WO2013119042A1

WO2013119042A1 - Composition for preventing or curing neuropathic pain comprising substance-p

Info

Publication number: WO2013119042A1
Application number: PCT/KR2013/000960
Authority: WO
Inventors: Young Sook Son; Eunkyung Chung; Hyun-Jeong Kim
Original assignee: University-Industry Cooperation Group Of Kyung Hee University
Priority date: 2012-02-09
Filing date: 2013-02-06
Publication date: 2013-08-15
Also published as: KR20130092470A

Abstract

The present invention provides a composition for preventing and curing of neuropathic pain, comprising substance P. Substance P of the present invention shows mitigating, preventive and/or therapeutic effects on neuropathic pain.

Description

COMPOSITION FOR PREVENTING OR CURING NEUROPATHIC PAIN COMPRISING SUBSTANCE-P

The present invention relates to a composition for preventing or curing of neuropathic pain, a chronic pain.

1. Definition and Classification of Pain

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. There are three classes of pain: nociceptive pain, inflammatory pain, and neuropathic pain. Chronic pain, which is of clinical significance, is generally defined as pain that lasts more than six months from the onset in spite of no apparent causes. Most chronic pains are expressed as neuropathic pains characterized by spontaneous pain, allodynia, and hyperalgesia. Patients with chronic pain complain of severe pain even upon a slight temperature change or trifling contact with clothes, suffering from significant difficulty in daily life. Further, chronic pain is unlikely to be cured with various conventional therapies. Nociceptive pain is relatively easy to cure like post-spinal surgery pain, pain following a wound or accident, labor pain, arthritis pain, etc. On the other hand, neuropathic pain results from damage or disease affecting neural cells or the nerve system, with the concomitant transmission of pain signals to the brain. It may be associated with abnormal sensations called dysesthesia, e.g., a sensation likened to an electric shock even in the absence of stimuli, or hyperalgesia, that is, a sensation of severe pain produced by normally non-painful stimuli. Representative among neuropathic pain are diabetic neuropathy, post-herpetic neuralgia, and trigeminal neuralgia. In many cases, neuropathic pain is accompanied by other disorders such as sleep disturbance, low vitality, decreased concentration, depression, etc. Complex pain exhibits characteristics of both nociceptive pain and neuropathic pain, and causes of complex pain include spine surgery, spinal stenosis, carpal tunnel syndrome, whiplash syndromes after traumatic cervical injury such as traffic accident, etc.

2. Treatment of pain

Nociceptive pain is caused by actual injuries in the body, such as trauma, e.g., burns or stab wounds, and tumor compression in the body. When injured, a person feels pain because the nerve in the injured tissue is activated to deliver a pain signal to the brain. Pain on visceral structures, such as the liver, called visceral pain, is diffuse and difficult to locate, and produces continual straining and smarting sensations. It may be accompanied by nausea, vomiting, and perspiration. Pain in the skin, the muscle, and the bone, called somatic pain, is characterized by sharp, stinging and suppressed sensations, and is clearly localized and well defined. All the pains can be effectively treated with narcotic analgesics or anti-inflammatory analgesics.

Long duration or repetition of nociceptive pain gives rise to a change of the nerve system, which leads to chronic neuropathic pain by delivering pain signals from the aberrant nerve system to the brain even in the absence of stimuli. Nerve injuries are caused by various factors such as trauma, post-spinal surgery pain, diabetic neuropathy, post-stroke central pain, depression, etc. Patients with neuropathic pain are sensitive to slight stimuli such as light touch. Nociceptive pain may be expressed as allodynia, such as trigeminal neuralgia characterized by episodes of intense pain in the face, hyperalgesia, which is an extreme, exaggerated reaction to a stimulus which is not normally painful, or sporadic pain such as an electric shock. Currently, antidepressants and anticonvulsants are primary therapy for neuropathic pain. If necessary, narcotic analgesics are administered. In general, however, neuropathic pain can be very difficult to treat. As for complex pain, its effective treatment requires an antidepressant and an anticonvulsant because it comprises neuropathic pain.

