WO2013062424A1

WO2013062424A1 - Method and composition for the treatment of pain and/or inflammation

Info

Publication number: WO2013062424A1
Application number: PCT/NZ2012/000195
Authority: WO
Inventors: Michael Cushman; John LYFTOGT
Original assignee: Anzamed International Limited
Priority date: 2011-10-26
Filing date: 2012-10-25
Publication date: 2013-05-02
Also published as: NZ596015A

Abstract

The invention relates to a method and composition for the treatment of pain and / or inflammation, especially neuropathic pain and neurogenic inflammation. A topical or transdermal composition containing vitamin D, one or more saccharides or sugar alcohols and / or a salt or salts is disclosed which surprisingly act synergistically to relieve pain. In some embodiments, the vitamin D may comprise vitamin D3, for example cholecalciferol.

Description

METHOD AND COMPOSITION FOR THE TREATMENT OF PAIN AND/OR INFLAMMATION

Field of Invention

The invention relates to a method and composition for the treatment of pain and/or

inflammation, especially neuropathic pain and neurogenic inflammation. A topical or transdermal composition containing vitamin D, one or more saccharides or sugar alcohols and/ or a salt or salts is disclosed which surprisingly act synergistically to relieve pain.

Background to the Invention

Chronic pain is estimated to affect 10-30% of people around the world. Few people who suffer from chronic pain obtain complete relief from pain using medicinal products that are currently available.

Pain is one of the most frequent symptoms for which patients seek medical help. Pain can be classified as acute or chronic. Acute pain is generally associated with excessive noxious stimulus resulting in a severe distressful sensation. Chronic pain is associated with physiological changes as a result of tissue or nerve injury leading to hyperalgesia, an increased amount of pain associated with a mild noxious stimulus, or allodynia, a pain induced by a non-noxious stimulus. Neuropathic pain is a neurological disease caused by the damage to the

somatosensory pathway that produces severe chronic pain. Whilst pain associated with tissue injury is self limiting, neuropathic pain is long lasting, and may develop days or month after the injury. This type of chronic pain is observed in diseases affecting the central nervous system such as stroke and multiple sclerosis or with conditions related to peripheral nerve damage such as diabetic neuropathy

Amongst the various types of chronic pain, understanding and management of neuropathic pain remains the most challenging task for researchers and clinicians. Despite the rapid development of neuroscience and the discovery of new drug molecules, effective treatment based on basic understanding of the mechanisms of neuropathic pain is still lacking (Zhuo 2007). Successful management of neuropathic pain requires an understanding of its contributing molecular mechanisms and directly targeting the receptors involved. Neuropathic pain involves changes in the function of both the peripheral and the central nervous system. It is thought to be by caused by changes in mechano-insensitive peptidergic

nociceptors called "silent"' or "sleeping" nociceptors. These nociceptors are chemo-sensitive and respond to noxious chemicals usually released in response to tissue/nerve trauma. Once sensitized they change phenotype and become "polymodal" and are called '"awake"

nociceptors. These "awake" nociceptors (C fibers) release large amounts of pro-inflammatory neuropeptides, CGRP and SP initiating neurogenic inflammation in combination with increased action potentials causing increased nociception.

Following a nerve injury increased excitability and sensitivity is observed in the cell body of the injured dorsal root ganglia neurons and neighbouring intact afferents. This enhanced stimulation involving the primary afferent neurones is defined as peripheral sensitization (Leone, Biasiotta et al. 201 1 ). Degradation of axon and myelin sheet as a result of a nerve injury signals the penetration of several types of immune cells including the macrophages, neutrophils and T cells followed by the release of proinflammatory cytokines (interleukins, tumour necrosis factor a), inflammatory mediators (bradykinin, prostaglandins) and nerve growth factors (Nickel, Seifert et al. 2012). These endogenous substances will sequentially activate the nociceptors located at the free nerve ending of unmyelinated C fibers and lightly myelinated Αδ fibers. Peripheral sensitization of these nociceptors is mediated by increased expression of transient receptor potential (TRP) family of non-specific cation channels including the TRP vanilloid 1 (TRPV1), which is expressed in C fibers and Αδ fibers (Lumpkin and Caterina 2007). Specifically bradykinin and prostaglandin E₂ activate protein kinase A and C, leading to up-regulation of the TRPV1 channels. Another mechanism leading to the peripheral sensitization is due to the accumulation of voltage gated sodium channels at the site of the damaged nerve and at the dorsal root ganglion, resulting in abnormal ectopic excitability of afferent neurons. These changes are perceived as spontaneous positive sensations such as paresthesia (a sensation of tingling, burning, pricking, or numbness of skin) and dysthesia (as an unpleasant, abnormal sense of touch).

