(19)
(11)EP 2 142 182 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
27.09.2017 Bulletin 2017/39

(21)Application number: 08714559.5

(22)Date of filing:  06.02.2008
(51)Int. Cl.: 
A61K 31/045  (2006.01)
A61K 31/122  (2006.01)
A61K 31/351  (2006.01)
A61P 29/00  (2006.01)
A61K 31/121  (2006.01)
A61K 31/22  (2006.01)
A61P 25/02  (2006.01)
(86)International application number:
PCT/CA2008/000236
(87)International publication number:
WO 2008/095297 (14.08.2008 Gazette  2008/33)

(54)

COMPOSITION COMPRISING TERPENE COMPOUNDS AND METHODS FOR INHIBITING NERVE TRANSMISSION

ZUSAMMENSETZUNG MIT TERPENVERBINDUNGEN UND VERFAHREN ZUR HEMMUNG VON NERVENÜBERTRAGUNG

COMPOSITION COMPRENANT DES COMPOSÉS TERPÉNIQUES ET PROCÉDÉS D'INHIBITION DE LA TRANSMISSION NERVEUSE


(84)Designated Contracting States:
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

(30)Priority: 06.02.2007 US 899642 P

(43)Date of publication of application:
13.01.2010 Bulletin 2010/02

(73)Proprietor: Neuroquest Inc.
Halifax, NS B3J 1N7 (CA)

(72)Inventors:
  • MCLELLAN, Alexander
    Halifax, Nova Scotia B3V 1K5 (CA)
  • GREENWAY, Frank
    Baton Rouge, Louisiana 70810-4320 (US)

(74)Representative: Smaggasgale, Gillian Helen et al
WP Thompson 138 Fetter Lane
London EC4A 1BT
London EC4A 1BT (GB)


(56)References cited: : 
WO-A-2008/063603
US-A- 5 260 313
US-A1- 2005 090 557
WO-A1-03/049726
US-A1- 2003 224 072
US-A1- 2006 222 690
  
  • ANONYMOUS: "Rose geranium essential oil information"[Online] XP002564431 Retrieved from the Internet: URL:http://www.essentialoils.co.za/essenti al-oils/rose-geranium.htm> [retrieved on 2010-01-20]
  • ANONYMOUS: "Bergamot essential oil information"[Online] XP002564432 Retrieved from the Internet: URL:http://www.essentialoils.co.za/essenti al-oils/bergamot.htm#Precautions> [retrieved on 2010-01-20]
  • ANONYMOUS: "Lavender essential oil information"[Online] XP002564433 Retrieved from the Internet: URL:http://www.essentialoils.co.za/essenti al-oils/lavender.htm> [retrieved on 2010-01-20]
  • GOLSHANI SAMIRA ET AL: "Antinociceptive effects of the essential oil of Dracocephalum kotschyi in the mouse writhing test." JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIÉTÉ CANADIENNE DES SCIENCES PHARMACEUTIQUES 20 APR 2004, vol. 7, no. 1, 20 April 2004 (2004-04-20), pages 76-79, XP002564434 ISSN: 1482-1826
  • GHELARDINI C. ET AL.: 'Local Anaesthetic Activity of Monoterpene and Phenylpropanes of Essential Oils' PLANTA MED. vol. 67, 2001, pages 564 - 566, XP008110034
  • JOHNSTON G.A.R.: 'GAGAA Receptor Channel Pharmacology' CURRENT PHARMACEUTICAL DESIGN vol. 11, 2005, pages 1867 - 1885, XP002412315
  • MOREIRA M.R. ET AL.: 'Effects of Terineol on the Compound Action Potential of the Rat Sciatic Nerve' BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH vol. 34, 2001, pages 1337 - 1340, XP008110062
 
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
 
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FIELD OF THE INVENTION



[0001] The present invention pertains to the field of compositions comprising one or more aromatic terpene compound. More specifically, the present invention pertains to non-naturally occurring compositions comprising an aromatic terpene compound, and methods of using such compositions for the inhibition of nerve cell transmission.

BACKGROUND



[0002] Ideal physiological functioning requires an appropriate balance between nerve cell excitation and inhibition. Therefore, the identification of compounds, and methods of utilizing these compounds, to alter this balance, is of great interest and value.

[0003] It is well known that nociceptive pain and neuropathic pain are caused by different mechanisms, and therefore respond to different treatment modalities. Nociceptive pain is mediated by receptors which are located in skin, bone, connective tissue, muscle and viscera. These receptors typically respond to noxious chemical, thermal and mechanical stimuli producing pain that is typically described as sharp, aching, throbbing, or gnawing. In contrast, neuropathic pain is produced by damage to, or pathological changes in, the peripheral or central nervous systems, typically producing pain that is described as "burning", "electric", "tingling", and "shooting" in nature. In fact, neuropathic pain is most often diagnosed based on the symptoms, so that any pain is that is characterized by burning sensations and/or shooting pain and/or numbness and/or tingling and/or allodynia is typically considered neuropathic. Other characteristics of neuropathic pain include hyperpathia (greatly exaggerated pain sensation to stimuli), hyperesthesia (an increased sensitivity to normal stimulation), dysesthesia (unpleasant abnormal sensations as if damage is being done when this is not the case), and paresthesia (an abnormal sensation, such as "pins and needles", whether spontaneous or evoked).

[0004] Nociceptive pain usually responds to opioids and non-steroidal anti-inflammatories (NSAIDS), whereas success treating neuropathic pain with these approaches has been limited. Conversely, agents employed to treat neuropathic pain, such as gabapentin, have little or no effect on nociceptive pain.

[0005] Current conventional pharmacologic strategies for treating neuropathic pain follow a number of different approaches as outlined below:

Antiarrhythmics: Certain antiarrhythmics have sodium-blocking activity. Low-dose IV lidocaine is sometimes used for temporary pain relief from peripheral nervous system injuries, including diabetic neuropathy and postherpetic neuralgia. However, IV lidocaine therapy requires constant monitoring of the patient's ECG and blood pressure to decrease the risk for seizures and arrhythmias.(1)

Antidepressants: Both tricyclic antidepressants and serotonin reuptake inhibitors have been used to treat neuropathic pain. Numerous clinical trials demonstrate the safety and efficacy of TCAs when used to treat either diabetic neuropathy or postherpetic neuralgia, yet response rates have been low at approximately 33%. Amitriptyline was the first tricyclic used to treat neuropathy, and it is still widely prescribed. Amitriptyline has a high incidence of anticholinergic side effects, including delirium in elderly patients. TCAs also have proarrhythmic effects which limit their use in populations with abnormal EKG. Serotonin specific reuptake inhibitors (SSRIs) have demonstrated less consistent effects on neuropathic pain, relieving neuropathic pain in only one of seven patients. Serotonin noradrenaline reuptake inhibitors have fared slightly better with a response rate of one in every 4-5 neuropathic pain sufferers. (2)

Anticonvulsants: Carbamazepine, phenytoin, gabapentin and lamotrigine have all been used to treat neuropathic pain. Inhibition of sodium channel blocking activity by agents such as carbamazepine, phenytoin, and lamotrigine is the proposed mechanism. Studies have shown the anticonvulsant gabapentin to be effective in painful diabetic neuropathy, mixed neuropathies, and postherpetic neuralgia. The most common adverse effects of anticonvulsants in general are sedation and cerebellar symptoms (nystagmus, tremor and incoordination). The most common side effects associated with gabapentin are asthenia, headache, dizziness and somnolence, and in some cases polyneuropathy. Lamotrigine was no better than placebo when used to treat neuropathic pain other than trigeminal neuralgia. (3)

NSAIDS: NSAIDS are not generally recommended first-line agents for treating neuropathic pain. Relief of neuropathic pain with nonsteroidal anti-inflammatory drugs (NSAIDs) is variable. (4)

Opioids: Treatment of neuropathic pain has with opioids has been controversial. Opioids were thought to be ineffective for treating neuropathic pain, but may be somewhat effective for patients who have failed other modalities. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain, while intermediate-term studies demonstrate significant efficacy of opioids over placebo. Reported adverse events of opioids are common and long-term efficacy, safety (including addiction potential), and effects on quality of life need to be further evaluated. Overall, neuropathic pain may be less responsive to opioids than other types of pain. (5)

Other Agents: Baclofen, which blocks both presynaptic and postsynaptic GABA B receptors, is used as a first-line agent to treat trigeminal neuralgia. The most common side effect is drowsiness, and there is concern about possible addictive effects. (6)

Ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, has garnered increased interest for treating neuropathic pain. Ketamine has been shown to relieve the symptoms of postherpetic neuralgia. However, ketamine causes sedation, slowed reaction times and hallucinations with long-term use. For this reason, it not currently recommended for use in chronic non-malignant pain. (7)

Dextromethorphan is also an NMDA antagonist. It has been used with some success to decrease pain in patients with diabetic neuropathy, but has not benefited those with postherpetic neuralgia, post stroke pain, or peripheral neuropathies other than diabetic. (8).