Cancer pain is a generic name for all the pain which may arise from tumor compression or infiltration of tissue, from treatments and diagnostic procedures, or secondarily from general prostration due to cancer, and from headache or rheumatoid diseases that the cancer patients retain irrespective of cancer. Cancer pain can be divided into nociceptive pain such as somatic pain and visceral pain, and neuropathic pain. Nociceptive pain in cancer is caused by infiltrating tumor cells into bones, or soft tissues such as visceral structures, blood vessels, nerve cells, etc., while the infiltration of inflammatory cells into peripheral nerve or spinal tissues, and an injury of nerve cells by surgery, chemotherapy or radiotherapy provoke neuropathic pain. Neuropathic pain is known to recur in about 10 % of patients who have been cured of nerve injury caused by a certain factor such as a trauma, an infection, a tumor, or a metabolic systemic disorder, e.g., diabetes. In addition, patients with neuropathic pain have recently increased in number because of an increase in the frequency of traffic accidents, or in the prevalence of diseases such as herpes zoster, tumor, diabetes, etc. in an increased elder population. However, the patients are not effectively treated because pathological mechanisms or promising therapies of neuropathic pain have not yet been established.

3. General Treatment of Neuropathic Pain

Neuropathic pain is diverse, chronic in most cases, and difficult to treat. For this reason, various drugs have been tried. Most common are non-steroidal anti-inflammatory drugs (NSAIDs). Muscle relaxants or antidepressants, such as Baclofen and Tizandine, and sedatives or anticonvulsants such as Clonasepam and Benzodiasepam, are also used in pain control. In addition, alpha sympatholytic agents, calcium channel blockers, steroids, and calcinonin, such as Clonidine, Phenoxybenzamine, Prazocine, Terazoxine (Hytrin), and Doxazocine (Cardura), are applied to the treatment of neuropathic pain. Systemic injection of lidocain or topical administration of capsaicin or EMLA cream is an alternative therapy. The NMDA receptor antagonists dextorphan and ketamin, and the anti-Parkinson drug Amantadine (Symmetril) are also considered for neuropathic pain therapy. An antidepressant is usually used for the treatment of diabetic neuralgia, post-herpetic neuralgia, atypical facial pain, and central pain, while an anticonvulsant is applied to patients with trigeminal neuralgia, diabetic neuralgia, facial pain, central pain, and irritable bowel syndrome. Neuropathy is generally stepwise treated with analgesics, primarily with non-narcotic analgesics, next with non-narcotic and weak narcotic analgesics, and finally with strong narcotic and auxiliary non-narcotic analgesics. However, complex chronic neuropathic pain is not easy to rapidly diagnose and is not well understood in terms of its mechanism. There are no promising therapies for the pain. Thus, so long as it exerts analgesic effect on a certain pain, any candidate may be an important target of drug development.

4. Study on Neuropathic Pain

Because pain, as described by the definition thereof, encompasses subjective experiences, scientific access is very important to understand and evaluate properties of various animal models of pain using suitable methods. That is, suitable animal models of pain, the selection of which is a pre-evaluation step, are essential for understanding pain mechanisms and developing effective drugs or therapies for pain.

5. Substance P

Substance P is a neuropeptide, consisting of 11 amino acids, which is found in sensory nerves, macrophages, eosinophils, endothelial cells, corneagenous cells such as epithelial cells and keratocytes, and granulation tissues. This undecapeptide, when released to the dorsal horn of the spinal cord, is known to function as a mediator of nociception (Seybold et. al., Handb. Exp. Pharmacol. 194: 451-491, 2009). In addition, substance P is found to greatly increase nociception capacity as measured in animal models of inflammatory pain and chronic pain (Sahbaie et. al, Pain 145:341-349, 2009). However, substance P exhibits contradicting activities according to dose. Substance P was reported to have analgesic effects in a hot plate test when it was intravenously injected at doses of 50 and 500 μg/kg, but induce hyperalgesia at lower doses (Oehme et al., Science 208: 305-307, 1980). On the other hand, another report showed that substance P has a narcotic analgesic effect, like morphine and can be used instead of morphine (Stewart et. al., Nature 262: 784-785, 1976). Substance P was found to have 25-fold more potent, compared to morphine, in the tail flick test in rats following intracerebral administration, via chronically indwelling cannulae, with the analgesic effect rapidly starting (1 min) and lasting for 30 min to 60 min. Hence, substance P was regarded as an intrinsic analgesic factor (Malick and Goldstein, Life Sciences 23:835-844, 1978).