Central sensitization, defined as the activation of second order nociceptive neurons in the dorsal horn of the spinal cord by peripheral nerve damage, is an important pathophysiological mechanism in neuropathic pain. In response to a pain stimulus, the central terminals of primary nociceptive afferents in the dorsal horn release glutamate, substance P and other transmitters and cytokines such as adenosine-5'-triphosphate (ATP), chemokine (C-C ligand 2) and gamma interferon (INF-Y). The postsynaptic response of glutamate is mediated through the N-Methyl- D-aspartic acid (NMDA) and 2-amino-3-(5-methyl-3-oxo-1 , 2- oxazol-4-yl) propionic acid (AMPA) receptors. The NMDA receptors are thought to have a critical role in synaptic plasticity of the dorsal horn such as long-term potentiation (long lasting increase in synaptic strength). Most NMDA receptors are generally inactive under normal conditions due to their unique blockage by magnesium cations. However in a nerve injury post synaptic depolarization results in the removal of magnesium and subsequent influx of calcium through the activated NMDA receptors. Calcium entry results in activation of protein kinases and phosphorylation of the NMDA. The overall effect of these changes is prolonged excitability of the spinal cord neurons (long-term potentiation).

Further contributing factors to the development of neuropathic pain include the involvement of spinal cord microglia and astrocytes in enhancing pain (Zhuo, Wu et al. 201 1 ). ATP activated microglial P2X4 and P2X7 receptors stimulate the p38 mitogen-activated protein kinases (p38- MAPK) signalling cascade leading to the release of substances such as brain-derived neurotrophic factor (BNDF), down regulating the potassium/chloride cotransporter and ultimately diminishing the inhibitory neurotransmission (GABAergic inhibition).

Following an injury, various inflammatory substances such as histamines, prostaglandins and cytokines are released from inflammatory cells which have migrated through the blood to the site of the injured tissue. When the injury results in nerve damage, the peripheral terminals of sensory neurones will be activated. This activation in turn results in neurogenic inflammation with is characterized by the release of neuropeptides such as substance P, calcitonin and calcitonin gene related peptide (CGPR) from the C fiber terminal. The overall effect of both processes is vasodilation, oedema and pain. Neurogenic inflammation plays an integral role in the pathophysiology of neuropathic pain.

Successful treatment of neuropathic pain requires direct targeting of the receptors and transmitters involved. Current therapeutic strategies, as described in a recent review by Baron et al. (Baron, Binder et al. 2010), aim to reduce the neuron excitability through altering ion channel activity (for example gabapentin and lidocaine) or inhibiting neurotransmission (for example opioids and tricyclic antidepressant). Despite consistent efficacy observed in several randomized trials and meta-analysis, the use of these agents is limited due to their debilitating side effects such as sedation, somnolence, dry mouth, urinary retention, erythema and ataxia. Furthermore patients must be closely monitored and dose tapering is required to prevent withdrawal symptoms. Research has been focusing in finding novel alternatives with optimal therapeutic alternatives and low incidence of side effects. NMDA receptors play an important role in long-term potentiation and central sensitization.

Therefore treatment with an NMDA antagonist could be highly valuable in management of neuropathic pain. Unfortunately however, most investigated antagonists are linked with memory impairment, motor incoordination and psychotomimetic effects (Zhuo, Wu et al. 201 1 ). Other investigative research has focused on GABAergic or glycinergic inhibition at the dorsal horn and blocking the voltage gated sodium and calcium channels. According to a recent review, effective glycinergic antagonists are yet to be identified (Zeilhofer, Benke et al. 2012).

Oral treatment with cholecalciferol and related analogues has been used for treatment of musculoskeletal pain and diabetic neuropathy (Lee and Chen 2008; Stewart and Leavitt 2008). The regimen is directed towards treatment of vitamin D deficiency, one of the main underlying causes of these painful conditions. However moderate alleviation of pain is a slow process with at least 3 months of high daily dose of vitamin D supplementation (2000-10,000 units) required to normalise the circulating levels of calcitriol.

In alternative treatments, various natural agents, sugars, salts and cations are used for alleviation of neuropathic pain. For example EP2454229 describes the use of amino acid derivatives for prevention of pain including neuropathic pain. Trivalent and divalent cations such as La³⁺, Ce³⁺, Ni²⁺ and Mg²⁺ have shown to produce analgesic effects in animal models (Barritt 1999). Specifically magnesium malate is used orally in the treatment of fibromyalgia, a painful neuropathic condition characterized by chronic wide spread pain and allodynia. Deficiency of magnesium, observed in patients suffering from fibromyalgia, is correlated with an increase in the level of neurotransmitter substance P and long- term potentiation. Both magnesium and malic acid plays an essential role in the production of energy through the Krebs cycle. The resting NMDA receptors are gated by magnesium, which can also antagonize these receptors. Animal studies have shown that systemic administration of magnesium prevents specific NMDA-mediated excitotoxic Injury (McDonald, Silverstein et al. 1990). An inverse relationship has also been observed between severity of pain and serum level of magnesium (Kara, Sahin et al. 2002). Zinc controls the secretion of substance P in afferent neurons with high

concentrations (10^~6-10^~4 M) showing inhibitory effects (Tang, Miyano et al. 2009). Specifically, zinc inhibits the NMDA dependent long-term potentiation (Ma and Zhao 200). Daily intake of D- ribose may be used as a metabolic supplementation to enhance nucleotide recovery and reduce pain intensity in patients suffering from fibromyalgia, although more accurate studies are required to confirm this finding (Teitelbaum, Johnson et al. 2006). S

