WO2007066305A1

WO2007066305A1 - Compositions comprising sesquiterpene compounds for use in the prophylaxis or treatment of pain

Info

Publication number: WO2007066305A1
Application number: PCT/IB2006/054649
Authority: WO
Inventors: Theo Trouw Bothma; Johan Henri Rossouw; Ann-Marie Richards; Johannes Petrus Cronje
Original assignee: Zelpy 2549 (Pty) Limited
Priority date: 2005-12-09
Filing date: 2006-12-07
Publication date: 2007-06-14

Abstract

According to the present application there is provided a preparation for use in the prophylaxis or treatment of pain in the human or animal body. The preparation is in the form of one or more sesquiterpene compounds or a composition containing at least 3 wt% of one or more sesquiterpene compounds.

Description

COMPOSITIONS COMPRISING SESQUITERPENE COMPOUNDS FOR USE IN THE PROPHYLAXIS OR TREATMENT OF PAIN

FIELD OF THE INVENTION

This invention relates to a preparation for use in the prophylaxis or treatment of pain. More particularly, but not limited thereto, the preparation is used for the treatment of pain such as arthritis pain, pain in muscles, or pain in joints. This invention also relates to the prophylaxis or treatment of pain.

BACKGROUND TO THE INVENTION

Arthritis is an autoimmune disease. It causes persistent synovitis (inflammation and swelling of the lining layer of joints), that can eventually lead to joint erosion and permanent structural damage. It is characterized by symptoms such as joint pain, swelling and morning stiffness. Current treatment for rheumatoid arthritis (RA) includes administration of drugs for control of the symptoms. Such drugs include non-steroidal anti-inflammatory drugs (NAISDs) (such as ibuprofen, naproxen, aspirin, diclofenac and acetaminophen), corticosteroids and slow-acting anti-rheumatic drugs (SAARDs), disease-modifying anti-rheumatic drugs (DMARDs), (such as methotrexate, sulfasalazine, antimalarials and leflunomide). Methotrex, however, has severe side effects. Revelex (infliximab) a biological third line of defense medication can be used with some success, but it is exorbitantly expensive. Osteoarthritis is a disease characterized by cartilage softening and degeneration. It can eventually progress to complete joint destruction. Analgesics and NSAIDs are prescribed for the symptomatic treatment of osteoarthritis. At this stage there are no drugs available to halt or reverse the process, although nutraceuticals such as glucosamine sulfate might slow the process.

Chronic muscle pain and joint pain are experienced by most individuals and many persons have such pain on a daily or weekly basis. An injury to the body may cause inflammation where swelling occurs in a localized area of the body or arthritic pain occurs in a joint due to wearing. Strenuous physical activity can subject the body to intense strain which may cause pain to result in their muscles and/or joints, in many cases as a result of muscle spasm. In some cases the pain experienced is a referred pain at a locus removed from the cause or an identified cause is lacking. At times people get frustrated when physical pain prevents them from operating near peak efficiencies. People in pain tend to take analgesics for their pain.

Current treatments of pain in muscles and joints, including back pain and neck pain, or viscera distal to the site of the pain include first line drugs for control of pain and inflammation classified as NSAIDs as above.

However, the use of DMARDs has been impeded by the potential of long-term side effects and toxicity, and by its relative high cost and hypersensitivity to the medications and infections due to TNF-α blockage. The treatment of the above painful ailments, in particular back pain, neck pain and arthritis pain, requires ingesting frequent doses of NSAIDs and the like, in order to obtain a level of active ingredient in a patient's bloodstream sufficient to maintain an analgesic or anti-inflammatory effect. The concentration levels of these drugs which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. Such a regimen is often difficult to maintain because the active ingredients result in chronic stomach upset, which can turn into gastritis and even spontaneous gastric bleeding. In addition the abovementioned drugs have a variety of toxic side effects, such as adverse effects on the kidneys and liver, which side- effects dictate against their use over extended periods of time. Many of these drugs are also cytotoxic. It has also been found that these drugs have limited advantages and their effects are mainly of short-term duration. Researchers who pooled 23 studies involving more than one million people found a 40% increased risk of cardiovascular events - mostly acute heart attacks - in people taking a certain NSAID. The drug appears to be harmful at commonly used doses, raising serious questions about its safety, according to a study released in September, 2006 - one month ahead of publication by the Journal of the American Medical Association, because of the public health implications.