That is, the roles of substance P in pain are generally associated with the transmission of pain signals, but may run counter to each other depending on pain type, concentration, and environment.

[Prior Art Document]

[Patent Document]

Korean Patent Publication No. 10-2008-0068950 (July 25, 2008)

Korean Patent Publication No. 10-2009-0035279 (April 09, 2009)

Korean Patent Publication No. 10-2011-0017345 (Feb. 21, 2011)

Korean Patent Publication No. 10-2011-0018273 (Feb. 23, 2011)

Korean Patent Publication No. 10-2011-0018272 (Feb. 23, 2011)

Korean Patent Publication No. 10-2010-0100502 (Sep. 15, 2010)

The subject of the present invention is to provide a composition for preventing and/or curing of chronic neuropathic pain.

Leading to the present invention, intensive and thorough research into various pharmaceutical activities of substance P resulted in the finding that substance P exerts an analgesic effect in animal models of neuropathic pain. Because pain mechanisms differ from one type of pain to another as described in the background art, there has been a need for a drug that can specifically exert an interruptive effect on a certain pain mechanism. The preventive and therapeutic effect of substance P on neuropathic pain was first identified by the present inventors.

In the present invention, substance P, known as a neurotransmitter mediating pain, was first found to exert an analgesic effect in animal models of chronic constriction injury (CCI), which causes neuropathic pain, following intravenous injection, and thus the present invention addresses the use of substance P as a relief of neuropathic pain.

In accordance with an aspect thereof, the present invention provides a pharmaceutical composition for mitigating, improving, preventing, or treating neuropathic pain, comprising substance P.

In accordance with an embodiment thereof, the present invention provides a pharmaceutical composition for mitigating, improving, preventing, or treating chronic neuropathic pain, comprising substance P.

As used herein, the term “neuropathic pain” refers to pain induced or caused by primary injury or dysfunction of the nerve system (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210).

As used herein, the term “chronic neuropathic pain” refers to neuropathic pain, caused by primary lesions or dysfunction of the nerve system or the peripheral nerve system, which is persistent or lasts long.

Examples of the neuropathic pain include diabetic neuralgia, spinal stenosis, post-spinal surgery pain, allodynia, causalgia, hyperalgesia, hyperpathia, neuralgia, post-herpetic neuralgia, post-thoracotomic pain, trigemial neuralgia, multiple sclerosis-related pain, thalamic pain, phantom limb pain, anesthesia dolorosa, HIV-related neuropathic pain, myelopathy-caused paraplegic pain or complex regional pain syndrome, post-seizure pain, neuropathy-related pain, e.g., idiopathic or post-traumatic neuropathy and mononeuritis, cancer-related neuralgia, carpal tunnel-related neuralgia, spinal cord injury-related pain, fibromyalgia-related neuropathic pain, back and cervical pain, reflex sympathetic dystrophy, phantom pain syndrome and spontaneous pain, trauma-induced neuropathic pain, demyelination-induced pain, phantom-limb pain, chemotherapy-induced neuralgia, back pain, bone pain, chronic alcoholism, hypothyroidism, uremia, vitamin deficiency-caused neuropathic pain, and post-stroke central pain (WO 2006/000903, WO 2006/032481, WO 2007/075752, WO 2008/015403, and Korean Patent Publication No. 10-2010-0020125).

The composition comprising substance P as an active ingredient in accordance with the present invention may further comprise a pharmaceutically suitable and physiologically acceptable additive, and an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, a slip modifier, or a flavorant may be taken as the additive.

For administration, the composition of the present invention may be formulated together with at least one pharmaceutically acceptable carrier into a pharmaceutical dosage form.

Granules, powders, tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions, emulsions, drips, injectable liquids, and sustained release agents may fall within the scope of the pharmaceutical dosage form of the composition.

