Use of botulinum toxin type e for preventing or treating neuropathic pain

Abstract

The present invention relates to use of botulinum toxin type E for preventing or treating neuropathic pain, and specifically, to a pharmaceutical composition comprising botulinum toxin type E for preventing or treating neuropathic pain, and a surgical operation analgesic comprising botulinum toxin type E as an active ingredient. The botulinum toxin type E of the present invention has an analgesic effect by significantly inhibiting neuropathic pain, and, after a single administration, the botulinum toxin type E of the present invention can alleviate side effects and provide an analgesic effect superior to that of Gabapentin, which is a conventional analgesic used for treating neuropathic pain, in mechanical allodynia caused by mandibular alveolar nerve injury. In addition, the botulinum toxin type E of the present invention has a short duration of analgesic action in the body after administration so as to enable faster recovery and rehabilitation than after administration of botulinum toxin type A, and thus can be effectively used for treatment of neuropathic pain.

Description

Uses of Botulinum Toxin Type E for the Prevention or Treatment of Neuropathic Pain

[0001] The present invention relates to the use of botulinum toxin type E for the prevention or treatment of neuropathic pain, and specifically, to a pharmaceutical composition capable of preventing or treating neuropathic pain by including botulinum toxin type E as an active ingredient.

[0002] Although various analgesics are being developed globally, currently used drugs are primarily based on mechanisms such as anti-inflammatory substances, Na+ channel blockers, Ca+ channel blockers, and anticonvulsants, and newly developed drugs follow similar mechanisms. However, these drugs alone have limitations in adequately controlling intractable chronic pain. To supplement this, drugs with completely different mechanisms, such as morphine, are sometimes used, but their use is restricted due to serious side effects that occur with long-term administration.

[0003] Among the aforementioned chronic pains, neuropathic pain, in particular, arises from damage or disease of the nervous system and is characterized by an abnormal pain response that reacts hypersensitively to specific stimuli due to sensory nerve dysfunction. This pain is not only chronic but also intractable, making it often difficult to achieve complete pain suppression with conventional analgesics. Currently, Gabapentin is a representative drug known to be effective in treating neuropathic pain; however, its use is highly limited because various side effects have been reported, including dizziness, drowsiness, ataxia, fatigue, edema, headache, amnesia, depression, nervousness, and gastrointestinal disorders, and it can cause liver damage. Consequently, there is an urgent need for a new approach to address chronic and difficult-to-control pain.

[0004] Against this backdrop, botulinum toxin (BoNT), which possesses the property of blocking muscle contraction by inhibiting acetylcholine secretion at the neuromuscular junction, is utilized for wrinkle removal, hyperhidrosis treatment, and muscle disease treatment, and has recently been attracting attention in pain research. Among them, botulinum toxin type A is known to be effective in alleviating intractable chronic pain by blocking pain conduction and inhibiting the release of neurotransmitters, and it is recommended by the American Academy of Pain Medicine as a therapeutic drug for intractable chronic pain. However, botulinum toxin type A also had limitations in treating neuropathic pain, a type of chronic pain.

[0005] For example, neuropathic pain, such as neuralgia caused by herpes zoster or episodic migraines, is often idiopathic or occurs for a relatively short duration, making it difficult to classify solely as chronic pain.

[0006] Furthermore, even in situations requiring rapid rehabilitation during the post-surgical recovery period, the use of botulinum toxin type A can cause the analgesic effect to persist for an excessively long time, potentially interfering with the recovery of normal muscle function necessary for daily life or hindering rehabilitation exercises. Additionally, prolonged blockage of pain sensation may prevent patients from accurately perceiving their recovery status, leading to difficulties in assessing physical changes or the progress of their recovery during the rehabilitation process.

[0007] Accordingly, the inventors focused on botulinum toxin type E, which has a short duration of action, to overcome the limitations of botulinum toxin type A used for the treatment of neuropathic pain. It was confirmed that botulinum toxin type E can be an effective new drug capable of compensating for the shortcomings of existing analgesics by temporarily alleviating acutely worsening pain thanks to its short duration of action and facilitating pain control necessary during the rehabilitation process. Furthermore, the present invention was completed by elucidating the analgesic mechanism of action of botulinum toxin type E.

[0008] The object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of neuropathic pain comprising botulinum toxin type E (BoNT-E) as an active ingredient, wherein the composition is characterized by having a shorter duration of effect compared to a composition comprising botulinum toxin type A (BoNT-A).

[0009] Another objective of the present invention is to provide a surgical analgesic comprising botulinum toxin type E (BoNT-E) as an active ingredient, characterized by a shorter duration of effect compared to botulinum toxin type A (BoNT-A).