It is well known that pain is often associated with trigger points, and that by treating the trigger points the associated pain is also treated. In this specification the term "trigger point" is used to mean a hyperirritable spot in or on the human or animal body resulting in a hypersensitive palpable nodule or spot in the body including skeletal muscle, muscle ligaments periosteum and skin; and/or resulting in an area of chronic tenderness in the body including the periosteum and including periosteum of joints. Trigger points in the muscle or muscle ligaments are often referred to as myofascial trigger points and can give rise to referred pain. Trigger points in the periosteum are often referred to as tender points, and in this specification joint pain and joint arthritis including osteoarthritis and rheumatoid arthritis is considered to be a hyperirritable spot resulting in an area of chronic tenderness in the periosteum and accordingly joint arthritis is considered to be associated with a trigger point.

Myofascial trigger points are well known and widely described in literature and can be inactivated in different ways such as osteopathic manipulative treatment, massage therapy, ultrasound therapy, "spray and stretch", as well as needling (acupuncture or injection) as pointed out in the Journal of the American Osteopathic Association, Vol. 104, No 6, June 2004, p244-249.

The above document also discloses that herbal remedies and essential oils are recommended for treating myofascial pain. It is also disclosed that nearly all of the herbs listed for such treatment contain linalool, a monoterpene. It is not stated how the herbal remedies should be used, that is orally, by injection or otherwise. However, it is known that linalool has been used for the treatment of myofascial trigger points in mice by means of injection. It is known that many monoterpenes at a concentration of about 1 to 6 wt% and in some cases even higher can alleviate pain when applied topically. Examples of such monoterpenes are camphene, camphor, limonene, linalool, menthol, phellandrene, pinene and many more. Menthol and camphor have been used in several OTC topical pain relieving compositions. It is also known that many essential oils containing monoterpenes at a concentration of 1 to 6 wt% and even higher, can alleviate pain when topically applied. Examples of such essential oils are angelica oil, bay lauryl oil, cajeput oil, camphor oil, cypress oil, eucalyptus oil, juniper berry oil, lavender oil, lemon oil, lime oil, orange oil, peppermint oil, petitgrain oil, rosemary oil, tea tree oil, wintergreen oil and many more. Eucalyptus oil, peppermint oil and wintergreen oil have been used in OTC topical pain relieving compositions. The use of essential oils or monoterpenes in the treatment of pain or in transdermal delivery systems (TDS) have also been described in US 4,933,184; US 6,444,234; US 6,444,238; US 6,528,076; US 5,013,726; US 5,124,320; US 6,649,194; and US 6,756,064.

It is also known that, in addition to monoterpenes, essential oils may include other terpenes such as sesquiterpenes. Traditionally essential oils are not applied directly onto the skin, as essential oils often contain contaminants and other dermatologically-damaging species. Instead, the essential oils would be diluted with a carrier which, in turn, dilutes the concentration of sesquiterpenes in the composition that would ultimately be applied onto the skin. It is general practice not to use essential oils at concentrations above about 3 wt% in compositions for application to the skin, resulting in compositions that contain sesquiterpenes at very low concentrations.

The present inventors have now found that sesquiterpene compounds are very effective in the treatment or prophylaxis of pain especially when used at concentrations of at least 3 wt% sesquiterpene compounds. As far as the present inventors could establish the prior art does not disclose the use of sesquiterpene compounds or compositions with sesquiterpene compounds at a concentration of at least 3 wt% in any application to the human or animal body. That is also true for cases where essential oils with a relatively high concentration of sesquiterpene compounds have been used in topical applications, since (as explained above) in such cases the essential oils were used at concentrations of below 3 wt% resulting in a lower wt% of sesquiterpenes.

DISCLOSURE OF THE INVENTION

According to a first aspect of the present invention there is provided a preparation for use in the prophylaxis or treatment of pain in the human or animal body which preparation is in the form of one or more sesquiterpene compounds or a composition containing at least 3 wt% of one or more sesquiterpene compounds. In this specification the term "sesquiterpene compound" is used to mean any organic compound of fifteen carbon atoms, or an organic compound which includes a moiety of fifteen carbon atoms, and which compound of fifteen carbon atoms or which moiety of fifteen carbon atoms is derived from three isoprene molecules.

Sesquiterpene compounds are not limited to any particular molecular arrangements, and known sesquiterpene compounds may have acyclic, mono-cyclic, bi-cyclic, tri-cyclic and tetra-cyclic molecular arrangements. The organic compound may be in the form of a hydrocarbon compound with fifteen carbon atoms; alternatively it may be in the form of heterohydrocarbon compound containing at least fifteen carbon atoms and at least one heteroatom which is not C or H, and preferably the heterohydrocarbon compound is an oxygenated hydrocarbon compound.

The one or more sesquiterpene compounds may be selected from the group consisting of a hydrocarbon compound with fifteen carbon atoms; an alcohol compound; a ketone compound; an aldehyde compound; an ester compound; an ether compound, a lactone compound, a ketolactone compound and a carboxylic acid compound.