For preparation into tablets or capsules, for instance, the active ingredient may be associated with an oral, non-toxic, pharmaceutically acceptable, inert carrier, such as ethanol, glycerol, water, etc. In addition, if desired or necessary, suitable binders, lubricants, disintegrants, and colorants may be added. Examples of the suitable binders include, but are not limited to, natural sugars, such as starch, gelatin, glucose and beta-lactose, natural or synthetic gums such as corn sweetener, acacia, tragacanth, and sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Examples of the disintegrants may include, but are not limited to, starch, methyl cellulose, agar, bentonite, and xanthan gum.

Pharmaceutical carriers suitable for liquid preparations are those that are sterilized and are physiologically acceptable, and include saline, sterile water, Ringer’s solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a combination thereof. If necessary, the pharmaceutical composition may further comprise a typical additive such as an antioxidant, buffer, a bacteriostat, etc. In addition, the pharmaceutical composition may be formulated into injections such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets, with the aid of a diluent, a dispersant, a surfactant, a binder and/or a lubricant. Moreover, the pharmaceutical composition may be formulated into suitable dosage forms according to a method well known in the art or the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA.

According to purpose, the pharmaceutical composition or the active ingredient of the present invention may be administered intravenously, intraarterially, intraperitoneally, intrathoracically, intramuscularly, transdermally, intranasally, via inhalation, topically, rectally, orally, intraocularly, or subcutaneously, with preference for intravenously.

The active ingredient in the composition of the present invention may be administered in an amount of from 0.2 nmole/kg to 2 nmole/kg for an adult weighing 60 kg. The therapeutically effective amount of the active ingredient may be easily determined by those skilled in the art and may vary depending on various factors including the kind of disease, the severity of disease, the content of other ingredients to be administered together, the kind of formulation, patient’s age, weight, health condition, gender, and diet, the time of administration, the route of administration, the rate of excretion, the duration of treatment, and drugs to be used together.

In accordance with another aspect thereof, the present invention provides a method for mitigating, improving, preventing or treating neuropathic pain, comprising administering substance P in a therapeutically effective amount to a mammal.

The term “therapeutically effective amount,” as used herein, refers to an amount in which the active ingredient or the pharmaceutical composition, in the opinion of researchers, veterinarians, physicians, or other clinicians, can induce a biological or medical response in an animal or human, and is intended to encompass any amount in which the symptom of a disease or disorder to be treated is mitigated. It is obvious to those skilled in the art that therapeutically effective amounts and administration frequencies of the active ingredient of the present invention will be changed according to desired effects.

In accordance with a further aspect thereof, the present invention provides a food composition for mitigating, improving or preventing neuropathic pain, comprising substance P as an active ingredient.

In accordance with a still further aspect thereof, the present invention provides a food composition for mitigating, improving or preventing chronic neuropathic pain, comprising substance P as an active ingredient.

Formulations of the food composition of the present invention may be prepared using typical methods. For example, the food composition may be dried together with a carrier, and then encapsulated or formulated into tablets, powders, beverages, soups, and other food forms.

Based on the total weight of the food composition of the present invention, the active ingredient may be used in an amount of 5.6 ~ 55.2 x 10^-7 % by weight.

With the aim of mitigating, preventing and/or improving neuropathic pain, the food composition of the present invention may be processed into tablets, capsules, powders, granules, liquids, pills, etc.

For example, a mixture of substance P plus an excipient, a binder, a disintegrant, and other additives may be granulized, and then compressed in combination with a lubricant or directly into tablets. These health functional foods in the form of tablets may further comprise a corrigent, and optionally may be coated with a suitable coating agent.

For health functional foods in the form of capsules, for example, a mixture of substance P and an additive such as an excipient, or granules or coated granules of the mixture may be loaded into hard capsules. Soft capsules may be prepared by loading a mixture of substance P and an additive such as an excipient into a capsule base such as gelatin. If necessary, the soft capsule may contain a plasticizer such as glycerin or sorbitol, a colorant, and a preservative.