[0010] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims, and drawings.

[0011] The present invention provides a pharmaceutical composition for the prevention or treatment of neuropathic pain comprising botulinum toxin type E (BoNT-E) as an active ingredient, wherein the composition is characterized by having a shorter duration of effect compared to a composition comprising botulinum toxin type A (BoNT-A).

[0012] In addition, the present invention provides a surgical analgesic comprising botulinum toxin type E (BoNT-E) as an active ingredient, characterized by a shorter duration of effect compared to botulinum toxin type A (BoNT-A).

[0013] The present invention relates to a pharmaceutical composition containing botulinum toxin type E (BoNT-E) as an active ingredient capable of preventing or treating neuropathic pain caused by damage or disease of the nervous system. It has the advantage of providing excellent pain relief while mitigating fatal side effects, such as liver damage, compared to existing drugs currently in use.

[0014] In addition, the above-mentioned botulinum toxin type E has a short duration of analgesic effect in the body after administration, allowing for faster recovery to daily life and rehabilitation compared to the administration of botulinum toxin type A; therefore, it can be effectively utilized for the treatment of pain after surgical procedures.

[0015] Figure 1 shows an overview of an animal model of trigeminal neuropathic pain.

[0016] Figure 2 shows the pattern of change in mechanical allodynia occurring after nerve damage.

[0017] Figure 3 shows the results of changes in mechanical allodynia over time after administration of botulinum toxin type E.

[0018] Figure 4 shows the long-term change pattern of mechanical allodynia after administration of botulinum toxin type E.

[0019] Figure 5 shows the pattern of change in mechanical allodynia occurring after inferior alveolar nerve injury.

[0020] Figure 6 shows the results of NLRP3 changes that occur during inferior alveolar nerve damage.

[0021] Figure 7 shows the results of changes in the concentrations of IL-1β, IL-6, IL-18, and TNF-α in the trigeminal ganglion after inferior alveolar nerve injury.

[0022] Figure 8 shows the results of changes in HIF-1α in the trigeminal ganglion during inferior alveolar nerve injury.

[0023] Figure 9 shows the results of changes in mechanical allodynia over time after administration of botulinum toxin type E.

[0024] Figure 10 shows the results of changes in NLRP3 in the trigeminal ganglion after administration of botulinum toxin type E (10 U / kg).

[0025] Figure 11 shows the results of changes in cytokines concentration in the trigeminal ganglion after administration of botulinum toxin type E.

[0026] Figure 12 shows the results of changes in HIF-1α in the trigeminal ganglion after administration of botulinum toxin type E.

[0027] Figure 13 shows the results of changes in mechanical allodynia over time after administration of PX-478.

[0028] Figure 14 shows the results of changes in NLRP3 in the trigeminal ganglion after administration of PX-478.

[0029] Figure 15 shows the results of changes in cytokine concentration in the trigeminal ganglion after administration of PX-478.

[0030] Figure 16 shows the results of changes in mechanical allodynia over time after administration of botulinum toxin type A.

[0031] Figure 17 shows the long-term results of mechanical allodynia after administration of botulinum toxin type A.

[0032] Figure 18 shows the results of the analgesic action of Gabapentine administered intraperitoneally.

[0033] Figure 19 shows the long-term results of mechanical allodynia after Gabapentin administration.

[0034] The present invention provides a pharmaceutical composition for the prevention or treatment of neuropathic pain comprising botulinum toxin type E (BoNT-E) as an active ingredient, wherein the composition is characterized by having a shorter duration of effect compared to a composition comprising botulinum toxin type A (BoNT-A).

[0035] In the present invention, botulinum toxin refers not only to the neurotoxin produced by Clostridium botulinum, but also to botulinum toxin (or its light or heavy chain) recombinantly produced by non-Clostridium species. In the present invention, the botulinum strain may be Clostridium botulinum or a variant thereof, and preferably may be Clostridium botulinum toxin type E.

[0036] In the present invention, neuropathic pain refers to pain resulting from damage or functional abnormalities of the nervous system, and may be caused by specific diseases such as cancer, diabetes, and AIDS, or by unspecified risk factors such as old age, depression, nicotine addiction, obesity, and stress, or by physical damage to peripheral nerves. Furthermore, neuropathic pain is characterized by occurring due to abnormal activation in pain sensory nerve pathways of the peripheral and central nervous systems, and manifesting as acute or chronic pain.