Preferably, the one or more sesquiterpene compounds may be selected from the group consisting of agoraspirol, amorphine, anhydro-β-rotunol, aromadendrine, azulene, bisabolene, bisabolol, cadalene, cadinene, cadrina- 1 ,4-diene, caryophyllene, cedrene, cedrol, cerapictol, ceratopicanol, clovene, copaene, cubebene, eudalene, eudesmol, famesene, farnesol, germacrene, guaiazulene, guaioi, gurjunene, hexahydrohumulene, himachalene, hinesol, humulene, junipene, Iongifolene, lubiminol, khusimone, khusinol, khusimol, nootkatone, santalene, santalol, santanol, santonene, selinene, solavetivone, spatulenol, sterpurine, sulcatine, thujopsene, valerenol, vetispirene, vetivazulene, vetivene, vetiverol, vetivone, viridiflorine, viridiflorol, zingiberene as well as all derivatives and isomers thereof including acetyl, acetate, phenylacetate, hydro, dihydro, formate, methyl ether, dimethylether, caprylate, valeriate, isovaleriate, alcohol, aldehyde, ketone, epoxide, lactone and cyclases derivatives.

It will be appreciated that if the preparation is in the form of a sesquiterpene compound, such a compound will be a single sesquiterpene compound in pure or substantially pure form.

In a preferred embodiment of the invention the preparation comprises a composition of two or more compounds.

The composition may include a single sesquiterpene compound, alternatively it may include more than one sesquiterpene compound.

The one or more sesquiterpene compounds may be provided in pure form or it may be provided as an essential oil containing one or more sesquiterpene compounds. Preferably the essential oil is one that contains at least 35 wt% of one or more sesquiterpene compounds. The essential oil containing one or more sesquiterpene compounds may be selected from the group consisting of carrot seed oil (daucus carota sativa seed oil); cedarwood atlas oil (cedrus atlantica wood oil); cedarwood china oil (cupressus funebris wood oil); cedarwood texas oil (juniperus ashei wood oil); cedarwood Virginia oil (juniperus virginiana wood oil); chamomile german (matricaria) oil (chamomilla recutita flower oil); ginger oil (zingiber officinale root oil); helichrysum (wild, African) oil (helichrysum splendidum flower oil); hemizygia (wild, African) oil (hemizygia petiolata flower oil); manuka oil (lepospermum scoparium leaf oil); linden tree oil (tilia cordata tree flower oil); patchouli oil (pogostemon cablin leaf oil); sandalwood west Indian oil (santalum album wood oil); sandalwood west Australian oil (santalum spicatum wood oil); and vetiver oil (vetiveria zizanoides root oil).

Preferably the one or more sesquiterpene compounds serve as the active ingredient(s) in the prophylaxis or treatment of pain.

Preferably the preparation is suitable for transdermal application to the human or animal body preferably to the human body. The preparation in the form of a composition may be in any suitable form such as a spray, a cream, an oil, a gel, a balm, a lotion, an ointment or a patch.

The preparation composition may include one or more additives and in one embodiment of the invention it includes at least one additive selected from the group consisting of a diluent; a solvent for a sesquiterpene compound; an antioxidant; an odour mask; a chelating agent; a consistency builder; an emulsifier; a defoamer; an emollient; a preservative; a humectant; a base; an acid; a gelling agent or a combination of one or more thereof. The preparation may also include one or more rubefacients. The rubefacient may be any suitable rubefacient and may be selected from the group consisting of camphor, menthol, a derivative of salicylic acid, capcaicin oleoresin, capcicum oleoresin and capsicum oleoresin. Preferably the rubefacient may be selected from the group consisting of camphor, menthol and a derivative of salicylic acid. The derivative of salicylic acid may be an organo salicylate and may be selected from the group consisting of ethyl salicylate, methyl salicylate and triethanolamine (trolamine) salicylate.

The rubefacient may be present at a concentration of at least 0.1 wt%. Preferably it is present at a concentration of at least 1.25 wt%.

Where the rubefacient is a derivative of salicylic acid it may be present at a concentration of at least 1 wt% and preferably not more than 60 wt%. Preferably it is present at a concentration of at least 10 wt%.

Where the rubefacient is camphor it may be present at a concentration of at least 0.1 wt% and preferably not more than 11 wt%. Preferably it is present at a concentration of at least 3 wt%. Where the rubefacient is menthol it may be present at a concentration of at least 0.1 wt% and preferably not more than 16 wt%. Preferably it is present at a concentration of at least 1.25 wt%. The preparation may include two, or all three of the rubefacients set out above and they may be present at the concentrations set out above.