'Neural Pelotherapy', invented by Dr. John Lyftogt, has been effective for management of many injuries and pain relating to tendon, ligaments, and muscles. The treatment involves direct targeting of the painful areas through injection of dextrose solution under the skin near peripheral nerves. The treatment can offer a success rate of more than 75% in patients treated. Dr Lyftogt has showed that a subcutaneous near-nerve injection of hypertonic dextrose 20% in combination with lignocaine 0.1 % was effective in treating a number of chronic (neuropathic) painful conditions. It was postulated that subcutaneous injections target pain generating subcutaneous nerves. Systematic analysis of the outcome of the effects of different hypertonic dextrose solutions showed no discernible difference between 10%, 20%, 30% and 40% dextrose solutions. Higher strength dextrose solutions caused more irritation and required higher concentrations of short and long acting local anaesthetics. Further, the rate of absorption from the subcutaneous deposit is usually difficult to control.

Pain management with oral therapy is associated with slow onset of action, low bioavailability due to first pass hepatic metabolism, and poor patient compliance. There is therefore the need to investigate other routes of delivery for treatment of neuropathic pain. Topical or transdermal drug delivery can overcome some of the limitations via direct targeting of the peripheral nociceptors in the damaged tissue. Desensitization of TRPV1 receptors with topical capsaicin is a well recognized therapeutic example of such an approach. Capsaicin results in an initial sensory efferent stimulation through its interaction with the TRPV1 receptors, followed by desensitization. However, burning pain at the site of application in the first few weeks of treatment is often a strong indicator for noncompliance and drop outs from clinical trials

(Szallasi, Cruz et al. 2006). WO2012012333 describes a method for treating neuropathic pain with topically applied alpha-2 adrenergic agonist clonidine in painful skin areas with functioning nociceptors. In GB244101 1 a cardiac glycoside and/or a diuretic are formulated in a topical emulsion or gel delivery system for treatment of neuropathic pain. Other topical antiinflammatory medicaments available in the market do not alleviate neuropathic pain. Therefore there is a clinical need for a more effective topical treatment of neuropathic pain.

PCT/NZ2009/000167 ("Medicament for the treatment of pain") discloses a medicament for treating neuropathic pain and neurogenic inflammation comprising cholecalciferol formulated for transdermal application. Trials have shown that this medicament significantly benefits the relief of pain. However the formulation may not be effective for all types of pain, as it may only inhibit the TRPV1 receptors, one of the many pathways involved in the pathophysiology of neuropathic pain. Topical and transdermal formulations of calcitriol and analogues have been previously reported (see for example, WO2005037755, US2007032461 , WO2004098522, US2004152680, and WO2004098612). However the formulations disclosed have not optimized the delivery of vitamin D across the skin. Furthermore the formulations have been used for management of a "vitamin D associated state" which include treatment of cancer, autoimmune diseases, antiinflammatory disorders, osteoporosis, and skin conditions such as psoriasis. Topical cholecalciferol formulations as low as 2.5 g/mL have also been developed for management of pruritus (for example, as described in US 5789399A). However such low concentrations, when used alone, are not effective for management of neuropathic pain or neurogenic inflammation.

Object of the Invention

Effective medicaments with acceptable side effect profiles for management of neuropathic pain are limited. Therefore it is an object of the invention to improve on the relief of pain and/or inflammation known in the prior art by providing rapid, convenient, safe and effective relief of pain and/or inflammation with minimal undesirable side effects.

Alternatively, it is an object to provide an improved medicament and/or method of administration for the rapid relief of pain and/or inflammation. The invention is directed at targeting multiple peripheral pathways involved in the pathophysiology of pain including neuropathic pain.

Alternatively, it is an object to develop a pharmaceutically acceptable carrier for topical delivery and relief of pain and/ or inflammation.

Alternatively, it is an object of the invention to at least provide the public with a useful choice. Summary of the Invention

According to a first aspect of the invention, there is provided a medicament for use in the treatment of pain and/or inflammation comprising:

vitamin D; and

one or more saccharides and/or sugar alcohols,

wherein the medicament is formulated for topical and/or transdermal application. Preferably, the medicament further comprises one or more salts. According to a second aspect of the invention, there is provided a medicament for use in the treatment of pain and/or inflammation comprising:

vitamin D; and

one or more salts,

wherein the medicament is formulated for topical and/or transdermal application.

Preferably, the medicament further comprises one or more saccharides and/or sugar alcohols.

It will be understood that vitamin D may be present in any known form of vitamin D or combinations thereof, including but not limited to: cholecalciferol (vitamin D3) and related analogues including functional analogues, 7-dehyrocholesterol, previtamin D3, ergocalciferol (vitamin D2), ergosterol, calciol (1a,25-dihyroxy vitamin D3), 24R, 25-dihyroxyvitamin D3, 25- hydroxy vitamin D3, tachysterol D3, lumisterol D3, pyro D3, isopryro D3, and suprosterol.