A pill of health functional foods may be prepared by formulating substance P with an excipient, a binder, a disintegrant, and the like. If necessary, the pill may be coated with sugar, or a suitable coating agent, such as starch, talc, etc.

Together with an excipient, a binder, a disintegrant, and/or other additive, substance P may be granulized. The granules may further comprise a flavorant and a corrigent, if desired.

Details described in the present invention are applied commonly to the use, the composition, and the method of the present invention unless they are contradictory to each other.

The composition comprising substance P in accordance with the present invention is useful in mitigating, improving, preventing and/or treating neuropathic pain, without causing side effects, such as inflammation, and loss of balance and vestibulo-motor function.

FIG. 1 is a graph showing the pain relief effect of SP, as assayed by von Prey testing.

FIG. 2 is a graph showing the dose-dependent pain relief of SP, as assayed by von Prey testing.

FIG. 3 is a graph showing that pain relief can be maintained by the repeated administration of SP, as assayed by von Prey testing.

FIG. 4 is a graph showing the pain relief mechanism of SP mediated by the NK-1 receptor, as assayed using an NK-1 receptor antagonist.

FIG. 5 is a graph showing that SP does not cause side effects in terms of balance and vestibule-motor function, as measured by rotarod testing.

A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention.

[EXAMPLES]

Although the preferred embodiment(s) of the present invention have(has) been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

EXAMPLE 1: Establishment of Neuropathic Pain Model - Spontaneous Healing Process of Sciatic Nerve Injury and Induction of Neuropathic Pain

The chronic constriction injury (CCI) model for neuropathic pain is a model of mononeuropathy induced by loose ligation to the sciatic nerve. The roles of substance P in pain are generally associated with the signal transmission of pain induction, but are also known to run counter to each other depending on concentrations and environments. The CCI model, an optimal model for chronic neuropathic pain, was used in the examination of the analgesic effect of substance P following intravenous injection.

For use as the animal model, ICR mice were purchased from Central Lab. Animal. Inc., Korea. A CCI model of 20 mice established for one experiment, and two weeks later, they were subjected to a von Frey test. A chronic constriction injury (CCI) model was established for mononeuropathy by loose ligation to the sciatic nerve. In this regard, CCI is performed under anesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting 3 cm through the connective tissue between the gluteus superficialis and biceps femoris muscles in the hindlimb. After the sciatic nerve was separated by 7 mm from the surrounding tissues, four 4-0 silk or chromic gut ligatures were tied loosely around the sciatic nerve at 0.5 - 1 mm intervals, to just occlude but not arrest epineural blood flow. If the ligation was too tight, the motility function was injured. Thus, the ligation was made to such an extent so as to cause neuropathic pain without damage to the motility function. During the ligation, the ligatures were tied to the point of the appearance of single contraction, so as to prevent the arrest of epineural blood flow. The CCI models thus obtained were used in the following experiments.

EXAMPLE 2: Pain Relief by SP Administration: Evaluation for Neuropathic Pain (von Frey Test)

For a behavioral test for evaluating neuropathic pain, the response of the mice was recorded when the mid-plantar surface of the hindpaw was stimulated using a von Frey filament. Each of the mice was placed on a wire net (12 x 12 mm) to which a transplant plastic cover (21 x 27 x 15 cm) was then applied, and they were allowed to acclimate to the environment for 30 min. The mid-plantar areas which are controlled by L5 and L6 spinal nerves were stimulated using von Frey filaments (Soelting Co. IL) at various forces in an ascending order (1.4 g, 2.0 g, 4.0 g, 6.0 g, 8.0 g, 10.0 g, 15.0g, 26.0 g) in an up-down technique until the filaments were slightly bent. Mechanical withdrawal responses were observed. The mice were regarded as showing a withdrawal response when they rapidly withdrew their limbs or avoided the stimuli. Upon no responses, stimuli with one-step more potent force were applied. Stimulation was performed for about 5 sec regular intervals of 30 sec. From six measurements, 50% von Frey filament Paw withdrawal threshold (PWT) was calculated.

The CCI models for neuropathic pain were injected with 0.1 mL of SP (1 nmole/kg) 0.1 ml or saline (control) via the tail vein.