It is believed that a rubefacient used in combination with one or more sesquiterpene compounds demonstrate a synergistic pain treatment effect.

Some sesquiterpene compounds and salicylic acid derivatives have a strong and lasting aroma with an often unpleasant initial impression. To eliminate the most annoying odors, where necessary, a pleasant smelling perfume oil can be added the preparation to mask these odors. A fragrance of preference would be one with fresh and floral top and middle notes and a woody bottom note.

Preferably the preparation contains at least 4 wt%, preferably at least 5 wt%, preferably at least 7 wt% and even at least 15 wt% of the one or more sesquiterpene compounds. The composition may in some cases include as much as 30 wt% or even 60 wt% or more of the one ore more sesquiterpene compounds.

The preparation may also include at least one monoterpene. The pain may be selected from pain of arthritis, pain of muscles, and pain of joints. The pain may be back and/or neck pain.

The pain may be pain associated with one or more trigger points.

In this specification the term "trigger point" is used to mean a hyperirritable spot in or on the human or animal body resulting in a hypersensitive palpable nodule or spot in the body including skeletal muscle, muscle ligaments periosteum and skin; and/or resulting in an area of chronic tenderness in the body including the periosteum and including periosteum of joints. Trigger points in the muscle or muscle ligaments are often referred to as myofascial trigger points and can give rise to referred pain, dysfunction (including motor dysfunction) and autonomic phenomena. Trigger points in the periosteum are often referred to as tender points, and in this specification joint pain and joint arthritis including osteo arthritis and rheumatoid arthritis is considered to be a hyperirritable spot resulting in an area of chronic tenderness in the periosteum and accordingly joint arthritis is considered to be a trigger point.

It is known that particular disorders, dysfunctions and conditions are associated with trigger point sources. For example, certain of these disorders, dysfunctions and conditions and their associated likely trigger point sources are disclosed in Table 2.5 of Travell & Simons' Myofascial Pain and

Dysfunction, The trigger point manual, by Janet G Travel and David G Simons

(second edition, 1998, vol. 1 ) page 95. The contents of this document are incorporated into this specification by reference. According to a second aspect of the present invention, there is provided the use of one or more sesquiterpene compounds in the manufacture of a preparation for the prophylaxis or treatment of a pain, which preparation contains at least 3 wt% of one or more sesquiterpene compounds.

According to a third aspect of the present invention there is provided a method for the prophylaxis or treatment of pain wherein a preparation in the form of one or more sesquiterpene compound or a composition containing at least 3 wt% of one or more sesquiterpene compounds is administered to a human or animal.

Preferably the preparation is administered topically to the human or animal.

The composition or compound may be applied topically where the pain is experienced. Alternatively when the pain is associated with one or more trigger points the composition or compound may be applied topically where the associated one or more trigger points are located.

The invention will now be further described by means of the following non- limiting examples:

Example 1 : Preparation of a composition in the form of a gel

A gel was manufactured by mixing together the following compounds using accepted and proven procedures: Table 1 : Gel composition with sesquiterpene compounds

BHT is an acronym for butylated hydroxytoluene. Glydant plus liquid is supplied by Lonza and is a mixture of DMDM hydantoin and iodopropynyl butylcatbamate.

The pain relief composition had a pH of 6.5

Example 2: Preparation of a composition in the form of a cream

A cream was manufactured by mixing together the following compounds using accepted and proven procedures:

Table 2: Cream composition with a sesquiterpene compound

Example 3: Preparation of a composition in the form of a spray

A spray was manufactured by mixing together the following compounds using accepted and proven procedures:

Table 3: Spray composition with essential oils containing sesquiterpene

compounds

The spray composition contained about 4.55 wt% sesquiterpene compounds due to the presence of the essential oils.

The pain relief composition had a pH of 6.3

Example 4: Preparation of a composition in the form of an oil

An oil was manufactured by mixing together the following compounds using accepted and proven procedures: Table 4: Oil composition with sesquiterpene compounds in a synthetic oil

Example 5: Preparation of a composition in the form of an oil

An oil was manufactured by mixing together the following compounds using accepted and proven procedures:

Table 5: Oil composition with essential oils containing sesquiterpene compounds in natural oils

The composition contained about 9.6 wt% sesquiterpene compounds due to the presence of the essential oils.

Example 6: Preparation of a composition in the form of a lotion

A lotion was manufactured by mixing together the following compounds using accepted and proven procedures: Table 6: Lotion composition with a sesquiterpene compound and an essential oil containing sesquiterpene compounds

The composition contained about 8.6 wt% sesquiterpene compounds.