In some embodiments of the invention, the vitamin D comprises vitamin D3. In preferred embodiments, the vitamin D3 comprises cholecalciferol. Cholecalciferol will be understood to be the pro-hormone form of vitamin D3, or calciol. Cholecalciferol is distinct from calcitriol, the hormonally active from of vitamin D3, and calcidiol.

In the context of the invention, it will be understood that the terms "pain" and "inflammation" may be taken to relate to the medical definitions of "neuropathic pain" and "neurogenic inflammation", respectively. However, the relevant terms in this document may relate to any form of pain or inflammation including but not limited to acute pain, chronic pain, cancer pain, postoperative pain, phantom pain, incident pain, breakthrough pain, and psychogenic pain syndrome.

For the purposes of this specification, "topical" drug delivery may be defined as "local and directed delivery of therapeutics to the dermal and epidermal layers of the skin with minimal systematic bioavailability" while "transdermal" delivery is the delivery of medication through percutaneous absorption, which may achieve therapeutic systemic levels of active drug comparable to oral medications. Transdermal pharmacotherapies may be administered distal to the site of injury and may deliver therapy over an extended period of time after a slow onset of action.

Preferably, the vitamin D is dissolved in an oil phase. Preferably, the saccharide comprises a monosaccharide with the general formula (CH₂0)_n, where n is 3 or more. More preferably, the monosaccharide is selected from but not limited to the group consisting of: ribose, xylose, fructose, dextrose (glucose), mannose, galactose and sorbose.

Alternatively, the saccharide comprises a disaccharide. Preferably, the disaccharide is selected from but not limited to the group consisting of: sucrose, maltose, lactose, lactulose, trehalose and cellobiose.

Preferably, the sugar alcohol has the formula H(HCHO)_n+1H, where n is zero or more. More preferably the sugar alcohol is selected from but not limited to the group consisting of: mannitol, sorbitol, xylitol, arabitol, glycerol, glycol, erythritol and maltitol.

Preferably, the saccharide and/or sugar alcohol is dissolved in an aqueous phase.

Preferably the one or more salts comprise a salt formed from an acid.

Preferably the acid comprises a first class salt former. It will be understood that first class salt formers are acids that can be used without any restriction as they form physiologically abundant ions or they are intermediate metabolites in biochemical pathways (Stahl, 2002).

Preferably the acid comprises a second class salt former. It will be understood that second class salt formers are acids which do not occur naturally, but their use is associated with low toxicity (Stahl, 2002).

Preferably the one or more salts comprise a mono-, di- or tri-valent cation.

More preferably, the cation is selected from the group consisting of but not limited to: sodium, calcium, potassium, zinc, iron and magnesium.

Preferably, the one or more salts comprise a salt of an anion selected from the group consisting of but not limited to: chloride, acetate, ascorbate, bicarbonate, citrate, formate, fumarate, phosphate, succinate, borate, gluconate, lactate, malate, trimalate, panthothenate, thiocyanate, glycinate, and sulphate. More preferably, the one or more salts are selected from the group consisting of: sodium chloride, sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium succinate, sodium borate, sodium gluconate, sodium citrate, sodium lactate, calcium citrate, calcium chloride, calcium

pantothenate, calcium gluconate, calcium phosphate, potassium chloride, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, potassium gluconate, magnesium sulphate, magnesium chloride magnesium gluconate, magnesium acetate, .magnesium malate, magnesium glycinate, magnesium lactate, zinc chloride, zinc sulphate and zinc acetate. Other exemplary salts may be formed from any combination of anions and cations listed in this specification and may include, anhydrous, hydrates, dehydrates and the like.

Preferably, the vitamin D is present in a concentration of 0.1-5%w/w.

Preferably, the one or more saccharides and/or sugar alcohols are present in a concentration of 1 - 15%w/w.

Preferably, the salt or salts are present in a concentration range of 0.1 - 6.5%w/w.

In preferred embodiments of the invention, the medicament comprises one or more excipients, wherein the excipients render the medicament suitable for topical or transdermal application. It will be understood that topical application comprises the application of the medicament to any body surface, and particularly the skin. Medicaments for topical or transdermal application comprise epicutaneous and inhalational medicaments. Topical or transdermal applications may include, but are not limited to, the following: lotions, creams, emulsions, ointments, gels, foams, powders, pastes, oils, transdermal patches, microneedles, lipid delivery systems, impregnated sheet materials, drops and sprays (aerosol and non-aerosol).

Preferably, the medicament comprises an emulsion base.

Preferably the medicament comprises an oil phase. For example the oil phase may be composed of vegetable oils, animal oils, mineral oils, silicone oils, synthetic oils, fatty acid, fatty alcohols and paraffin waxes.

Preferably, the medicament comprises one or more solubilising agents. Examples of solubilising agents include cyclodextrins, non-ionic surfactants, organic solvents, alcohols, and

polysorbates. Preferably, the medicament comprises one or more viscosity increasing agents. Examples of viscosity increasing agents include microcrystalline cellulose, carboxymethylcellulose sodium, propylene glycol alginate, xanthan gum and polyacrylic acid.