For a sham group, the ligation was not made after the exposure of the sciatic nerve, but the fascia was tied immediately so that the mice would be rapidly cured. The mice in the sham group showed the same responses to pain stimuli as normal mice.

Pain sensitivity was measured in the von Frey test, 10 min, 1 hr, 1 day, and 3 days after the injection. It was observed that pain relief started from 1 hr after the intravenous injection of SP and reached a peak 1 day after the injection in which they did not feel pain even at the highest force, and that they again felt pain after one day (FIG. 1).

EXAMPLE 3: Dose-Dependent Pain Relief Effect of SP

To examine the pain relief effect of SP according to concentration, the same procedure for the von Frey test as in Example 2 was repeated for with the exception that SP was injected at a dose of 0.2, 1, and 2 nmole/kg into respective groups.

At higher doses, pain relief was provoked more rapidly, and persisted for a longer period (FIG. 2).

EXAMPLE 4: Maintenance of Pain Relief Effect by Repeated Administration of SP

An examination was made of the resumption of the pain relief effect of SP. SP was intravenously injected again at the same dose as in Example 2, when the pain relief was disappeared 3 days after the first injection.

The repeated administration of SP was observed to resume a pain relief effect from 1 day after injection, and cause the pain relief to last for a prolonged time (boosting effect) (FIG. 3).

EXAMPLE 5: Assay of SP for Pain Relief Mechanism of SP by Use of NK-1 Receptor Antagonist

To examine whether SP directly induces pain relief, SP was injected, together with 1 μM of the NK-1 receptor antagonist RP67580 (Tocris Bioscience Cat. no. 1635), in the same manner as in Example 2, followed by performing the von Frey test.

As a result, the pain relief of SP was not elicited, indicating that SP-induced pain relief is mediated by the NK-1 receptor in the animal model of neuropathic pain (FIG. 4).

EXAMPLE 6: Rotarod Test

To examine animal models for balance and vestibulo-motor function, a rotarod test was performed in which a mouse was placed on a rotating rod to measure riding time without falling. Three groups of 8 were intravenously injected with SP, saline and MK-801, respectively, 15 min before rotarod testing. MK-801, a non-competitive antagonist of the NMDA receptor, is a drug causing the loss of balance and vestibule-motor function, and was used for comparison with SP in this experiment. The rotation speed of the rod was accelerated from 4 rpm to 40 rpm over 5 min. Average values of riding time were obtained from three measurements. The mice were subjected to rotarod testing immediately, 1 hr, 4.5 hrs, 1 day, and 3 days after injection. SP was found to not cause the side effect of losing balance and vestibule-motor function (FIG. 5).

Claims

A pharmaceutical composition for mitigating, improving, preventing or treating neuropathic pain, comprising substance P as an active ingredient.
The pharmaceutical composition of claim 1, wherein the neuropathic pain is chronic.
The pharmaceutical composition of claim 1, wherein the neuropathic pain is selected from the group consisting of diabetic neuralgia, spinal stenosis, post-spinal surgery pain, allodynia, causalgia, hyperalgesia, hyperpathia, neuralgia, post-herpetic neuralgia, post-thoracotomic pain, trigeminal neuralgia, multiple sclerosis-related pain, thalamic pain, phantom limb pain, anesthesia dolorosa, HIV-related neuropathic pain, myelopathy-caused paraplegic pain or complex regional pain syndrome, post-seizure pain, neuropathy-related pain, e.g., idiopathic or post-traumatic neuropathy and mononeuritis, cancer-related neuralgia, carpal tunnel-related neuralgia, spinal cord injury-related pain, fibromyalgia-related neuropathic pain, back and cervical pain, reflex sympathetic dystrophy, phantom pain syndrome and spontaneous pain, trauma-induced neuropathic pain, demyelination-induced pain, phantom-limb pain, chemotherapy-induced neuralgia, back pain, bone pain, chronic alcoholism, hypothyroidism, uremia, vitamin deficiency-caused neuropathic pain, and post-stroke central pain.
A food composition for mitigating, improving or preventing neuropathic pain, comprising substance P as an active ingredient.