The pain relief composition had a pH of 6.2

Example 7: Preparation of a composition in the form of an ointment

An ointment was manufactured by mixing together the following compounds using accepted and proven procedures:

Table 7: Ointment composition with essential oils containing

sesquiterpene compounds

The composition contained about 6.7 wt% sesquiterpene compounds due to the presence of the essential oils. Example 8: Preparation of a composition in the form of a balm

A balm was manufactured by mixing together the following compounds using accepted and proven procedures:

Table 8: Balm composition with sesquiterpene compounds

I TRIETHANOLAMINE 1 0.31 I pH ADJUSTER |

The pain relief composition had a pH of 6.5

Examples 9 to 18: Treatment Examples

Example 9

Patient

The patient was a female, age 52 with a length of 180 cm and a weight of 75 kg.

Medical history of patient

Healthy patient with pain and discomfort in both hands. Swollen joints of fingers and discoloration of skin. She had a gall bladder operation about 10 years ago. The patient has no other medical history of other medical conditions. No other allergies reported.

Indication of using this product(s)

Painful fingers - immobilized hands.

Product used

Product 1 : (comparative)

Contains about 1.4 wt% sesquiterpene compound.

Product 2:

Contains about 7 wt% sesquiterpene compound.

Product 3:

PERFUME OIL 0.50

MENTHOL 1.00

Contains about 21 wt% sesquiterpene compound.

Application of product 1 - (comparative example)

Topically applied to joints of fingers. Ten minutes after application, only 10% better than before application. Thirty minutes after application, 40% better. Effect lasted for 1 hour.

Application of product 2

Topically applied to joints of fingers. Ten minutes after application, 40% better than before application. Thirty minutes after application, 50% better. Effect lasted for 4 hours.

Application of product 3

Topically applied to joints of fingers. Ten minutes after application, 60% better than before application. Thirty minutes after application, 90% better. Effect lasted for 10 hours.

After application of product 3 the patient's hands were mobilized in a normal way and she had only slight discomfort. Her fingers appeared even and straight and she could make a fist. Example 10

Patient

The patient was a female, age 60 with a length of 157 cm and a weight of 90 kg.

Medical history of patient

Patient suffered from chronic thyroid problems - hyper thryroidism. Five years ago had a thyroidectomy. Only certain nodules were removed. Patient takes thyroxine sodium anhydrite for hypothyroidism after thyroidectomy. Also taking mineral and vitamin supplements every day, i.e. vitamin C, multivitamins, salmon oil, Cal/Mag combination. She is also using amitriptyline HCL 25mg nocte, for last 5 years, for chronic headache/migraines due to tension and an old whiplash incident + 40 years ago. She has also been suffering from deep vein thrombosis for the last 32 years which causes severe blood circulation problems in her left leg distal to the knee and superior from ankle. This problem causes her leg to be discolored black, and it feels hard and full of edema, and makes it difficult to walk. Also very painful. No allergies reported.

Indication for using this product(s)

The tension headaches was an indication for trying the product, because nothing could help her so far to relief headaches. The leg with the bad circulation was also an indication, because it was becoming a serious problem which can lead to her loosing her leg. The leg restrained her from doing her daily work and she had to lay down most of the day.

Product used

Contains about 6 wt% sesquiterpene compound. Results before and after applying product(s)

The patient experienced a "tight band" around the head with pain referring into left eye. Sometimes her vision is impaired due to this condition. Her pain normally increased during nighttime.

The product was topically applied to the tender areas on the base of scull, behind ears down into the neck. After 10 minutes she had a 90% improvement. After 30 minutes the pain was completely gone. The pain only returned after 24 hours. With daily treatment the pain returned only slightly, and diminished over two weeks.

Her leg was treated on the effected area. Within an hour the swelling diminished and the pain disappeared and the discoloration changed to an "pinkish" color which is a sign of healthy blood flow with oxygen richer blood. With daily application of the product the leg improved to such an extend that the patient can walk normally and do her daily work. His own words were that it "induces a feeling of tension release and relaxation".

Example 11

Patient

The patient was a male, age 66 with a length of 175 cm and a weight of 75 kg. Medical history of patient

Patient has been suffering from a frozen shoulder for a few years. Due to this condition he experienced a lot of pain and his mobility was constrained so that he could not perform his daily duties, because he is a builder doing most of the work himself. His medical practitioner did radiology and confirmed nothing mechanical wrong. The only solution was to loosen the shoulder under general anesthetic and to perform a laparoscopic procedure. This will be costly and will put him out of work, which mean no income. No allergies reported.