Preferably, the medicament comprises one or more emulsifying and/or co-emulsifying agents. More preferably the emulsifying and/or co-emulsifying agents comprise a non-ionic surfactant. Examples of emulsifiers include polyethylene glycol esters, polyoxypropylene glycol ethers, sorbitan esters, ethoxylated sorbitan esters and poly esters.

Preferably, the medicament comprises one or more emulsion stabilising agents. Examples of stabilising agents include abietic acid, hydrogenated lanolin alcohol, calcium myristate, hydroxyaluminium distearate, aluminum isostearate aluminum isostearates / stearates, 7, 8- didehydrocholesterol, aluminum magnesium hydroxide, stearic acid, lauryl alcohol and hydroxyethyl cellulose.

Preferably, the medicament comprises one or more preservatives or preserving agents.

Examples of preservatives include sorbic acid, methyl paraben, propyl paraben, benzoic acid, sodium benzoate cetrimide, phenoxyethanol, chlorphenisin and methylchloroisothiazolinone.

Preferably, the medicament may also contain a penetration enhancer. Examples of penetration enhancers include sulphoxides, azone, pyrrolidones, fatty acids, alcohols, fatty alcohols and glycols, surfactants, phospholipids and urea.

Other ingredients such as, gelling agents, humectants and antioxidants may also be added to the formulation.

According to a third aspect of the invention, there is provided the use of vitamin D together with one or more saccharides and/or sugar alcohols in the manufacture of a medicament for the treatment of pain and/or inflammation, wherein the medicament is formulated for topical and/or transdermal application.

According to a fourth aspect of the invention, there is provided the use of vitamin D together with one or more salts in the manufacture of a medicament for the treatment of pain and/or inflammation, wherein the medicament is formulated for topical and/or transdermal application. According to a fifth aspect of the invention, there is provided a method for the treatment of pain and/or inflammation comprising topically and/or transdermal^ applying a medicament comprising vitamin D together with one or more saccharides and/or sugar alcohols to a treatment area.

Preferably, the method further comprises applying sonophoresis, iontophoresis, electroporation, or massaging the treatment area following the topical / transdermal application of the

medicament.

Preferably the medicament used in the method of the invention further comprises one or more salts.

According to a sixth aspect of the invention, there is provided a method for the treatment of pain and/or inflammation comprising topically and/or transdermal^ applying a medicament comprising vitamin D together with a salt or salts to a treatment area.

Preferably, the method further comprises applying sonophoresis, iontophoresis, electroporation or massaging the treatment area following the topical / transdermal application of the

medicament.

Preferably the medicament used in the method of the invention further comprises one or more saccharides and/or sugar alcohols.

Further aspects of the invention, which should be considered in all its novel aspects, will become apparent to those skilled in the art upon reading of the following description which provides at least one example of a practical application of the invention.

Detailed Description of Preferred Embodiments of the Invention

A previous patent application (PCT/NZ2009/000167) disclosed that a non-ionic topical cream containing 0.2% cholecalciferol is effective as an analgesic. The inventors have now found that treating pain and/or inflammation is surprisingly much more effective with the use of one or more saccharides and/or sugar alcohols, and/or one or more salts included in a medicament formulated for topical or transdermal administration. Preliminary studies on patients using a cream containing 0.2%w/w cholecalciferol and 5%w/w dextrose (a saccharide) indicated an improved analgesic effect compared to the cream containing only cholecalciferol, with the dextrose cream acting faster and for longer.

Further investigation has demonstrated that other saccharides and/or sugar alcohols, and/or salts are also particularly effective when combined with cholecalciferol or other forms of vitamin D in a topically administered pain relief formulation.

Examples of efficacy

Initial trials on the formulation of the invention were conducted on subjects with a history of persistent neuropathic pain who had previously responded well to a topically administered formulation containing only vitamin D3 (cholecalciferol) as an active ingredient (described in PCT/NZ2009/000167).

A formulation containing 0.2%w/w cholecalciferol, 5%w/w dextrose, 2%w/w sodium chloride and a number of excipients to form a cream (see examples 9 and 10) suitable for topical administration was trialled. This formulation is referred to herein as the "combination cream". Subjects were told to administer about 1 gram of the combination cream 2-3 times a day to the affected area and gently massage for 2 to 3 minutes. The subjects were asked to observe the effects of the combination cream and compare it to their experience using the cholecalciferol- only cream.

Example 1 - Mrs GD, age 74, retired. Since the age of nine, GD has suffered 30 bouts of osteomyelitis requiring surgical draining and long spells in hospital. She developed areas of persistent neuropathic pain known as a Complex Regional Pain Syndrome (CRPS) in the many surgical incisions all over her body. These have responded to neural prolotherapy and she uses vitamin D3 topical cream applications for maintenance and breakthrough pain. She has been able to stop all other painkillers on this regime. GD volunteered to trial the combination cream. She experienced an immediate improvement in all her painful areas. The combination cream was described as better with an instant analgesic effect, and also importantly lasting longer.

