dose of the particular composition.

Arthritis (or inflammation) is scored by the mean increase in tail and rear paw pad thicknesses, mean change of weight and mean forepaw thickness increase in an arbitrary index of scale 0 to 6+.

The results were as follows:

TABLE 1 Treatment Parameters

Rear Pads (mm) Tail (mm) Front Pads (index) Change wt(g)

Control 1 .59 1 . 15 5+ -21

L1 -0 .79 -0 . 10 1+ -14

L2 0.86 0 2+ -07

L3 1 .37 0.55 5+ -11

L4 1 . 52 0 . 10 5+ -12

From the above Table 1, it will be seen that the results for the L1 and L2 formulations were statistically significant and gave significant reduction in inflammation. The L3 and L4 formulations provided no statistically different results to the controls. This is perhaps

surprising in the case of the L4 formulation which contains 35% linseed oil, but this ineffectiveness may be attributable to the low content of the linseed oil, the competitive presence of inert corn oil and the low content of thinner.

The above test is indicative of anti-inflammatory activity rather than any analgesic effect created by the topical application of the composition. The antiinflammatory effect noted with the combination of linseed oil and mineral turpentine is unexpected and surprising in the light of present knowledge. Moreover, there appears to be a slight reduction in the effect with the use of 25% gum turpentine and 25% mineral turpentine. However, there is still a significant reduction in inflammation and accordingly it is still to be embraced by the present invention.

The preceding treatment protocol was also used in determining the efficacy of the compositions described in the following examples.

Example 2

Further experiments were conducted with 2 component formulations, that is edible linseed oil mixed with ethyl salicylate in varying proportions/isopropyl salicylate/other esters/eucalyptus oil.

The two most active drug preparations known to the inventors that will prevent arthritis expression over the time period routinely used in these liniment assays are

Piroxicam dissolved in DMSO and copper-phenylbutazone dissolved in DMSO-glycerol. They were accordingly compared with linseed oil thinned with either an eucalyptus oil of illdefined composition or with ethyl salicylate. The results given in Table 2 are all the more satisfying inasmuch as the Piroxicam and Cu-phenylbutazone formulations each cause gastric bleeding, even though given topically. By contrast the linseed oil formulations were both effective and non gastro-irritant.

In the following Tables, mean rear paw pad thickness increase is identified under the columns headed by the numerals 1 and 5, mean tail thickness increase identified under the columns headed by the numerals 2 and 6, mean front paw pad thickness increase identified under the columns headed 3 and 7, and mean change of weight identified under the columns headed by the numerals 4 and 8.

* Piroxicam = 1mg/ml (3mM) in DMSO-Glycerol

** (50mM Cu(II)-200mM Phenylbutazone in DMSO-Glycerol

ELO = Edible Linseed Oil

Es = Ethyl Salicylate

Eo = Eucalyptus Oil

DMSO-G = DMSO Glycerol

Example 3

Table 3 gives the data from one experiment in which the proportions of oil: ethyl salicylate were varied from 9:1 to 6:4. Activity was evident in all 4 mixtures but no one mix was clearly optimal. Replacing the ethyl salicylate with isopropyl salicylate gave a somewhat less pungent (more pleasant) liniment that was certainly active. Thus either the methyl, ethyl or isopropyl salicylates will effectively thin the linseed oil and promote skin penetration for antiarthritic activity. Two other esters, methyl benzoate and amyl acetate were not adequate for this purpose. The amyl acetate was an excellent thinner (resembling acetone), as far as reducing the viscosity of linseed oil, even though it did not promote the anti-arthritic activity. Perhaps it could be used nonetheless in preparing mobile, relatively nonvolatile, oil preparations (e.g. for spray-on) that do have anti-arthritic activity.

IS = Isopropyl Salicylate

MB = Methyl Benzoate

AA = Amyl Acytate Example 4

Experiments were conducted with 2 - component liniments composed of:

a) esters of unsaturated fatty acids with ethyl

salicylate;

b) linseed oils thinned with eucalyptol (also known as cineole).

The results indicated linolenic acid (18:3) to be the principal active agent for suppressing inflammation in rats with experimental polyarthritis.

Ethyl oleate, methyl linoleate and methyl linolenate were procured as 90% pure. They were mixed with ethyl salicylate (23%) for topical application.