Topical Agents: Topical agents offer the advantage of local relief without systemic toxicity. Transdermal clonidine has been used with mixed results to treat diabetic neuropathy. Capsaicin cream, which contains an extract of chili peppers, is sometimes used to treat neuropathic pain. It may act on unmyelinated primary afferent nerves by depleting substance P. Depletion requires repeated and consistent use of capsaicin, and patient compliance can be an issue due to the common side effect of an intense burning sensation that decreases with consistent use. Overall, relief with capsaicin cream in clinical trials of neuropathic pain has been inconsistent.(4) Ketamine is a parenteral anesthetic agent that provides analgesic activity at sub-anesthetic doses. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with opioid receptor activity. Controlled studies and case reports on transdermal ketamine demonstrate efficacy in neuropathic pain. (9) Geranium oil, a steam distillate of the geranium plant (Pelargonium spp) that is used in flavors and fragrances, is generally regarded as safe by the U.S. Food and Drug Administration. Topical application of geranium oil has been shown to relieve the pain of post-herpetic neuralgia in 2/3 subjects, with 1/4 of subjects having a dramatic clinical response (10).



[0006] Overall, the efficacy of these pharmacological treatments is often limited by side effects at the doses required for analgesia, as well as in some cases long delays before the onset of analgesia, a substantial rate of non responsiveness to therapy, and a potential for addiction. In conclusion, neuropathic pain does not have an ideal or even a very good treatment at the present time. A new and novel non-toxic topical or oral preparation to treat neuropathic pain is therefore of great interest and has the potential to benefit a wide range of chronic pain sufferers.

[0007] Natural substances provide a rich diversity of chemical structures, many of which have shown efficacy as therapeutic agents. In terms of inhibition of nerve function, a variety of classes of naturally derived compounds has shown the ability to inhibit neuronal firing by various methods, including affects on nerve cell receptors and associated ion channels. For example, flavanoids, terpenes, terpenoids, ginsenosides, and a variety of other dietary and environmental compounds have been shown to influence nerve transmission rates (17).

[0008] Borneol, for instance, is a bicyclic monoterpene present in the essential oils of a number of medicinal plants, and has been shown to have a "highly efficacious" modulating action on nerve cell receptors (18). Interestingly, traditional herbs containing borneol, such as valerian officinalis, matricaria chamomilla, and lavandula officinalis, have been used as sedatives to relieve anxiety, restlessness, insomnia and as analgesics. No other terpene has been previously found to have effect on nerve cell transmission.

[0009] In fact, many plant derived essential oils have been reported to have beneficial analgesic and anti-inflammatory properties for the treatment of nociceptive pain. For example, a number of species of ginger (Zingiber spp.) have been shown to possess antinociceptive properties. Oil of ginger is a complex mixture of constituents, consisting of monoterpenes (phellandrene, camphene, cineole, citral, and borneol), sesquiterpenes (zingiberene, zingiberol, zingiberenol, β-bisabolene, sesquiphellandrene, and others), aldehydes and alcohols (11). Menthol is a common and naturally occurring compound of botanical origin found in plants of the Mentha genus which has also been shown to possess analgesic properties with regard to nociceptive pain (12). There has been, however, very little research into plant extracts for the treatment of neuropathic pain. One controlled trial of a Cannabis based extract given as an oromucosal spray (Sativex®), however, did show benefit in centrally mediated neuropathic pain in 64 multiple sclerosis patients (13).

[0010] Geranium oil has been used extensively in perfumery, as an insect repellent, and for other related purposes. For example, U.S. Pat. No. 4,940,583, Thompson, describes the use of geranium oil as a component in an animal repellent composition. U.S. Pat. No. 4,923,685, Forg et al., describes the use of geranium oil as part of a mouth wash composition. U.S. Pat. No. 4,579,677, Hooper et al., describes the use of geranium oil as a scenting agent in a bleaching composition. U.S. Pat. No. 4,311,617, Ansari et al., describes the use of geranium oil in perfumery compositions. United States Patent 5,260,313, Frome, entitled "Diagnosis and treatment of various neuralgias," relates to a method of diagnosing and treating neuropathic pain syndromes with a composition of which Pelargonium graveolens Ait. oil is the principle therapeutic agent. This essential oil distillate is alternatively called geranium oil bourbon, oil geranium reunion, and oil rose-geranium.

[0011] The use of an essential oil distillate geranium oil, however, as taught by Frome, employs a complex mixture of naturally derived compounds, some of which may be effective for neuropathic pain relief and some which may be ineffective or which may be irritating or toxic. For example, a number of constituents found in natural geranium oil are known irritants and thereby may cause skin rash when applied topically or even exacerbate pain. For instance a-pinene, a constituent of natural geranium oil, is considered irritating to the skin and exposure can cause rash, burning pain, headache, vomiting and even kidney damage (15). B-phellandrene has known hypersensitizing effects which can cause contact dermatitis (16). P-cymene, another component of natural geranium oil, is also considered a "primary skin irritant", which can cause erythema upon contact and headache, nausea and vomiting if exposure is oral or inhaled (17).

[0012] There remains a need for alternative therapies for inhibition of nerve cell transmission that do not suffer the drawbacks associated with existing pharmaceuticals, including essential oil distillates.

[0013] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.

SUMMERY OF THE INVENTION



[0014] An object of the present invention is to provide a composition and method for the inhibition of nerve transmission. The present invention relates to a composition and method for the inhibition of nerve cell transmission. The composition and method of the present invention have wide ranging applications, such as, but not limited to, the development of therapeutic agents with analgesic, sedative, anxiolytic, anti-convulsant, hypnotic, muscle relaxant, anti-hypertensive, anti-depressant, and anti-psychotic properties.

[0015] In accordance with one aspect of the present invention, there is provided a composition for treating a disorder characterized by an imbalance between nerve excitation and inhibition said composition consisting of an isolated and/or purified terpene compound or a combination of isolated and/or purified terpene compounds and, optionally, one or more pharmaceutically acceptable diluent or excipient, wherein said terpene compound is selected from the group consisting of nerol, geraniol, neral, geranial, geranyl formate, geranyl butyrate, geranyl tiglate, citronellyl formate, citronellyl butyrate, citronellyl tiglate, menthone, rose oxide, and pharmaceutically acceptable isomers, salts, esters and solvates thereof.

[0016] In accordance with a second aspect of the present invention, there is provided a composition for treating neuropathic pain comprising an isolated and/or purified terpene or terpenoid compound, or a combination of isolated and/or purified terpene or terpenoid compounds and, optionally, one or more pharmaceutically acceptable diluents or excipients, wherein said terpenoid is a terpenoid aldehyde, a terpenoid acid, a terpenoid ester, a terpenoid oxide.