Example 2 - Ms SW, age 40, administrative assistant. SW has a long history of a fibromyalgia- like syndrome affecting her whole body, resulting in many surgical interventions, only to have more intense neuropathic pain. No specific underlying conditions have been identified, but there is a strong genetic influence. SW has been treated successfully with neural prolotherapy and uses vitamin D3 topical cream for maintenance and breakthrough pain. She cannot use any other analgesics due to hypersensitivity to all drugs. SW volunteered to trial the combination cream and noticed a huge change in her pain control. The analgesic effect is instant and more complete. As the effect also lasts much longer, she only needs to use the combination cream once daily and occasionally for breakthrough pain.

Example 3 - Mrs AW, age 36, medical receptionist. AW has a hereditary Charcot-Marie-Tooth neuropathy and has suffered for many years from severe peripheral neuropathic pain in both lower legs, which she describes as a diffuse deep burning, aching pain. This neuropathic pain has affected her sleep, usually waking her up every 2-3 hours. She has found the combination cream allows her to sleep undisturbed, immensely improving her quality of life. It also obviates the need for additional analgesic medication during the night.

Example 4 - Mrs SJ, age 47, primary school teacher and national level netball umpire. SJ has had long standing recurrent problems with Achilles, hamstrings, low back and shoulders. She has tried all manner of treatments over the last 25 years, but has found the combination of neural prolotherapy and vitamin D3 topical cream to be the best for her. It allows her to continue teaching and operate at a high level in her chosen sport. She offered to trial the combination cream and described this as "fantastic". She describes the onset of analgesia as immediate, better and longer lasting.

In addition to the above findings the combination cream has been found to be also highly effective for management of pain and/or inflammation not related to nerve damage, as illustrated in the following examples.

Example 5 - Miss PS, age 14. PS injured her right knee while playing hockey due to subluxation of the right patella. She was unable to run and had difficulty walking. She had swelling and tenderness in her right anterior knee. She was treated with the combination cream twice daily by administration to the affected area. Within 4 weeks, she was able to run comfortably and partake in a PE assessment test for netball.

Example 6 - Mr DD, age 50, landscaper and gardener. His preferred leisure activity is hunting. He has a history of mild osteoarthritis of both knees, which can be quite troublesome on downhill tramping. He has successfully used vitamin D3 cream for maintenance and

breakthrough pain, also during tramping. He trialled the combination cream on a trip and was pain free for most of the tramp. He felt the combination cream had an effect with a faster onset; it was described as more complete and lasted longer.

Example 7 - Mr BD, age 49, sheep shearer and black belt karate exponent. He has suffered many knee injuries and manages his pain with occasional neural prolotherapy and regular vitamin D3 topical cream. When trialling the combination cream he noticed an immediate improvement in his knees and described a faster onset, more complete and longer lasting effect.

Example 8 - Mr JL, age 65, medical practitioner. JL developed right medial and lateral elbow pain (respectively 'golfers' and 'tennis' elbow) while shifting 2 ton of border stones to landscape an undeveloped section. Pain levels were at times extreme affecting handshakes, turning doorknobs and lifting the electric jug. It also affected his normal daily function adversely. JL started to treat his medial and lateral elbow with twice daily combination cream and within 6-8 weeks pain levels were virtually zero and full function and strength had returned.

Example 9 - The efficacy of a number of different formulae was trialled by a 69 year old man with severe osteoarthritic pain in his right knee. Substitution of dextrose by sucrose and fructose in the combination cream formulation were observed to be as effective to alleviating pain as the combination cream including dextrose. Substitution of sodium chloride by sodium succinate in the combination cream formulation was observed to provide a cooling effect while pain relief was as good as with sodium chloride.

The addition of magnesium chloride and zinc chloride to the combination cream formulation used by this patient produced excellent pain relief while increasing the observed duration of analgesic activity.

Example 10 - A female hiker suffering from chronic lower back, lower leg and foot pain was relieved of all pain by a formulation containing cholecalciferol, dextrose, magnesium malate, sodium chloride and zinc chloride.

Some of the above patients have been suffering from neuropathic pain for many years and have found most products available in the market to be ineffective. Compared to the other products, the patients have found the combination cream to be highly effective, with significant improvement of their symptoms within 24 hours of application. The formulation is thought to improve on other topical and transdermal pain relief products due to the synergistic effects of the actives targeting multiple receptors in pain pathways at the same time.

The inventors postulate that salts or sugars in the formulation work synergistically with vitamin D and in particular cholecalciferol by antagonising the TRPV1 receptors expressed on C fibres. Optional inclusion of a salt or salts (for example magnesium) in the formulation can decrease the N DAR activity by blocking the receptor-coupled calcium channel or by an antagonist action on the receptor. Alternatively the analgesic effects of a salt or salts (for example zinc) might be related to the control of section of substance P and possible inhibitory effects on the acid sensing ion channels (ASICs), which are highly up-regulated following peripheral inflammation. Therefore the formulations described herein have enhanced analgesic effects due to possible targeting of several key pathways of neuropathic pain. Surprisingly the efficacy of pain relief found by patients using the formulations of the invention was better than the reported efficacy of the active ingredients when used separately topically or transdermally.