[0037] In the present invention, the neuropathic pain may be acute pain or chronic pain. Acute pain as neuropathic pain refers to pain that persists for a relatively short period, caused by a situation in which a nerve is damaged or stimulated by trauma, surgery, infection, or acute disease; chronic pain as neuropathic pain refers to pain that persists for three months or more, caused by nerve damage, trauma, diabetes, neuritis, post-herpetic neuralgia, chronic neurological disease, etc. Acute and chronic pain as neuropathic pain differ depending on the duration and cause of the pain. Botulinum toxin type E used for the treatment of neuropathic pain in the present invention is suitable for alleviating and treating the phenomenon of acute pain, such as pain induced by inferior alveolar nerve damage, as neuropathic pain, due to its short duration of action following treatment, unlike botulinum toxin type A.

[0038] In the present invention, the neuropathic pain may be peripheral neuropathic pain or central neuropathic pain.

[0039] In the present invention, the neuropathic pain may be caused by damage to the inferior alveolar nerve. The neuropathic pain caused by damage to the inferior alveolar nerve refers to neuropathic pain resulting from damage to the trigeminal ganglion. According to one embodiment of the present invention, damage to the inferior alveolar nerve not only causes severe mechanical allodynia but also significantly increases the expression of HIF-1α, IL-1β, IL-6, IL-18, and TNF-α in the trigeminal ganglion on the 5th day after nerve damage.

[0040] In the present invention, the pharmaceutical composition may contain botulinum toxin type E in a specific amount. Specifically, the botulinum toxin type E may be included at a concentration of 1 to 10 U / kg, preferably at a concentration of 3 to 10 U / kg, and more preferably at a concentration of 6 to 10 U / kg, but is not limited thereto.

[0041] In the present invention, the term "short duration of effect" means that the duration of the effect after the initial administration of botulinum toxin type E is shorter than that of botulinum toxin type A. In the present invention, regarding the therapeutic effect of neuropathic pain, the effect of administering botulinum toxin type E may act for a shorter duration at a ratio of 1:2 to 1:3 compared to the effect of administering botulinum toxin type A, preferably at a ratio of 1:2.5 to 1:3, and more preferably at a ratio of 1:2.8 to 1:2.9, but is not limited thereto.

[0042] In the present invention, the botulinum toxin type E may inhibit the expression of one or more selected from the group consisting of NLRP3, IL-1β, IL-6, IL-18, TNF-α, and HIF-1α. The expression may increase due to nerve damage in the trigeminal ganglion.

[0043] The pharmaceutical composition of the present invention has use for the prevention and / or treatment of neuropathic pain. In the present invention, said pharmaceutical composition may be administered to an individual. For preventive use, the pharmaceutical composition of the present invention is administered to an individual who has the neuropathic pain of the present invention or is suspected of being at risk of developing it. For therapeutic use, the pharmaceutical composition of the present invention is administered in a sufficient amount to treat or at least partially stop the symptoms of the neuropathic pain of the present invention to an individual, such as a patient who is already suffering from the neuropathic pain of the present invention.

[0044] The pharmaceutical composition of the present invention may comprise a pharmaceutically effective amount of botulinum toxin type E alone or one or more pharmaceutically acceptable carriers. In this case, the pharmaceutically acceptable carrier is one that is commonly used in formulations and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, in addition to the above components, it may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc.

[0045] In the present invention, the term "administration" means introducing a pharmaceutical composition to an individual experiencing neuropathic pain. The pharmaceutical composition of the present invention may be administered in any suitable manner according to the intended method, but the administration may be parenteral. Preferably, the administration may be administered or locally in one or more selected from the group consisting of subcutaneous, intramuscular, intradermal, transdermal, and subcutaneous; more preferably, the administration may be administered subcutaneously; and even more preferably, the administration may be administered subcutaneously to the facial area, but is not limited thereto.

[0046] In the present invention, the pharmaceutical composition has a formulation and composition suitable for subcutaneous administration, which is a preferred example according to the administration of the present invention, and may be administered subcutaneously via an injection route, but is not limited thereto.

[0047] In the present invention, the individual may include, without limitation, mammals such as humans, primates including chimpanzees, dogs, cats, cattle, horses, sheep, goats, mice, and rats.

[0048] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the time, but can be appropriately selected by a person skilled in the art. Specifically, the pharmaceutical composition of the present invention may be administered in an amount of 1 to 10 U / kg, preferably in an amount of 3 to 10 U / kg, and more preferably in an amount of 6 to 10 U / kg, but is not limited thereto. However, since the dosage for a patient is determined by considering various factors such as the patient's age, gender, condition, weight, absorption rate, inactivation rate, and excretion rate of the active ingredient in the body, as well as the route of administration and frequency of administration, a person with ordinary knowledge in the art can determine an appropriate dosage of the pharmaceutical composition of the present invention; therefore, the above dosage does not limit the scope of the present invention in any way. Meanwhile, the "U (Unit)" is an amount of active botulinum toxin standardized to have a therapeutic effect for neuropathic pain equivalent to a Unit of commercially available botulinum toxin type E.