[0017] In accordance with another aspect of the present invention, there is provided a composition for the inhibition of nerve transmission comprising one or more compounds of Formula I or Formula II, or a pharmaceutically acceptable isomer, salt, ester or hydrate thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C20 unbranched alkyl group, C1-C20 branched alkyl group, C1-C20 unbranched alkoxy group, C1-C20 branched alkoxy group, C1-C20 unbranched acyloxy group and C1-C20 branched acyloxy group, C1-C20 unbranched allyl group and C1-C20 branched allyl group, or

one or more of R3 and R4, R5 and R6, R7 and R8, or R10 and R11, together form =O,

wherein the alkyl, alkoxy, acyloxy and allyl groups are optionally substituted with an aryl, amine, amide, halide, phosphate or thiols,

and, optionally, one or more pharmaceutically acceptable diluent or excipient.



[0018] A disorder charcterized by an imbalance between nerve excitation and inhibition may be treated by administering a therapeutically effective amount of a composition as described herein to a mammalian subject, wherein said therapeutically effective amount is an amount that inhibits nerve cell transmission. The mammalian subject is preferably a human. Preferably, the disorder which is treated is neuropathic pain, caused by, for example, diabetic peripheral neuropathy, herpes zoster, post herpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, phantom limb syndrome, chronic disease (multiple sclerosis, HIV, etc), trauma (causalgia), impingement (e.g., sciatica, carpal tunnel, etc), drug exposure, toxic chemical exposure, current infection, past infection, impaired organ function, vascular disease, metabolic disease, cancer, cancer treatment, autoimmune disease, fibromylagia, or it is idiopathic.

[0019] Neuropathic pain may be treated by administering one or more terpene molecules, such as geraniol, citronellol and related compounds. In particular, the present invention provides compositions for, in general inhibiting nerve transmission, and in particular, treating a range of neuropathies, which can be administered, usually via topical or oral administration, to a mammal comprising one or more terpene moledules, such as geraniol, citronellol, or related compounds, alone or in combination.

[0020] Thus, according to a further aspect of the present invention, there is provided an isolated and/or purified terpene compound or a combination of isolated and/or purified terpene compounds for use in treating a disorder characterised by an imbalance between nerve excitation and inhibition, wherein said terpene compound is selected from the group consisting of nerol, geraniol, neral, geranial, geranyl formate, geranyl butyrate, geranyl tiglate, citronellyl formate, citronellyl butyrate, citronellyl tiglate, menthone, rose oxide, and pharmaceutically acceptable isomers, salts, esters and solvates thereof.

[0021] According to a still further aspect of the present invention, there is provided an isolated and/or purified terpene or terpenoid compound or a combination of isolated and/or purified terpene or terpenoid compounds for use in treating neuropathic pain wherein said terpene compound is geraniol, citronellyl, geranicil, citronellal, linalool, menthane, rose oxide, alpha-terpinerol, or a pharmaceutically acceptable salt, ester or solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES



[0022] 

Figure 1 depicts current-voltage plots obtained from patch clamp elecrophysiological studies of mouse hippocampal slices using sample #4 (Geraniol) and a Control, which demonstrate a reduction of membrane currents (geraniol vs. control).

Figure 2 depicts typical current voltage relationship in a cortical neuron (A=Control: B=Geraniol: C=After Washout) and the typical respons of a cortical neuron following depolarizing current pulse (D=Control condition: E=in the presence of geraniol: F=After recovery).

Figure 3 graphically demonstrates the net current reduction in the presence of various treatments during patch clamp testing.


DETAILED DESCRIPTION OF THE INVENTION



[0023] The present invention overcomes the many of the limitations and drawbacks associated with the prior use of essential oil distillates.. By employing isolated and/or purified compounds, and compositions thereof, which are responsible for the inhibition of nerve transmission, the desired effect can be better controlled and enhanced than when the same compounds are present in an unpurified form in a natural oil distillate. Therapeutic agents can therefore be better designed and the quality of these agents controlled by standardizing to the known active ingredients. Compounds that are ineffective, irritating or toxic can be excluded from such synthetic compositions. Furthermore, the use of synthetically derived versions of these compounds are more economical to acquire and supply is not affected by climatic conditions or severe weather that often affects medicinal plant production.

[0024] The present invention provides a previously unavailable and novel means of restoring balance between nerve excitation and inhibition by the administration of a composition comprising a compound or mixture of compounds that inhibit nerve transmission. The composition of the present invention comprises at least one terpene compound, or a pharmaceutically acceptable salt, ester or solvate thereof, and, optionally, a pharmaceutically acceptable diluent or carrier.

[0025] As used herein, the term "terpene compound" is intended to refer to a terpene, a terpenoid, or a pharmaceutically acceptable is salt, ester or solvate thereof. A "terpenoid" is a chemically modified terpene. Examples of terpenoids include, but are not limited to, terpenoid aldehydes, terpenoid acids, terpenoid esters and terpenoid oxides.

[0026] In accordance with a specific embodiment of the present invention, the terpene compound in the composition is geraniol, citronellol, geranial, citronellal, linalool, menthone, rose oxide, alpha-terpineol, a pharmaceutically acceptable is salt, ester or solvate thereof, or any mixture thereof.

[0027] Preferably the terpene compound has the structure of Formula I or II,

where,

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C20 unbranched alkyl group, C1-C20 branched alkyl group, C1-C20 unbranched alkoxy group, C1-C20 branched alkoxy group, C1-C20 unbranched acyloxy group and C1-C20 branched acyloxy group, C3-C20 unbranched allyl group and C3-C20 branched allyl group, or

one or more of R3 and R4, R5 and R6, R7, and R8, and R10 and R11, is =O.

wherein the alkyl, alkoxy, acyloxy and allyl groups are optionally substituted with one or more aryl groups, amine groups, amide groups, halides, phosphate groups or thiols.



[0028] In accordance with another embodiment of the composition comprises a compound of Formula I or II, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C10 unbranched alkyl group, C1-C10 branched alkyl group, C1-C10 unbranched alkoxy group, C1-C10 branched alkoxy group, C1-C10 unbranched acyloxy group and C1-C10 branched acyloxy group, C3-C10 unbranched allyl group and C3-C10 branched allyl group, or one or more of R3 and R4, R5 and R6, R7, and R8, and R10 and R11, is =O.

[0029] In accordance with another embodiment of the composition comprises a compound of Formula I or II, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C5 unbranched alkyl group, C1-C5 branched alkyl group, C1-C5 unbranched alkoxy group, C1-C5 branched alkoxy group, C1-C5 unbranched acyloxy group and C1-C5 branched acyloxy group, C3-C5 unbranched allyl group and C3-C5 branched allyl group, or one or more of R3 and R4, R5 and R6, R7, and R8, and R10 and R11, is =O.

[0030] In accordance with another embodiment of the composition comprises a compound of Formula I, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R12 are H and R10 and/or R11 is selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C20 unbranched alkyl group, C1-C20 branched alkyl group, C1-C20 unbranched alkoxy group, C1-C20 branched alkoxy group, C1-C20 unbranched acyloxy group and C1-C20 branched acyloxy group, C1-C20 unbranched allyl group and C1-C20 branched allyl group or R10 and R11 are together =O.

[0031] In accordance with a related embodiment, the composition comprises one or more compound of Formula I, which is:

geranial (3,7-dimethyl -2,6-octadienal),

neral (cis 3,7-dimethyl -2,6-octadienal),

geraniol (2,6-Octadien-1-ol, 3,7-dimethyl-, (2E)-),

nerol (cis-3,7-dimethyl-2,6,-octadien-1-ol),

geranyl formate (2,6-Octadien-1-ol, 3,7-dimethyl-, formate, (2E)-),

geranyl butyrate (Butanoic acid, (2E)-3,7-dimethyl-2,6-octadienyl ester),

geranyl tiglate (2-Butenoic acid, 2-methyl-, (2E)-3,7-dimethyl-2,6-octadienyl ester,(2E)-) or a pharmaceutically acceptable isomer, salt, ester or solvate thereof.