Product used

Contains 7 wt% sesquiterpene compound. Indication for using this product(s)

Frozen shoulder with loss of mobility and lots of pain

Results before and after applying product(s)

The product was locally and topically applied to the affected area of the shoulder and within 20 minutes the patient could move his arm, without pain, and even lift a hammer with no pain. The overall strength of the arm/shoulder improved daily within a week to normal. His mobility of the arm was also back within days to such an extend that he could tuck in his shirt behind his back. Something he could not do for years with that specific arm.

Example 12

Patient

The patient was a male, age 63 with a length of 175 cm and a weight of 75 kg.

Medical history of patient

Patient had Bells Palsey years ago. Result was that he suffers from dry eyes. Stiffness in left ring finger, probably in the form of some sort of arthritis. He complains of pain in his finger/hand and no mobility in his left hand. No allergies reported.

Product used

Contains about 6.5 wt% sesquiterpene compounds. Indication for using this product(s)

Stiffness on joint of ring finger of left hand. Loss of mobility of left hand.

Uncomfortable and painful hand. Results before and after applying product(s)

Left ring finger is stiff and painful. After topically applying the product to the specific finger and the joint, the pain disappeared within 10 minutes and stayed away for hours. Not only did the pain disappear, but also the swelling and the dark color of the skin in that area. The patients mobility of his finger and hand was normal within 30 minutes. His own words: 'Excellent, quick results".

Example 13 Patient

The patient was a male, age 27 with a length of 176 cm and a weight of 90 kg.

Medical history of patient

Very healthy young male patient. No medical history of any chronic medical conditions. No history of any medical operations or procedures. He has not been to any medical practitioner during the last 2 years. No allergies reported, although a sensitivity to aspirin was mentioned associated with nose bleeding. The patient fell off a ladder about 1 week prior to using this product. His right arm and shoulder was hurt and immobilized. The patient had localized pain and seemed to have soft tissue damage, associated with symptoms of local inflammation. He used pain killers and topical pain agents like flurbiprofen patches. The patient was stubborn and had not seen a medical practitioner, leading to the assumption of a soft tissue damage accident and not one with mechanical problems, however this is only an assumption and not a diagnoses. Not enough medical history like pathology and histology.

Product used

Contains about 5.6 wt% sesquiterpene compounds.

Indication for using this product(s)

Stiffness of shoulder and arm that persisted after self treatment with anti- inflammation medication. Persisting pain and lack of proper use of shoulder and arm.

Results before and after applying product(s)

Before applying the product the patient had pain and stiffness and could not lift his arm. After applying the product topically to the neck, shoulder and upper arm, the patient had an immediate result. Within 10 minutes the patient had only 50% of the pain which he experienced before using the product. After 30 minutes of application the pain was gone. The shoulder was mobilized in such a way that he could lift the arm without stiffness or pain. This effect lasted for about 12 hours before a next application was done. The shoulder improved in such away that after one week no treatment was needed. The patient reported in his own words "it works, cool feeling, works almost immediately". Example 14

Patient

The patient was a female, age 79 with a length of 165 cm and a weight of 54 kg.

Medical history of patient

The patient was diagnosed with a sarcoma in the right shoulder about 2 years ago. She had extensive surgery to remove this sarcoma, as well as some soft tissue. The operation was so successful that no chemotherapy nor radiology was needed. During the last 2 years she had all her follow-up examinations, as well as the tests needed. She came out clean with no cancer suspected. She suffers from hypertension which is kept under control with ACE inhibitors- lisinopril 20mg nocte. She also use a aspirin/ecotrin combination as an anticoagulant. To improve her well-being she has been using omega oil and L-arginine 1g/day to improve her vessel tone and elasticity. She suffers occasionally from heartburn and stomach discomfort. She is using a proton pump inhibitor namely esomeprazole 40 mg prn. Lately she had been complaining about lower back pain and discomfort in the sciatica region. She had a neurogical examination done by a neurosurgeon which confirmed that the pain was due to muscle spasms.

Product used

Product 1 : 1.5 wt% menthol in cyclomethicone

Product 2: 4 wt% famesol and 4 wt% vetiveryl acetate in cyclomethicone Product 3: 1.5 wt% menthol, 4 wt% farnesol and 4 wt% vetiveryl acetate in cyclomethicone

Indication for using this product(s)

The stiffness and pain in lower back was a good indication for using these products.

Results before and after applying product(s)

Before using, pain, discomfort, swelling and immobility.

Product 1 - Menthol 1.5 wt% in cyclomethicone

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 30% better than before application.

Thirty minutes after application, 50% better. Effect lasted for 2 hours.