[0049] Meanwhile, the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art.

[0050] In addition, the present invention provides a surgical analgesic comprising botulinum toxin type E (BoNT-E) as an active ingredient, characterized by a shorter duration of effect compared to botulinum toxin type A (BoNT-A).

[0051] When used as a surgical analgesic containing the above-mentioned botulinum toxin type E as an active ingredient, administration can be selectively performed before, simultaneously with, or after the surgical procedure, taking into account the timing of rehabilitation along with the patient's rapid analgesic effect.

[0052] Additionally, supplementary administration may be included. Supplementary administration may include a physician's or patient's evaluation of the results of administering a surgical analgesic containing botulinum toxin type E as an active ingredient, and the supplementary administration method of the present invention is not limited in any way.

[0053] Meanwhile, among the components of the above-mentioned surgical analgesic, technical features that overlap with those described in the above-mentioned pharmaceutical composition are omitted from the description.

[0054]

[0055] Hereinafter, the present invention will be described in detail with reference to examples to aid in understanding. However, the following examples are merely illustrative of the content of the present invention and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0056]

[0057] Example 1. Preparation of an animal model of neuropathic pain and method for evaluating pain

[0058]

[0059] Mature white rats (SD) were used as experimental animals. In compliance with the ethical guidelines of the International Association for the Study of Pain regarding experiments on conscious animals, the second molars were extracted and implants were inserted after anesthesia with ketamine. The implants were inserted along the direction of the nerve fibers to induce damage to the inferior alveolar nerve, and the control group consisted of experimental animals in which only the second molars were extracted without implants.

[0060] After the experimental animals recovered following surgery, the occurrence of mechanical allodynia was observed using various methods starting from the third day after surgery.

[0061] To evaluate mechanical allodynia occurring in the maxillofacial region, the "Air Puffs Test" was conducted. In the Air Puffs Test, air stimulation was applied 10 times at 10-second intervals, and the animals' withdrawal behavioral responses were observed. The intensity of the air stimulation at which the rats bit or avoided the stimulation was used as the criterion for pain evaluation, and the stimulation threshold was assessed as the case where a response was observed in 50% or more of the total trials.

[0062]

[0063] Example 2. Administration of Botulinum Toxin Type E (BoNT-E) to an Animal Model of Neuropathic Pain

[0064]

[0065] Figure 2 shows the results of evaluating mechanical allodynia over time following inferior alveolar nerve injury. Mechanical allodynia occurred on the 1st day after nerve injury, showed characteristics of persistence for a long period thereafter, and then showed a pattern of recovery after 43 days after nerve injury.

[0066] Generally, experiments to observe analgesic effects are conducted between the 3rd day after nerve injury, when mechanical allodynia begins to appear at its maximum, and the 7th day, when pain persists.

[0067] Accordingly, in the present invention, botulinum toxin type E was administered on the third day after nerve injury to observe an analgesic effect.

[0068]

[0069] Example 3. Confirmation of the analgesic effect of botulinum toxin type E (BoNT-E)

[0070]

[0071] Example 3-1. Confirmation of the onset and duration of analgesic action of botulinum toxin type E (BoNT-E)

[0072] Figure 3 shows the results of observing changes in mechanical allodynia after administering botulinum toxin type E to the facial subcutaneous tissue, where pain is most severe starting from the third day after nerve injury.

[0073] As a result of administering botulinum toxin type E (6, 10 U / kg), mechanical allodynia was significantly suppressed (F(3, 24)=784.2, p<0.05), and the air stimulation threshold before administration of botulinum toxin type E was an average of 3.7±0.8, but increased to the cut-off value of 40 when botulinum toxin type E (10 U / kg) was administered.

[0074] An increase in the threshold of air stimulation implies a decrease in mechanical allodynia, which demonstrates that botulinum toxin type E exhibited analgesic effects.

[0075] These analgesic effects began to appear about 8 hours after administration of botulinum toxin type E, and when botulinum toxin type E was administered at a concentration of 10 U / kg, the analgesic effect disappeared 72 hours after administration, as shown in Figure 3. The average duration of the analgesic effect after a single administration was observed to be about 64 hours.