[0032] In accordance with one embodiment of the composition comprises a compound of Formula 2, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R12, R13 and R14, are H and R10 and/or R11 is selected from H, OH, COOH, COOCH3, CH2OH, OCOH, C1-C20 unbranched alkyl group, C1-C20 branched alkyl group, C1-C20 unbranched alkoxy group, C1-C20 branched alkoxy group, C1-C20 unbranched acyloxy group and C1-C20 branched acyloxy group, C1-C20 unbranched allyl group and C1-C20 branched allyl group or R10 and R11 are together =O.

[0033] In accordance with a related embodiment, the composition comprises one or more compound of Formula II, which is
citronellal (3,7-dimethy-6-octen-1-al),
citronellol (3,7-dimethyloct-6-en-1-ol),
citronellyl formate (6-Octen-1-ol, 3,7-dimethyl-, formate),
citronellyl butyrate (butanoic acid, 3,7-dimethyl-6-octenyl ester),
citronellyl tiglate (2-Butenoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester, (2E)-), or a pharmaceutically acceptable isomer, salts, ester or solvate thereof.

[0034] Specific examples of terpene compounds that can be incorporated in the compositions of the present invention, alone or in combination, are geraniol (2,6-Octadien-1-ol, 3,7-dimethyl-, (2E)-), citronellol (6-Octen-1-ol, 3,7-dimethyl-, (2E)-), and their derivatives. These compounds have now been shown to effectively inhibit nerve transmission in both animal cortical nerve cells and dorsal root ganglion cells.

[0035] The terpene compounds of Formula I and Formula II have been found to be useful in treating the often unbearable and untreatable pain known as neuropathic pain, which is believed to be caused by aberrant nerve transmission due to damage to nerve tissue. The present invention describes a method of treating neuropathic pain using any of a class of aromatic terpene compounds, some of which can be found naturally occurring in Pelargonium graveolens Ait. essential oil or other plant sources, or which can be prepared synthetically. In particular, this invention discloses the class and structures of those terpene compounds which can be used to treat neuropathic pain. This invention thereby provides previously unavailable information regarding the active constituents found in Pelargonium graveolens Ait. oil, other possible related plant species, as well as can be found in synthetic commercial essential oil blends, and those related compounds which can be synthesized chemically by one skilled in the art. The identification of these purified compounds represents an inventive step over United States Patent 5,260,313 and other related references, and is not readily obvious to one skilled in the art.

[0036] It is well known that essential oils are complex mixtures of aromatic compounds comprising a broad range of molecular structures including both carbon rings or chains with or without double bonding and with a range of functional side groups. A typical plant essential oil chromatogram may contain in the order of 200 or more distinct peaks. Plant essential oils are a complex mixture of terpenes, sesquiterpenes, esters, alcohols, phenols, aldehydes, ketones, organic acids, and various miscellaneous molecular structures. Furthermore, each class of compound above contains many subclasses. For example, the terpene classification includes hemiterpenes, monoterpenes, diterpenes, sesquiterpenes, triterpenes, tetraterpenes, and associated terpenoids formed by the modification or oxidation of the carbon skeleton. Moreover, any of these compounds may have a wide range of physiological activity in a mammal, and in some cases may show adverse effects or toxicity if applied topically or administered orally. Due to this wide diversity, some of the compounds may even inhibit the effect of nerve transmission inhibition, or may cause an excitation of nerve transmission. Due to the wide range of compounds present, and the extreme complexity of receptor channel pharmacology, it is not obvious to one skilled in the art which compounds have desirable or undesirable effects on nerve transmission.

[0037] Therefore, in terms of pain relief, for example, it would not have been obvious to one skilled in the art, having regard to the previous use of essential oil distillates, which compounds within previous essential oil distillates inhibit pain, have no effect on pain, or even exacerbate pain. To determine which compounds are efficacious requires extensive research both on live mammalian subjects and live cell cultures of neuronal tissue.

[0038] Furthermore, since the mechanism of neuropathic pain development and the mechanism of relief of neuropathic pain are not well understood, it is not obvious to one skilled in the art as to which compounds would have the most effect on the relief of neuropathic pain, which compounds may inhibit the relief of neuropathic pain, or which compounds may have potential toxicity. It is therefore possible, but not obvious, that identification, purification, and testing of specific compounds found in essential oils may elucidate those compounds responsible for the relief of neuropathic pain. Also, in many well documented instances, the elucidation of active drug compounds from medicinal plants is not possible. One common reason for these failed attempts is that the physiological affect of the heterogeneous mixture of compounds found in the naturally derived plant extract or whole plant achieves its effects due to a synergy of compounds. Successive attempts to fractionate heterogeneous mixtures and elucidate one or more distinct active ingredients therefore fail because the synergistic effects of the complex mixture are lost. This phenomenon also supports the non-obviousness of the present invention.

[0039] In developing the compositions and methods of the present invention, extensive research was carried out using both in vitro and in vivo methods, with the goal of determining the active constituents found in geranium oil and/or other natural and synthetic aromatic oil sources which have a beneficial effect on nerve transmission. Geranium oil is composed of an abundance of chemical entities, many of which are known, but some of which are not yet elucidated (Table 1) In an effort to determine the active ingredient, or ingredients, in geranium oil, a synthetic blend was provided, which contains known amounts of compounds present in naturally-derived geranium oil (Table 1), and tested in a patch clamp assay (see Example 1). This synthetic geranium oil was then compared to the naturally-derived geranium oil. The synthetic geranium oil gave a 50% inhibition of current compared to a 40% inhibition for naturally-derived geranium oil. Thus, a synthetic blend of geranium oil had a greater activity than the naturally derived geranium oil, indicating that synthetically derived terpenes are superior.

[0040] Individual purified compounds contained within geranium oil were then tested both in vivo and in vitro. Specifically, whole cell patch clamp testing revealed that specific compounds found in geranium inhibited delayed rectifying potassium channels at a concentration of 10 ppm. Results were positive for the compounds carvone, linalool, terpineol, rose oxide, menthone, geraniol, and citronellol, with purified geraniol and purified citronellol giving the highest amount of inhibition.

[0041] A synthetic blend of geranium oil (Table 1) was also tested in a panel of human neuropathic pain sufferers known to respond to naturally derived geranium oil. The geranium oil was topically applied in therapeutically effective amounts to areas of the human body affected with symptoms of neuropathic pain. Dosage amounts depended on the size of the patient's affected areas. Typically, 1-10 drops were used, 1 drop for smaller affected areas and 10 drops with larger affected areas or areas exhibiting more severe pain symptoms. Once administered, a typical positive response is a significant reduction in pain, often in minutes. A significant number of patients in the panel of neuropathic pain sufferers preferred the pain relieving effects of the synthetic blend of geranium, with known purified constituents, over the natural geranium. This indicates that the synthetic geranium oil blends of the present invention offer improved efficacy over natural geranium oil.