Product 2 - Sesouiterpenes only: 4 wt% farnesol, 4 wt% vetiveryl acetate in cvclomethicone

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 30% better than before application. Thirty minutes after application, 60% better. Effect lasted for 6 hours. Product 3 - Sesquiterpenes and menthol combination: 4 wt% farnesol, 4 wt% vetiveryl acetate and 1.5 wt% menthol in cvclomethicone

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 30% better than before application. Thirty minutes after application, 60% better. Effect lasted for 10 hours.

The above demonstrates a synergistic pain treatment effect when a rubefacient is combined with sesquiterpenes. Example 15

Patient

The patient was a female, age 63 with a length of 170 cm and a weight of 75 kg.

Medical history of patient

The patient is a female medical practitioner. She has had an allergic reaction to the sulphates in her hypertension medication and ended up in ICU with

Steven Johnson Syndrome. She miraculous recovered and has to be very careful with medication she uses. She also suffers from very aggressive arthritis in the hands. Due to this medical condition she has very painful joints in her hands, which almost restrict her from performing her day to day medical work. Product used

The products 1 , 2 and 3 used were the same as those used in Example 9.

Indication for using this product(s)

Rheumatoid arthritis in hands.

Results before and after applying product(s)

Painful joints in hands which immobilized the hands with lots of swelling. Product 1 - (comparative)

Applied topically to tender joints in both hands. Ten minutes after application, only 30% better than before application. Thirty minutes after application, 50% better. Effect lasted for 2 hours. Product 2

Applied topically to tender joints in both hands. Ten minutes after application, only 30% better than before application. Thirty minutes after application, 60% better. Effect lasted for 6 hours. Product 3

Applied topically to tender joints in both hands. Ten minutes after application, only 50% better than before application. Thirty minutes after application, 80% better. Effect lasted for 10 hours. Example 16

Patient

The patient was a male, age 32 with a length of 165 cm and a weight of 75 kg.

Medical history of patient

Healthy patient with pain and discomfort in neck, shoulders and upper back. Tension headaches that sometimes turn into migraines. He has been using 25mg amitriptyline HCL nocte for tension headaches. An accountant as profession. No other allergies reported.

Product used

Product 1 (comparative)

Contains about 1.4 wt% sesquiterpene compound. Product 2

Contains about 7 wt% sesquiterpene compound.

Product 3

Contains about 21 wt% sesquiterpene compound.

Indication for using this product(s)

Tension headache and neck - upper back spasms.

Results before and after applying product(s)

Before using - pain, discomfort and swelling. Product 1 - (comparative)

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 20% better than before application.

Thirty minutes after application, 40% better. Effect lasted for 2 hours.

Product 2

Thirty minutes after application, 50% better. Effect lasted for 6 hours.

Product 3

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 50% better than before application.

Thirty minutes after application, 90% better. Effect lasted for 12 hours.

Example 17

Patient

The patient was a male, age 40 with a length of 175 cm and a weight of 82 kg.

Medical history of patient

Healthy patient with pain and discomfort in neck, shoulders and upper back.

Tension headaches that sometimes turn into migraines. Been using 25mg amitriptyline HCL nocte for tension headaches. A medical practitioner as profession. Also using HMG-CoA reductase inhibitors (statins) namely simvastatin 40 mg nocte for hypercholesterolaem. Patient had 4 months ago a laminectomy. No other allergies reported.

Product used

The products 1 ,2 and 3 were the same as those in example 16 above.

Indication for using this product(s)

Tension headache and neck - upper back spasms. Results before and after applying product(s)

Before using - pain, discomfort and swelling.

Product 1 - (comparative)

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 20% better than before application. Thirty minutes after application, 40% better. Effect lasted for 1 hour.

Product 2

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 30% better than before application. Thirty minutes after application, 50% better. Effect lasted for 4 hours. Product 3

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 50% better than before application. Thirty minutes after application, 90% better. Effect lasted for 10 hours.

Example 18

Patient

The patient was a male, age 27 with a length of 180 cm and a weight of 75 kg.

Medical history of patient

Healthy patient with pain and discomfort in lower back. The patient fell about 2 months ago and strained or hurt his back. He has been using OTC pain killers which were not effective. The patient has no other medical history of other medical conditions. No other allergies reported.

Product used

The products used were the same as those used in example 9. Indication for using this product(s)

Lower-back pain and swelling and discomfort.

Results before and after applying product(s)

Before using - pain, discomfort and swelling Product 1 - (comparative)

Thirty minutes after application, 40% better. Effect lasted 1 hour.

Product 2

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 40% better than before application.

Thirty minutes after application, 60% better. Effect lasted 5 hours.

Product 3

Applied topically to tender spots and trigger points in neck, chest and under arms. Ten minutes after application, only 60% better than before application.

Thirty minutes after application, 99% better. Effect lasted for 12 hours.