The linoleate (18:2) liniment reduced rear paw swelling (column 1 Table 4) but there was no rebound after cessation of dosing and this group may have included a poor reactor. The linolenate (18:3) liniment was certainly remarkable in preventing increase in inflammation, even suppressing preestablished inflammation in the rear paws and tail. On ceasing treatment, there was a very definite increase in the size of inflamed paws and tail. Both the linoleate (18:2) and linolenate (18:3) liniments caused scaliness of the skin at the site of application. The oleate (18:1) liniment also caused some scaling but this was much less apparent.

Another batch of edible linseed oil was used with and without added pure eucalyptol (10%v/v). The results show (i) that ELO alone is not effective and (ii) that eucalyptol can be added to the list of useful thinners.

EOl= Ethyl Oleate (18:1)

ML = Methyl Linoleate (18:2)

MLL= Mtthyl Linolenate (18:3)

Eul= Eucalyptol

Example 5

A sample of linseed oil low in linolenate (18:3) was obtained from C.S.I.R.O. and compared with the ELO in admixture with 20% ethyl salicylate (Table 5). This 80% ELO liniment was certainly active. The low-linolenate liniment was less active.

* Linseed Oil contains 1.5% Linolenic Acid (18:3)

** Linseed Oil contains 47% Linolenic Acid (18:3) Example 6

A number of linolenate oils (see Table 6) were tested in combination with ethyl salicylate, to compare with the linseed oil/ethyl salicylate formulation. The results are shown in Table 7 and Table 8.

TABLE 6 .

LINOLENATE (18:3) CONTENT OF SOME OILS alpha - 18:3 in: % Source of data

- Edible Linseed (Blackmore's) 47 product label *

- Walnut 10.9 S.I.W.

- Soybean 6.8 S.I.W.

- Rapeseed 8.6 S.I.W.

- Experimental Linseed 1.5 C.S.I.R.O.

gamma - 18:3 in:

- Evening Primrose (Efamol) 9 product label *

- Borage seed 11.2 C.S.I.R.O.

* typical analysis as quoted.

S.I.W. Sheppard et al. Handbook of Lipid Research 1:341. C.S.I.R.O. Divn. Plant Industry, unpublished data.

Three oils with significant content of alpha-linolenate (which is abundant in linseed oil) showed topical activity when thinned with ethyl salicylate. These were walnut, soybean and rapeseed. Muttonbird oil was tested as a

formulation with 20% ethyl salicylate and found inactive.

Formulations contained oil: Es of 8:2 by volume.

WO = Walnut oil

SO = Soybean oil

RO = Rapeseed oil

IM = Isopropyl Myristate

MO = Muttonbird oil

The low-linolenate experimental linseed oil from CSIRO was tested with 20% ethyl salicylate and found to have minimal topical activity (Table 8). Two oils containing gamma-linolenate, when tested with ethyl salicylate, were also topically active. These were evening primrose and borage seed oils (Table 8).

BO = Borage seed oil

EPO = Evening primrose oil

ELO*= Experimental linseed oil.

In a previous study (unreported) using isopropanol or acetone as thinners, the evening primrose oil showed antiarthritic activity.

Example 7

The efficacy of Ateol (tea tree oil) as a thinner and synergistic agent for linseed oil is shown in experiments described in Table 9.

A = Ateol

CO = Corn oil

The invention is further illustrated by reference to the following examples using human subjects but the results are based on a more subjective reaction of the subject to the composition.

Example 8

FORMULATION 1

linseed oil 50% v/v

mineral turpentine 50% v/v

The above agents were mixed together and about 1% v/v eucalyptus oil was added to confer a pleasant smell to the composition. The composition is massaged into the skin surrounding the affected joint once or twice a day. Complete pain relief was noted for several hours after treatment.

COMPARATIVE FORMULATIONS A-C

The linseed oil in the above composition was replaced by castor oil (A), vegetable oil (B) and olive oil (C). None of the compositions A to C gave any appreciable relief of pain over a period of several days as compared to Formulation 1 in which pain relief was significant. Accompanying relief in pain, there is noted also a substantial reduction in the stiffness of the joint.

Example 9

FORMULATION 2

turpentine oil 25% v/v

mineral turpentine 25% v/v

linseed oil 50% v/v

The above components were mixed to a homogenous mixture and about ten drops of eucalyptus oil per 100ml formulation was added.

COMPARATIVE FORMULATION D

turpentine oil 25% v/v

mineral turpentine 25% v/v

olive oil 50% v/v

The above components were mixed and about ten drops of eucalyptus oil were added per 100ml formulation.