[0042] To further investigate the effectiveness of the synthetic geranium oil blend, a human double blind placebo controlled clinical trial was carried out with 64 subjects suffering from all-cause neuropathic pain. Two active medications and one placebo were studied over a six week period. Each active medication contained approximately 28% by volume of geranium essential oil. One of these active medications contained the naturally derived essential oil of pelargonium spp., and the other contained an equal proportion of the synthetic geranium oil blend detailed in Table 1. As set out in Example 3 (and shown in Table 2), the active medication containing the synthetic oil blend resulted in statistically significant pain reduction in 95% of patients vs. 85% of patients using the naturally derived essential oil. In addition, this trial demonstrated pain reduction of significantly longer duration (7.5 hrs vs. 6.5 hrs) following treatment application of the synthetic blend vs. the naturally derived active medication.
Figure 1. Components of synthetic oil compared to Geranium oil bourbon
(Analyzed by gas chromatography on DB-5 column.)
Component% in Synthetic Blend% in Geranium Oil Bourbon
cis hex-3-en-1-ol 0.31  
linalool 6.41 10.23
phenylethyl alcohol 0.88  
rose oxide, tr 1.69 0.52
menthone 0.63 0.76
isomenthone 4.38 7.53
borneol 0.93  
a-terpineol 0.96 1.01
nerol 1.55 0.63
citronellol 27.17 19.89
neral 0.25 0.42
geraniol 23.11 18.00
linalyl acetate 0.63  
geranial 0.54 0.65
citronellyl formate 6.63 8.30
neryl formate 0.42  
geranyl formate 5.50 6.77
furanoperlargone A 0.35  
geranyl tiglate 15.00 1.25
a-thujene   0.11
a-pinene   0.94
sabinene   0.09
b-pinene   0.66
myrcene   0.34
a-phellandrene   0.11
a-terpinene   1.00
p-cymene   1.32
limonene   4.47
b-phellandrene   12.43
benzyl alcohol   0.07
cis-b-ocimene   0.19
trans-b-ocimene   0.13
g-terpinene   0.49
terpinolene   2.54
camphor   0.56
terpin-1-en-4-ol   6.48
lavandulyl acetate   0.14
geranyl acetate   0.35
b-caryophyliene   0.95
a-guaiene   0.22
aromadendrene   1.46
6,9-guaiadiene   0.33
geranyl propionate   0.29
germacrene D   0.17
bicyclogermacrene   0.07
b-bisabolene   0.06
g-cadinene   0.08
geranyl isobutyrate   0.32
d-cadinene   0.33
geranyl butyrate   0.14
furanopelargone A   2.67
phtalate ester   1.31
unidentified   0.88
unidentified   1.17
unidentified   0.89
unidentified   0.96
% Total 97.34 92.84


[0043] Further testing was carried out on human neuropathic pain sufferers using geraniol (2,6-Octadien-1-ol, 3,7-dimethyl-, (2E)-). Results indicated that pure, synthetically produced geraniol, provided almost immediate pain relief. As demonstrated by this activity of geraniol, this class of compounds has beneficial activity for the relief of neuropathic pain. Individual chemical entities in this class include, but are not limited to geraniol (2,6-Octadien-1-ol, 3,7-dimethyl-, (2E)-), geranial (3,7-dimethyl -2,6-octadienal), geranyl formate (2,6-Octadien-1-ol, 3,7-dimethyl-, formate, (2E)-), geranyl tiglate (2-Butenoic acid, 2-methyl-, (2E)-3,7-dimethyl-2,6-octadienyl ester, (2E)-), geranyl butyrate (Butanoic acid, (2E)-3,7-dimethyl-2,6-octadienyl ester), citronellol (3,7-dimethyloct-6-en-1-ol), citronellyl formate (6-Octen-1-ol, 3,7-dimethyl-, formate), citronellal (3,7-dimethy-6-octen-1-al), citronellyl butyrate (butanoic acid, 3,7-dimethyl-6-octenyl ester), and citronellyl tiglate (2-Butenoic acid, 2-methyl-, 3,7-dimethyl-6-octenyl ester, (2E)-).

[0044] Studies were also conducted on dissociated rat Dorsal Root Ganglion (DRG) neurons and mouse hippocampal brain slice preparations (Example 5). Mean current-voltage plots for 6 cortical neurons are shown in Figure 1. Note the reduction of membrane currents in presence of pure geraniol, representing an inhibition of nerve transmission.

[0045] The results of in vitro studies and human clinical trials described above and detailed in the Examples, demonstrate that the synthetic compositions comprising geraniol and citronellol, and related terpenes of Formula I or II, have a significant effect on the inhibition of nerve transmission. For example, the synthetic compositions of the invention have been found to be useful in treating neuropathic pain. Preferably the composition contains geraniol and/or citronellol. The synthetic compositions comprising individual terpene compounds are more effective that the whole essential oil distillate. This is apparent from the in vitro and in vivo research Examples. Thus, a novel composition of purified terpenes of Formula I or II, for example, geraniol and citronellol and/or their derivatives, used alone or in combination, is effective as an inhibitor of nerve transmission and, in one preferred embodiment of the invention, is effective in the treatment of neuropathic pain.

[0046] A wide variety of physiologically undesirable states and frank medical pathologies have been generally accepted to be the result of imbalances between nerve excitation and inhibition in mammalian subjects. For instance, disorders of mood and sleep, such as insomnia, anxiety, restlessness, depression, cognitive disorders, schizophrenia, addictions, post traumatic stress disorder (PTSD) and disturbances of learning and memory have been associated with excess excitation of neuronal firing. This excess firing has also been associated with a wide variety of neurological conditions, some examples being restless leg syndrome, seizures, epilepsy, tremors, Huntington's disease, attention deficit disorder, autism and Tourettes's syndrome.

[0047] An imbalance between excitation and inhibition of the nerves is also known to be involved in various musculoskeletal disorders such as muscle spasm, inflammation and pain.

[0048] Thus, the compositions of the present invention, which show inhibition of nerve cell transmission, have wide ranging applications. These applications include, but are not limited to, use as analgesics, anesthetics, anti-convulsants, anxiolytics, sedatives, hypnotics, muscle relaxants, anti-hypertensives, anti-depressants, anti-psychotics, etc.

[0049] One aspect of the present invention provides methods of treating neuropathic pain in mammalian subjects by administering a therapeutically effective amount of a composition comprising a terpene compound of Formula I or II, for example, geraniol and/or citronellol. Neuropathic pain is pain caused by various types of nerve damage. Some examples of neuropathic pain conditions that can be treated by the method of the present invention include, but are not limited to, diabetic peripheral neuropathy, herpes zoster, post herpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine headache, phantom limb syndrome, neuropathic pain due to chronic disease (multiple sclerosis, HIV, etc), neuropathic pain due to trauma (causalgia), neuropathic pain due to impingement (i.e. sciatica, carpal tunnel, etc.), neuropathic pain due to drug exposure or toxic chemical exposure, neuropathic pain due to infection or post infection, neuropathic pain due to impaired organ function, neuropathic pain due to vascular disease, neuropathic pain due to metabolic disease, neuropathic pain due to cancer or cancer treatment, neuropathic pain due to autoimmune disease, neuropathic pain due to fibromylagia, and neuropathic pain with no know cause (idiopathic).

[0050] The pharmaceutical compositions of the present invention can be prepared using standard, well known techniques. The pharmaceutical compositions of the present invention do not necessarily require inclusion of any pharmaceutically acceptable diluent or excipient. However, such diluents or excipients can be incorporated into the composition as required depending on the desired characteristics of the composition. A used herein, the term "composition" can refer to a pharmaceutical preparation containing a terpene compound alone.

[0051] The compositions of the present invention are prepared using isolated or purified terpene compounds, for example, one or more compounds of Formula I or II, or corresponding pharmaceutically acceptable salts, esters or solvates thereof as active components. The term "solvate" is intended to include "hydrate". The compositions of the present invention are not natural oils derived as distillates of plant material, however, the terpene compounds used to prepare the synthetic compositions of the present invention can include one or more compounds that have been isolated from plant material.

[0052] The compositions of the present invention can be prepared and administered in a wide variety of dosage forms. The composition of the invention can be in the form of a suspension, pill, gel, oil, cream, patch, spray or aerosol. The composition can be formulated to be suitable for oral administration, topical administration, intranasal delivery, transdermal administration. It will be obvious to those skilled in the art that the following dosage forms can comprise as the active component, a compound of Formula I or II, a corresponding pharmaceutically acceptable salt, ester or solvate thereof, or any combination thereof.

[0053] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0054] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

[0055] In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0056] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0057] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0058] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.

[0059] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0060] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0061] A particularly preferred mode of administration of the composition of the present invention is to a skin surface via a topical route. Such a composition is topically applied in the form of a lotion, solution, cream, ointment or powder. For example, the composition can be formulated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin or can be incorporated at a concentration between 1 and 10% into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required. The topical compositions can contain additional ingredients such as binders, excipients, antioxidants, and dyes.

[0062] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted creams, lotions, ointments, tablets, capsules, or powders in tubes, vials or ampoules. Also, the unit dosage form can be a capsules, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0063] The quantity of active component in a unit dose preparation may be varied or adjusted according to the particular application and the potency of the active component. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.