Examples of Composition

Topical delivery across the skin can be limited due to the highly impermeable nature of the stratum corneum, the outer most layer of the skin. There is also the possibility of skin allergies and toxicities due to high concentration of excipients such as surfactant and permeation enhancers, used to ensure enhanced absorption and formulation stability. The following describes examples of topical delivery formulations which improve the delivery of cholecalciferol through the epidermal and dermal layers of the skin with improved skin feel during and after topical administration without irritating the skin.

Preferred embodiments of the invention may contain one or more of the following excipients, listed below with typically preferred concentrations:

• Solubiliser of oil soluble actives / emollient, 8-30%w/w, e.g. C₈-C₁₀ acid triglycerides, C₈- C₁₂ acid triglycerides;

• Viscosity increaser / emulsion stabilizer, 1-7.5%w/w, e.g. a fatty alcohol such as cetyl alcohol and cetearyl alcohol, calcium myristate, lauryl alcohol

• Emulsifier / co-emulsifier, 2-7%w/w, e.g. polyethyleneglycol ethers such as steareth 10, ceteareth 20, laureth 10;

• Emollient / bodying agent, 0.5-1.5%w/w, e.g. cetyl esters; • Permeation enhancer, 0.1-5%w/w;

• Preservative, 0.2 -0.4%w/w, e.g. methyl pararben, propyl paraben, phenoxyethanol.

The following formulations are provided in particular embodiments of the invention.

Formulation 1 - An example of an emulsion formulation prepared for topical delivery of vitamin D comprises emulsifiers PEG-8 Beeswax (5% w/w), a mixture of cetyl alcohol, ceteth-20 and steareth-20 (3% w/w), vitamin D (0.15%) dissolved in mineral oil (30% w/w), carbomer (0.10 %w/w), sorbic acid (0.05% w/w), methyl paraben sodium salt (0.05% w/w), glucose (2% w/w), sodium chloride (2%) and purified water (57.8% w/w).

To prepare the emulsion, the emulsifiers are added to the oily phase containing vitamin D and heated at 70°C. The aqueous soluble components are dissolved in water. The oily phase is poured into the aqueous phase under moderate stirring. The emulsion is then cooled down to room temperature whilst stirring.

Formulation 1 is a diverse formulation which can hold up to 40-50% of the oil phase, as well as other oil phases. Further the formulation is compatible with the actives over the pH of 4.5-7. By changing the concentration of the emulsifier between 4-7%, the formulation can be changed from a cream to a lotion. This formulation is non-greasy, rich in texture and feels soft during the application.

Formulation 2 - Another example of a formulation comprises glyceryl stearate and PEG-75 stearate (3% w/w), cetyl Ceteth-20 and steareth-20 (3% w/w), cetyl alcohol (3% w/w), oleoyl macrogo!-6 glycerides (2% w/w), vitamin D (0.15 % w/w) dissolved in mineral oil (10% w/w), sorbic acid (0.10% w/w), methyl paraben sodium salt (0.05% w/w), sorbitol (3% w/w), magnesium chloride (2.5% w/w) and purified water (73.2% w/w).

This formulation is stable over a wide range of pH (from 3-12) and has excellent heat stability. Further the concentration of the emulsifier can be varied between 3-8% and is compatible with a wide range of viscosity modifiers and gelling agents even at low levels of the emulsifier. When applied to the skin, the formulation provides a soft velvet touch.

Physical Permeation Enhancers

In the trial described above, subjects were told to gently massage the cream to the affected area. The massaging is intended to assist in the movement of actives into the skin.

In alternative embodiments of the invention, one or more methods for assisting delivery of medicaments through the skin may be used. For example, sonophoresis may be used in one embodiment to assist in the absorption of the medicament by the skin. Ultrasound waves applied to the skin create acoustic cavitations which allow absorption of small molecules between keratinocytes in the stratum corneum.

In other embodiments, iontophoresis, electroporation or occlusion techniques may be used.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to".

The entire disclosures of all applications, patents and publications cited above and below, if any, are herein incorporated by reference.

Reference to any prior art in this specification is not, and should not be taken as, an

acknowledgement or any form of suggestion that prior art forms part of the common general knowledge in the field of endeavour in any country in the world.

The invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features.

Where in the foregoing description reference has been made to integers or components having known equivalents thereof, those integers are herein incorporated as if individually set forth. It should be noted that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the spirit and scope of the invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be included within the present invention.

Journal References

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Claims

1. A medicament for use in the treatment of pain and/or inflammation comprising:

vitamin D; and

one or more saccharides and/or sugar alcohols,

2. A medicament as claimed in claim 1 , wherein the medicament further comprises one or more salts.

3. A medicament for use in the treatment of pain and/or inflammation comprising:

vitamin D; and

one or more salts,

4. A medicament as claimed in claim 3, wherein the medicament further comprises one or more saccharides and/or sugar alcohols.