After product 3 the patient could walk normally with about no pain or discomfort. Swelling has also subsided.

Claims

1. A preparation for use in the prophylaxis or treatment of pain in the human or animal body which preparation is in the form of one or more sesquiterpene compounds or a composition containing at least 3 wt% of one or more sesquiterpene compounds.

2. The preparation of claim 1 wherein the one or more sesquiterpene compounds are selected from the group consisting of a hydrocarbon compound with fifteen carbon atoms; an alcohol compound; a ketone compound; an aldehyde compound; an ester compound; an ether compound, a lactone compound, a ketolactone compound and a carboxylic acid compound.

3. The preparation of claim 2 wherein the one or more sesquiterpene compounds are selected from the group consisting of agoraspirol, amorphine, anhydro-β-rotunol, aromadendrine, azulene, bisabolene, bisabolol, cadalene, cadinene, cadrina-1 ,4-diene, caryophyllene, cedrene, cedrol, cerapictol, ceratopicanol, clovene, copaene, cubebene, eudalene, eudesmol, farnesene, farnesol, germacrene, guaiazulene, guaiol, gurjunene, hexahydrohumulene, himachalene, hinesol, humulene, junipene, longifolene, lubiminol, khusimone, khusinol, khusimol, nootkatone, santalene, santalol, santanol, santonene, selinene, solavetivone, spatulenol, sterpurine, sulcatine, thujopsene, valerenol, vetispirene, vetivazulene, vetivene, vetiverol, vetivone, viridiflorine, viridiflorol, zingiberene as well as all derivatives and isomers thereof including acetyl, acetate, phenylacetate, hydro, dihydro, formate, methyl ether, dimethylether, caprylate, valeriate, isovaleriate, alcohol, aldehyde, ketone, epoxide, lactone and cyclases derivatives.

4. The preparation of any one of claims 1 to 3 wherein the one or more sesquiterpene compounds are provided in pure form.

5. The preparation of any one of claims 1 to 3 wherein the one or more sesquiterpene compounds are provided as an essential oil containing one or more sesquiterpene compounds.

6. The preparation of claim 5 wherein the one or more essential oils contain at least 35 wt% of one or more sesquiterpene compounds.

7. The preparation of claim 5 wherein the one or more essential oils containing one or more sesquiterpene compounds are selected from the group consisting of carrot seed oil (daucus carota sativa seed oil); cedarwood atlas oil (cedrus atlantica wood oil); cedarwood china oil

(cupressus funebris wood oil); cedarwood texas oil (juniperus ashei wood oil); cedarwood Virginia oil (juniperus virginiana wood oil); chamomile german (matricaria) oil (chamomilla recutita flower oil); ginger oil (zingiber officinale root oil); helichrysum (wild, African) oil (helichrysum splendidum flower oil); hemizygia (wild, African) oil (hemizygia petioiata flower oil); manuka oil (lepospermum scoparium leaf oil); linden tree oil (tilia cordata tree flower oil); patchouli oil (pogostemon cablin leaf oil); sandalwood west Indian oil (santalum album wood oil); sandalwood west Australian oil (santalum spicatum wood oil); and vetiver oil (vetiveria zizanoides root oil).

8. The preparation of any one of the preceding claims which is in a form selected from the group consisting of a spray, a cream, an oil, a gel, a balm, a lotion, an ointment and a patch.

9. The preparation of any one of the preceding claims which includes one or more additives.

10. The preparation of any one of the preceding claims which includes one or more rubefacients.

11. The preparation of claim 10 wherein the one or more rubefacients are selected from the group consisting of camphor, menthol, a derivative of salicylic acid, capcaicin oleoresin, capcicum oleoresin and capsicum oleoresin.

12. The preparation of claim 11 wherein the one or more rubefacients are selected from the group consisting of camphor, menthol and a derivative of salicylic acid.

13. The preparation of any one of the preceding claims which contains at least 4 wt% of the one or more sesquiterpene compounds.

14. The preparation of claim 13 which contains at least 5 wt% of the one or more sesquiterpene compounds.

15. The preparation of any one of the preceding claims wherein the pain is selected from pain of arthritis, pain of muscles, and pain of joints.

16. Use of one or more sesquiterpene compounds in the manufacture of a preparation for the prophylaxis or treatment of a pain, which preparation contains at least 3 wt% of one or more sesquiterpene compounds.

17. A method for the prophylaxis or treatment of pain wherein a preparation in the form of one or more sesquiterpene compounds or a composition containing at least 3 wt% of one or more sesquiterpene compounds is administered to a human or animal.

18. The method of claim 17 wherein the preparation is administered topically to the human or animal.