[0064] To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in any way.

EXAMPLES


EXAMPLE 1: Patch Clamp Electrophysiological recordings (K+ Channels



[0065] Potassium channels have been associated with a number of important cellular functions including the regulation of heart rate, muscle contraction, neurotransmitter release, and neuronal excitability (14). As such, K+ channels have been recognized as potential drug targets and have been utilized as screening agents for potential therapeutic molecules, including potential therapeutic drugs for pain. The role of K+ channels in controlling cell membrane potential and neuronal cellular excitability makes them of interest in modulating neruronal hyperexcitability states, including neuropathic pain.

[0066] Whole cell patch clamp recordings (Axopatch 200B) were made using borosilicate patch pipettes of resistance 3-8 MΩ with an intracellular solution utilizing potassium chloride as the current carrier. Current clamp recording were conducted holding the membrane potential at -60 mV to characterize the firing property of the cells. Voltage clamp was performed to investigate the delayed rectifier current (Ikv), specifically Ikv 1.5 subtype. Statistical significance was assessed using ANOVA followed by Duncan's multiple-range test with P <, 0.05 taken as indicating significance. Geranium oil was found to inhibit the delayed rectifying potassium channel at 10 mcmol or 10 ppm, and the EC50 of geranium oil was 5.4 ppm. At a concentration of Geranium oil that gave 40% inhibition of the delayed rectifier potassium current, the following components of geranium oil gave these corresponding percent inhibitions: Carvone 22%, Linalool 18%, Terpineol 14%, Rose Oxide 14%, Menthone 22%, Geraniol 26%, and Citronellol 27%. A synthetic blend of geranium oil containing proportions of geraniol and citronellol similar to natural geranium oil, but with other components removed, was compared to the following ratios of geraniol:citronellol; 2:8, 3:7, 4:6 and geranium oil. The synthetic blend of geranium oil gave a 50% inhibition of the delayed rectifying potassium channel current compared to a 40% inhibition for natural geranium oil. All ratios of geraniol:citronellol tested also significantly inhibited these channels.

[0067] The finding that a synthetic blend of geranium oil was superior to geranium oil of plant origin is very significant. Geranium oil from natural sources contains approximately 50 individual gas chromatography peaks with at least 6% of chemical compounds that are difficult to identify. It would be very difficult to isolate active ingredients from this mix given the number of constituents and the number of unidentified components found in geranium from plant origin. By comparison, a synthetic blend of geranium can be used, in this case containing only 19 constituents, all of which are known chemical entities. Also of significance is the result that of all the individual compounds tested, geraniol and citronellol showed the highest activity in the patch clamp testing. Furthermore, purified geraniol and purified citronellol, at various ratios, also showed a high degree of efficacy in these tests.

EXAMPLE 2: Human screening using synthetic geranium in neuropathic pain (postherpetic neuralgia)



[0068] Since natural geranium oil relieves neuropathic pain and inhibits the delayed rectifying potassium channel, and since synthetic geranium oil, geraniol, and citronellol all inhibit the delayed rectifying potassium channel, synthetic geranium oil and geraniol were tested on patients with post-herpetic neuralgia. A synthetic blend of geranium oil was tested in patients with post-herpetic neuralgia that were positive responders to natural geranium oil. Pain relief with a synthetic blend of geranium oil (see Table 1 for constituents their relative amounts in the synthetic blend) was self reported to be as good or better than pain relief with natural geranium oil. Pure geraniol was then tested in these subjects. Results indicated that geraniol had the greatest effect on neuropathic pain relief.

EXAMPLE 3: Human Clinical Trial of 64 patients with all cause neuropathy



[0069] A total of 64 individuals with diagnosed peripheral neuropathy of at least 3 months duration and experiencing daily plantar cutaneous foot pain were recruited and screened for eligibility. Of these individuals, 18 were excluded because they did not meet the predetermined inclusion criteria for foot pain (VAS = 3-8). The remaining participants completed three weeks of pain-relieving intervention as described below. One participant did not complete the intervention due to unknown reasons. Of those participants that competed all testing procedures (n=45), five participants reported pre-test foot pain levels outside of the predetermined criteria (VAS < 3 or > 8) at least once throughout the study period. All data acquired from these participants was excluded from subsequent analyses. There was no adverse event during the study period to report.

[0070] Pain was recorded before treatment and for 8 hrs after treatment on an 11 point (0-10) numeric scale. One of three treatments (synthetic geranium oil (see Table 1), placebo, and naturally-derived geranium oil) was randomly applied to all subjects in a repeatable fashion according to predetermined application instructions. A one week wash out period was maintained between each application. Each active medication contained approximately 28% by volume of geranium essential oil in a topical cream. One of these active medications contained the naturally derived essential oil of pelargonium spp., and the other contained an equal proportion of the synthetic geranium oil blend detailed in Table 1.

[0071] Forty participants completed all pain reduction testing (men = 16, women = 24, age = 71.5 ± 1.5 years, height = 171.0 ± 1.8 cm, body mass = 80.6 ±21.0 kg, PN duration since diagnosis = 6.63 ± 0.70 years). Causes of PN were diabetes (n = 16), chemotherapy (n = 4) and unknown cause (n = 20). Inputted pain scale data were downloaded to a computer and analyzed at a later time. Two-factor (Time and Treatment) analyses of variance with repeated measures (ANOVA) were used for data analysis. Tukey post-hoc analysis was employed whenever necessary. Significance level was set at alpha = .05. The immediate pain reduction effects were evaluated by comparing pain level (VAS) 30 minutes before (i.e., Pre) and after (i.e., Post) the treatment applications. There was no statistical difference in pain levels before the treatment applications. Each treatment had different pain relieving effects. (see Table 1) As shown in Table 3, the active medication containing the synthetic oil blend resulted in statistically significant pain reduction in 95% of patients vs. 85% of patients using the naturally derived essential oil. In addition, this trial demonstrated pain reduction of significantly longer duration (7.5 hrs vs. 6.5 hrs) following treatment application of the synthetic blend vs. the naturally derived active medication.
Table 2. Summary of pain relieving effects of three treatments
 Reduced PainNo Change Pain Increase
 N%Mean ΔVASN%Mean ΔVASN%Mean ΔVAS
Synthetic 38 95 -2.74 1 3 0 1 3 +3
Placebo 23 58 -2.13 13 32 0 4 10 +1.5
Natural 34 85 -2.82 6 15 0 0 0 0

EXAMPLE 4: Case Study



[0072] 77 yo caucasian male, Ht 68 inches, Weight 162 lb. BMI 24.7. History of shingles 4 years prior to study with residual pain (post herpetic neuralgia). Tried Neurontin™ for 1 week with only some help and quit 3 - 4 years prior to this study.

[0073] He had moderate pain that made it hard to concentrate on things other than the pain. He did not want to wear clothing and felt uncomfortable most of the time. He could sleep, but had to keep changing positions to do so. He described the post-herpetic neuralgia as the worst thing to have happened to him. The subject's pain decreased by 78% with pure geraniol over the course of 30 minutes after topical application as measured on a standard visual analog scale.

EXAMPLE 5: Patch Clamp Electrophysiological studies of mouse hippocampal slices



[0074] Studies were conducted on mouse hippocampal brain slice preparations. In terms of the slice preparations, 200-400 µM coronal brain slices were prepared from animals housed in a 12 hour light (ZT 0-12):12 hour dark (ZT 12-24) environment. Animals were anesthetized with isoflurane, decapitated, the brain rapidly removed and placed in ice cold, oxygenated (95% O2:5% CO2), bicarbonate-buffered artificial cerebral spinal fluid (ACSF). A 1 cm2 block of brain tissue containing the hippocampi was glued to a cutting surface and coronal slices were prepared using a Leica VT1000S microtome (Leica Microsystems). All slices were left to equilibrate for approximately one hour prior to the transfer to a recording chamber. Once transferred to the chamber, slices were continuously superfused with oxygenated ACSF at a rate of 3 ml/min @30°C and recordings are generally made for the next 6-12 hours. Patch microelectrodes (5-8MΩ) made from borosilicate glass (Garner Glass Co.) and filled with K+ based internal patch solution composed of: (in mM) 120 K-acetate, 40 HEPES, 10 EGTA, 6 MgCl2, nystatin (450µg/ml) or gramicidin B (5µg/ml) and pluronic acid F127.