5. A medicament as claimed in any one of the preceding claims, wherein the vitamin D comprises vitamin D3.

6. A medicament as claimed in claim 5, wherein the vitamin D3 comprises cholecalciferol.

7. A medicament as claimed in any one of the preceding claims, wherein the vitamin D is dissolved in an oil phase.

8. A medicament as claimed in any one of claims 1 , 2 or 4-7, wherein the saccharide

comprises a monosaccharide with the general formula (CH₂0)_n, where n is 3 or more.

9. A medicament as claimed in claim 8, wherein the monosaccharide is selected from the group consisting of: ribose, xylose, fructose, dextrose (glucose), mannose, galactose and sorbose.

10. A medicament as claimed in any one of claims 1 , 2 or 4-7, wherein the saccharide

comprises a disaccharide.

11. A medicament as claimed in claim 10, wherein the disaccharide is selected from the group consisting of: sucrose, maltose, lactose, lactulose, trehalose and cellobiose.

12. A medicament as claimed in any one of claims 1 , 2 or 4-1 1 , wherein the sugar alcohol has the formula H(HCHO)_n+iH, where n is zero or more.

13. A medicament as claimed in claim 12, wherein the sugar alcohol is selected from the group consisting of: mannitol, sorbitol, xylitol, arabitol, glycerol, glycol, erythritol and maltitol.

14. A medicament as claimed in any one of claims 1 , 2 or 4-13, wherein the saccharide and/or sugar alcohol is dissolved in an aqueous phase.

15. A medicament as claimed in any one of claims 2-14, wherein the one or more salts comprise a salt formed from an acid.

16. A medicament as claimed in claim 15, wherein the acid comprises a first class salt former.

17. A medicament as claimed in claim 15, wherein the acid comprises a second class salt former.

18. A medicament as claimed in any one of claims 2-17, wherein the one or more salts comprise a mono-, di- or tri-valent cation.

19. A medicament as claimed in claim 18, wherein the cation is selected from the group consisting of: sodium, calcium, potassium, zinc, iron and magnesium.

20. A medicament as claimed in any one of claims 2-19, wherein the one or more salts comprise a salt of an anion selected from the group consisting of: chloride, acetate, ascorbate, bicarbonate, citrate, formate, fumarate, phosphate, succinate, borate, gluconate, lactate, malate, trimalate, panthothenate, thiocyanate, glycinate, and sulphate.

21. A medicament as claimed in claim 18-20, wherein the one or more salts are selected from the group consisting of: sodium chloride, sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium succinate, sodium borate, sodium gluconate, sodium citrate, sodium lactate, calcium citrate, calcium chloride, calcium pantothenate, calcium gluconate, calcium phosphate, potassium chloride, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, potassium gluconate, magnesium sulphate, magnesium chloride magnesium gluconate, magnesium acetate, .magnesium malate, magnesium glycinate, magnesium lactate, zinc chloride, zinc sulphate and zinc acetate.

22. A medicament as claimed in any one of the preceding claims, wherein the vitamin D is present in a concentration of 0.1 - 5%w/w.

23. A medicament as claimed in any one of claims 1 , 2 or 4-22, wherein the one or more saccharides and/or sugar alcohols are present in a concentration of 1 - 15%w/w.

24. A medicament as claimed in any one of claims 2-23, wherein the one or more salts are present in a concentration range of 0.1 - 6.5%w/w.

25. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises an emulsion base.

26. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises one or more solubilising agents.

27. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises one or more viscosity increasing agents.

28. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises one or more emulsifying and/or co-emulsifying agents.

> 29. A medicament as claimed in any one of the preceding claims, wherein the emulsifying and/or co-emulsifying agents comprise a non-ionic surfactant.

30. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises one or more emulsion stabilising agents.

31. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises one or more preservatives or preserving agents.

32. A medicament as claimed in any one of the preceding claims, wherein the medicament comprises a penetration enhancer.

33. The use of vitamin D together with one or more saccharides and/or sugar alcohols in the manufacture of a medicament for the treatment of pain and/or inflammation, wherein the medicament is formulated for topical and/or transdermal application.

34. The use of vitamin D together with one or more salts in the manufacture of a

medicament for the treatment of pain and/or inflammation, wherein the medicament is formulated for topical or transdermal application.

35. A method for the treatment of pain and/or inflammation comprising topically or

transdermal^ applying a medicament comprising vitamin D together with one or more saccharides and/or sugar alcohols to a treatment area.

36. A method as claimed in claim 35, wherein the medicament further comprises one or more salts.

37. A method as claimed in claim 35 or 36, wherein the method further comprises applying sonophoresis, iontophoresis, electroporation, or massaging the treatment area following the topical / transdermal application of the medicament.

38. A method for the treatment of pain and/or inflammation comprising topically and/or transdermally applying a medicament comprising vitamin D together with a salt or salts to a treatment area.

39. A method as claimed in claim 38, wherein the medicament further comprises one or more saccharides and/or sugar alcohols.

40. A method as claimed in claim 38 or 39, wherein the method further comprises applying sonophoresis, iontophoresis, electroporation, occlusion or massaging the treatment area following the topical / transdermal application of the medicament.