The compositions of Formulation 2 and comparative Formulation D were tested on two different subjects, one of whose elbow joints were seriously affected by arthritis and one of whose fingers on both hands were seriously affected by arthritis.

The composition of Formulation 2 was rubbed on skin surrounding the joints of one limb and the composition of

Formulation D was rubbed on the skin surrounding the joints of the other limb.

Over a period of five days, significant pain relief and amelioration of stiffness in the joints with the composition of Formulation 2 were noted whereas the composition of

Formulation D had little significant effect. The subjects were not advised as to the nature of either solution and the solutions were only identified by numbers. Both subjects noted the significant relief afforded by the composition of Formulation 2 as compared to Formulation D.

Example 10

FORMULATION 3

turpentine oil 50% v/v

linseed oil 50% v/v

The above components were mixed and topically applied to an affected joint. Significant relief of pain associated with arthritis was noted over a period of several days with twice daily applications of the composition.

COMPARATIVE FORMULATION E.

The efficacy of the composition of Formulation 3 was compared with pure linseed oil, over a period of several days with twice daily application of the compositions to affected joints. No appreciable affect was noted with the linseed oil alone. Example 11

FORMULATION 4

linseed oil 90% v/v

Thinner : oil of wintergreen 7% v/v

eucalyptus oil 3% v/v

The above components were mixed and the composition tested by application to an affected joint over a period of several days twice daily. A significant reduction in pain was noted over that period.

Example 12

Each of the above five formulations were mixed separately to a homogeneous mixture and applied to an affected joint. Significant relief of pain associated with arthritis was noted over a period of several days with twice daily applications of each formulation.

Various modifications may be made in details of composition constituents and method of application without departing from the scope or ambit of the invention.

Claims

1. A composition for topical application to the skin, adjacent a locus of inflammation, said composition comprising an oil, being linseed oil or a substantially equivalent oil thereto, or an effective amount of a component thereof, and a thinner therefor which assists in moving said oil or

component through the skin to said locus.

2. The composition of claim 1 wherein the substantially equivalent oil is selected from one or more members of the group comprising walnut oil, soybean oil and rapeseed oil.

3. The composition of claim 1 wherein the substantially equivalent oil is selected from one or more members of the group comprising evening primrose oil and borage seed oil.

4. The composition of claim 1 or claim 2 wherein the component of the said oil is alpha-linolenic acid or a derivative thereof.

5. The composition of claim 1 or claim 3 wherein the component of the said oil is gamma-linolenic acid or a derivative thereof.

6. The composition of any one of claims 1 to 5 wherein the thinner is selected from one or more members of the group comprising mineral or distilled turpentine, methyl

salicylate, ethyl salicylate, isopropyl salicylate, cineole, ateol and wintergreen oil.

7. The composition of any one of claims 1 to 6 wherein the said oil is present in the composition at about 80% by volume.

8. The composition of any one of claims 1 to 7 further including an antioxidant.

9. The composition of claim 8 wherein the antioxidant is wheatgerm oil or Vitamin E.

10. The composition of claim 1 wherein the oil is linseed oil present in the composition at about 80% by volume and the thinner is methyl salicylate.

11. The composition of claim 1 wherein the oil is linseed oil present in the composition at about 80% by volume and the thinner comprises 10% by volume methyl salicylate and 10% by volume ateol.

12. The composition of claim 1 wherein the oil is linseed oil present in the composition at about 80% by volume and the thinner is ateol.

13. The composition of any one of claims 10 to 12 including an antioxidant conferring amount of Vitamin E.

14. The composition of any one of claims 1 to 13 further including a propellant for application to the skin as an aerosol spray-on.

15. A method for the relief of inflammation, particularly of the joints, said method comprising topically applying to the skin adjacent a locus of inflammation a composition comprising an oil being linseed oil, or a substantially equivalent oil thereto or an effective amount of a component thereof, dissolved in a thinner therefor, which thinner assists in moving said oil or component thereof through the skin to the locus.

16. The method of claim 15 wherein the composition is defined in any one of claims 2 to 14.

17. A composition for topical application to the skin adjacent a locus of inflammation, said composition being substantially as hereinbefore described with reference to the Examples, excluding those used as comparative examples.

18. A method for the relief of inflammation, particularly of the joints, said method comprising topically applying to the skin adjacent a locus of inflammation a composition being substantially as hereinbefore described with reference to the Examples, excluding those used as comparative examples.