[0075] The perforated patch recording technique and will be used (Korn & Horn, 1989) and viable Hippocampal neurons were visually targeted using Infrared Differential Interference Contrast (IR-DIC) microscopy using a Leica DM LFSA scope. The perforated patch configuration provides access resistances to the cell comparable to conventional whole cell recordings and such access is generally obtained 2-15 minutes after gigaohm seals are formed. Recordings were made from 3 different patch rigs equipped with either Axopatch 700B patch clamp amplifiers interfaced via a Digidata 1322A to a PC computer or on, in terms of the studies performed on dissociated DRG neurons, a Zeiss Axoscop 200 inverted microscope equipped with an Axopatch 200B/Digidata 1322A using Pclamp 9.0 and Axoscope 9 software.

[0076] Test compounds were bath-applied by superfusion to examine for changes in excitability and/or attenuation of ion channels and the effects of compounds on evoked synaptic responses. Stimulating electrodes (concentric or bipolar) were placed within the slices and in accordance with the well known fiber tract pathways of passage for the DH and the hippocampus.

[0077] Typical current-voltage (I-V) relation in a cortical neuron is shown in Figures 2A, 2B, and 2C. Superimposed responses to a series of 10 mV steps (250 ms) ranged from -110 to -20 mV are shown, (A) in control condition, (B) in presence of geraniol, and (C) after washout of the drug. Note the reduction in the membrane current amplitude and the inhibition of action potentials in presence of geraniol.

[0078] Typical response of a cortical neuron following a depolarizing current pulse of 0.4 nA is shown in Figures 2D, 2E and 2F, (D) in control condition, (E) in presence of geraniol, and (F) after recovery. Note the inhibition of action potential in presence of the tested compound.

[0079] Mean current-voltage plots for 6 cortical neurons are plotted in Figure 1. Note the reduction of membrane currents in the presence of geraniol (test compound #4).

[0080] Figure 3 shows the net current reduction in the presence of various naturally-derived geranium essential oils, and pure compounds, for each tested drug following the most negative voltage step (-110 mV). Samples 1, 2 and 6 are examples of naturally-derived geranium oils; sample 3 is the synthetic composition as set out in Table 1, sample 4 is pure geraniol, sample 5 is pure citronellol and sample 4+5 is 50:50 (by volume) combination of geraniol and citronellol. Net current represents the difference between current measured in control condition and in presence of tested compound, in response to the same voltage step. Note that of the compounds tested, sample #4 (geraniol) resulted in the greatest inhibition (current differential between control and tested compound).

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U.S. PATENT DOCUMENTS



[0082] 
4,311,617 January 1982 Ansari
4,599,677 July 1986 Lawless
4,923,685 May 1990 Wuelkhitz
4,940,583 July 1990 Thompson
5,260,313 November 1993 Frome
2003/0224072 December 2003 Frome



Claims

1. A composition for use in treating a disorder characterized by an imbalance between nerve excitation and inhibition said composition comprising at least one synthetic and/or purified terpene compound or a combination of synthetic and/or purified terpene compounds and, optionally, one or more pharmaceutically acceptable diluent or excipient, wherein said terpene compound is selected from the group consisting of geraniol and pharmaceutically acceptable salts and solvates thereof
 
2. The composition for use of claim 1, wherein said terpene compound is geraniol.
 
3. The composition for use of claim 1, wherein said composition comprises a pharmaceutically acceptable diluent or excipient.
 
4. The composition of any one of claims 1 - 3, wherein the composition is in the form of a suspension, pill, gel, oil cream, patch, spray or aerosol.
 
5. The composition for use of any one of claims 1-4, wherein the mammalian subject is a human.
 
6. The composition for use of claim 5, wherein the composition is suitable for oral administration, topical administration, intranasal delivery or transdermal administration.
 
7. The composition for use of claim 5, wherein the disorder is neuropathic pain.
 
8. The composition for use of claim 7, wherein said neuropathic pain is caused by diabetic peripheral neuropathy, herpes zoster, post herpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, phantom limb syndrome, chronic disease (multiple sclerosis, HIV, etc), trauma (causalgia), impingement (e.g., sciatica, carpal tunnel, etc), drug exposure, toxic chemical exposure, current infection, past infection, impaired organ function, vascular disease, metabolic disease, cancer, cancer treatment, autoimmune disease, fibromylagia, or it is idiopathic.
 
9. The composition for use according to claim 5, wherein the disorder is pain that is characterized by burning sensations and/or shooting pain and/or numbness and/or tingling and/or allodynia.
 
10. The composition for use of claim 7, which comprises one or more purified and/or synthetic terpenes compounds selected from selected from geraniol (2,6-Octadien-1-ol, 3,7-dimethyl-, (2E)-) or a pharmaceutically acceptable salt or solvate thereof.
 
11. The composition for use of claim 10, wherein said composition comprises geraniol.
 
12. The composition for use according to Claim 10, wherein said composition comprises a pharmaceutically acceptable diluent or excipient.
 
13. The composition for use according to any one of claims 10 to 12 wherein said therapeutically effective amount reduces neuropathic pain.
 
14. The composition for use of claim 13, wherein the mammalian subject is a human.
 
15. The composition for use of claim 13, wherein the composition is in the form of a suspension, pill, gel, oil, cream, patch, spray or aerosol.
 
16. The composition for use of claim 14, wherein the composition is suitable for oral administration, topical administration, intranasal delivery or transdermal administration.
 
17. The composition for use of claim 13, wherein said neuropathic pain is caused by diabetic peripheral neuropathy, herpes zoster, post herpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, phantom limb syndrome, chronic disease (multiple sclerosis, HIV, etc), trauma (causalgia), impingement (e.g., sciatica, carpal tunnel, etc), drug exposure, toxic chemical exposure, current infection, past infection, impaired organ function, vascular disease, metabolic disease, cancer, cancer treatment, autoimmune disease, fibromylagia, or it is idiopathic.
 


Ansprüche

1. Zusammensetzung für die Verwendung bei der Behandlung einer Störung, die durch ein Ungleichgewicht zwischen Nervenerregung und -hemmung gekennzeichnet ist, wobei die Zusammensetzung mindestens eine synthetische und/oder aufgereinigte Terpenverbindung oder eine Kombination aus synthetischen und/oder aufgereinigten Terpenverbindungen und optional ein oder mehrere pharmazeutisch verträgliche Verdünnungsmittel oder Hilfsstoffe umfasst, wobei die Terpenverbindung aus der Gruppe ausgewählt ist, die aus Geraniol und pharmazeutisch verträglichen Salzen und Solvaten davon besteht.
 
2. Zusammensetzung für die Verwendung nach Anspruch 1, wobei die Terpenverbindung Geraniol ist.
 
3. Zusammensetzung für die Verwendung nach Anspruch 1, wobei die Zusammensetzung ein pharmazeutisch verträgliches Verdünnungsmittel oder einen pharmazeutisch verträglichen Hilfsstoff umfasst.
 
4. Zusammensetzung für die Verwendung nach einem der Ansprüche 1-3, wobei die Zusammensetzung in Form einer Suspension, Tablette, eines Gels, Öls, einer Creme, eines Pflasters, Sprays oder Aerosols vorliegt.
 
5. Zusammensetzung für die Verwendung nach einem der Ansprüche 1-4, wobei das Säugersubjekt ein Mensch ist.
 
6. Zusammensetzung für die Verwendung nach Anspruch 5, wobei die Zusammensetzung für die orale Verabreichung, topische Verabreichung, intranasale Abgabe oder transdermale Verabreichung geeignet ist.
 
7. Zusammensetzung für die Verwendung nach Anspruch 5, wobei die Störung neuropathischer Schmerz ist.
 
8. Zusammensetzung für die Verwendung nach Anspruch 7, wobei der neuropathische Schmerz durch Folgendes verursacht wird: diabetische periphere Neuropathie, Herpes zoster, post-herpetische Neuralgie, Trigeminusneuralgie, komplexes regionales Schmerzsyndrom, sympathische Reflexdystrophie, Phantomschmerzsyndrom, chronische Erkrankung (Multiple Sklerose, HIV, usw.), Trauma (Kausalgie), Impingement (z. B. Ischialgie, Karpaltunnel, usw.), Drogenexposition, Exposition gegenüber toxischen Chemikalien, bestehende Infektion, frühere Infektion, gestörte Organfunktion, Gefäßerkrankung, Stoffwechselerkrankung, Krebs, Krebsbehandlung, Autoimmunerkrankung, Fibromyalgie, oder er idiopathisch ist.
 
9. Zusammensetzung für die Verwendung nach Anspruch 5, wobei die Störung Schmerz ist, der durch brennendes Gefühl und/oder stechender Schmerz und/oder Taubheit und/oder Kribbeln und/oder Allodynie gekennzeichnet ist.
 
10. Zusammensetzung für die Verwendung nach Anspruch 7, die eine oder mehrere aufgereinigte und/oder synthetische Terpenverbindungen, die ausgewählt sind aus Geraniol (2,6-Octadien-1-ol, 3,7-Dimethyl-, (2E)-), oder ein pharmazeutisch verträgliches Salz oder Solvat davon umfasst.
 
11. Zusammensetzung für die Verwendung nach Anspruch 10, wobei die Zusammensetzung Geraniol umfasst.
 
12. Zusammensetzung für die Verwendung nach Anspruch 10, wobei die Zusammensetzung ein pharmazeutisch verträgliches Verdünnungsmittel oder einen pharmazeutisch verträglichen Hilfsstoff umfasst.
 
13. Zusammensetzung für die Verwendung nach einem der Ansprüche 10 bis 12, wobei die therapeutisch wirksame Menge neuropathischen Schmerz verringert.
 
14. Zusammensetzung für die Verwendung nach Anspruch 13, wobei das Säugersubjekt ein Mensch ist.
 
15. Zusammensetzung für die Verwendung nach Anspruch 13, wobei die Zusammensetzung in Form einer Suspension, Tablette, eines Gels, Öls, einer Creme, eines Pflasters, Sprays oder Aerosols vorliegt.
 
16. Zusammensetzung für die Verwendung nach Anspruch 14, wobei die Zusammensetzung für die orale Verabreichung, topische Verabreichung, intranasale Abgabe oder transdermale Verabreichung geeignet ist.
 
17. Zusammensetzung für die Verwendung nach Anspruch 13, wobei der neuropathische Schmerz durch Folgendes verursacht wird: diabetische periphere Neuropathie, Herpes zoster, post-herpetische Neuralgie, Trigeminusneuralgie, komplexes regionales Schmerzsyndrom, sympathische Reflexdystrophie, Phantomschmerzsyndrom, chronische Erkrankung (Multiple Sklerose, HIV, usw.), Trauma (Kausalgie), Impingement (z. B. Ischialgie, Karpaltunnel, usw.), Drogenexposition, Exposition gegenüber toxischen Chemikalien, bestehende Infektion, frühere Infektion, gestörte Organfunktion, Gefäßerkrankung, Stoffwechselerkrankung, Krebs, Krebsbehandlung, Autoimmunerkrankung, Fibromyalgie, oder er idiopathisch ist.
 


Revendications

1. Composition pour une utilisation dans le traitement d'un trouble caractérisé par un déséquilibre entre l'excitation et l'inhibition nerveuse, ladite composition comprenant au moins un composé de terpène synthétique et/ou purifié ou une combinaison de composés de terpène synthétiques et/ou purifiés et, éventuellement, un ou plusieurs diluants ou excipients pharmaceutiquement acceptables, où ledit composé de terpène est choisi dans le groupe constitué par le géraniol et les sels et solvates pharmaceutiquement acceptables de celui-ci.
 
2. Composition pour une utilisation selon la revendication 1, où ledit composé de terpène est le géraniol.
 
3. Composition pour une utilisation selon la revendication 1, où ladite composition comprend un diluant ou excipient pharmaceutiquement acceptable.
 
4. Composition pour une utilisation selon l'une quelconque des revendications 1-3, où la composition se trouve sous la forme d'une suspension, d'une pilule, d'un gel, d'une huile, d'une crème, d'un patch, d'un spray ou d'un aérosol.
 
5. Composition pour une utilisation selon l'une quelconque des revendications 1-4, où le sujet mammalien est un être humain.
 
6. Composition pour une utilisation selon la revendication 5, où la composition est convenable pour une administration orale, une administration topique, une administration intranasale ou une administration transdermique.
 
7. Composition pour une utilisation selon la revendication 5, où le trouble est une douleur neuropathique.
 
8. Composition pour une utilisation selon la revendication 7, où ladite douleur neuropathique est provoquée par une neuropathie périphérique diabétique, un zona, une algie post-zona, une névralgie faciale, un syndrome douloureux régional complexe, une algodystrophie sympathique réflexe, une illusion des amputés, une maladie chronique (sclérose en plaques, VIH, etc.), un traumatisme (syndrome causalgique), un coincement (par exemple, sciatique, tunnel carpien, etc.), une exposition à des médicaments, une exposition à des substances chimiques toxiques, une infection actuelle, une infection passée, une fonction déficiente d'un organe, une maladie vasculaire, une maladie métabolique, un cancer, un traitement cancéreux, une maladie auto-immune, une fibromyalgie, ou elle est idiopathique.
 
9. Composition pour une utilisation selon la revendication 5, où le trouble est une douleur qui est caractérisée par des sensations de brûlure et/ou des douleurs fulgurantes et/ou des engourdissements et/ou des fourmillements et/ou une allodynie.
 
10. Composition pour une utilisation selon la revendication 7, comprenant un ou plusieurs composés de terpène synthétiques et/ou purifiés choisis parmi le géraniol (2,6-octadién-1-ol, 3,7-diméthyl-, (2E)-) ou un sel ou solvat pharmaceutiquement acceptable de celui-ci.
 
11. Composition pour une utilisation selon la revendication 10, où ladite composition comprend du géraniol.
 
12. Composition pour une utilisation selon la revendication 10, où ladite composition comprend un diluant ou excipient pharmaceutiquement acceptable.
 
13. Composition pour une utilisation selon l'une quelconque des revendications 10 à 12, où ladite quantité thérapeutiquement efficace réduit une douleur neuropathique.
 
14. Composition pour une utilisation selon la revendication 13, où le sujet mammalien est un être humain.
 
15. Composition pour une utilisation selon la revendication 13, où la composition se trouve sous la forme d'une suspension, d'une pilule, d'un gel, d'une huile, d'une crème, d'un patch, d'un spray ou d'un aérosol.
 
16. Composition pour une utilisation selon la revendication 14, où la composition est convenable pour une administration orale, une administration topique, une administration intranasale ou une administration transdermique.
 
17. Composition pour une utilisation selon la revendication 13, où ladite douleur neuropathique est provoquée par une neuropathie périphérique diabétique, un zona, une algie post-zona, une névralgie faciale, un syndrome douloureux régional complexe, une algodystrophie sympathique réflexe, une illusion des amputés, une maladie chronique (sclérose en plaques, VIH, etc.), un traumatisme (syndrome causalgique), un coincement (par exemple, sciatique, tunnel carpien, etc.), une exposition à des médicaments, une exposition à des substances chimiques toxiques, une infection actuelle, une infection passée, une fonction déficiente d'un organe, une maladie vasculaire, une maladie métabolique, un cancer, un traitement cancéreux, une maladie auto-immune, une fibromyalgie, ou elle est idiopathique.
 




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REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description




Non-patent literature cited in the description