[0076]

[0077] Example 3-2. Determination of the optimal pain-inhibiting concentration of botulinum toxin type E (BoNT-E)

[0078] In Figure 3, the effect of botulinum toxin type E on mechanical allodynia was evaluated by administering it at three concentrations (2, 6, and 10 U / kg). No analgesic effect was observed at the 2 U / kg concentration, but significant analgesic effects were observed at both the 6 U / kg and 10 U / kg concentrations.

[0079] In particular, at a concentration of 10 U / kg, the analgesic effect tended to last longer.

[0080] Based on these results, it was confirmed that the optimal concentration for exhibiting the analgesic effect of botulinum toxin type E is at least 6 U / kg and 10 U / kg.

[0081]

[0082] Example 3-3. Confirmation of the long-term analgesic effect of botulinum toxin type E (BoNT-E) and its influence on pain recovery

[0083] After administering botulinum toxin type E on the 3rd day after nerve injury, a long-term observation was conducted to evaluate the effect of the analgesic effect on the long-term pain recovery time, and the results are shown in Figure 4.

[0084] When botulinum toxin type E was administered at a concentration of 10 U / kg, long-term observation confirmed that it did not have a significant effect on additional analgesic effects or pain recovery time.

[0085]

[0086] Example 4. Measurement of material changes in the trigeminal ganglion after inferior alveolar nerve injury

[0087]

[0088] Example 4-1. Evaluation of Neuropathic Pain Occurrence and NLRP3 Expression Following Inferior Alveolar Nerve Injury

[0089] After evaluating mechanical allodynia through the Air Puffs Test following inferior alveolar nerve injury, it was confirmed that inferior alveolar nerve injury causes severe mechanical allodynia in experimental animals (Fig. 5).

[0090] Mechanical allodynia occurred on the first day after nerve injury and subsequently showed characteristics of persistence for a long period, followed by a recovery pattern after 43 days after nerve injury.

[0091] Generally, experiments to observe analgesic effects are conducted between the 3rd day after nerve injury, when mechanical allodynia begins to appear at its maximum, and the 7th day, when pain persists.

[0092] In the present invention, after inducing nerve damage in experimental animals, on the 5th day when pain appeared stably, the experimental animals were anesthetized, the trigeminal ganglion area was collected, and NLRP3 expression was evaluated by Western blot analysis.

[0093] As a result, it was confirmed that inferior alveolar nerve injury not only causes severe mechanical allodynia but also significantly increases NLRP3 expression in the trigeminal ganglion on day 5 after nerve injury compared to the sham group (P<0.05, Fig. 6).

[0094]

[0095] Example 4-2. Evaluation of various cytokine changes in the trigeminal ganglion after inferior alveolar nerve injury

[0096] On the 5th day after inferior alveolar nerve injury, experimental animals were anesthetized, and the trigeminal ganglion area was collected to measure various cytokine concentrations using the ELISA method.

[0097] As a result, it was confirmed that the concentrations of IL-1β, IL-6, IL-18, and TNF-α on the 5th day after nerve injury were all significantly increased compared to the control group (P<0.05, Fig. 7).

[0098]

[0099] Example 4-3. Evaluation of HIF-1α changes in the trigeminal ganglion after inferior alveolar nerve injury

[0100] In addition to causing mechanical allodynia, inferior alveolar nerve injury was found to significantly increase the expression of HIF-1α in the trigeminal ganglion (P<0.05, Fig. 8).

[0101]

[0102] Example 5. Evaluation of the effect of botulinum toxin type E (BoNT-E) on inflammatory bodies and related substances altered after nerve injury

[0103]

[0104] Example 5-1. Confirmation of NLRP3 reduction in the trigeminal ganglion after administration of botulinum toxin type E (BoNT-E).

[0105] Changes in mechanical allodynia were observed after administering botulinum toxin type E into the facial subcutaneous tissue on the 3rd day after nerve injury. When botulinum toxin type E (10 U / kg) was administered, mechanical allodynia was significantly suppressed (F(3, 24)=784.2, P<0.05, Fig. 9).

[0106] These analgesic effects began to appear approximately 8 hours after administration of botulinum toxin type E, and when administered at a concentration of 10 U / kg, the analgesic effect subsided 72 hours after administration. The average duration of the analgesic effect after a single administration was found to be approximately 64 hours.

[0107] Trigeminal ganglion samples were collected within 48 hours after administration of botulinum toxin type E (10 U / kg) and NLRP3 expression was analyzed.

[0108] Botulinum toxin type E (10 U / kg) was administered on the 3rd day after nerve injury, and the experimental animals were anesthetized on the 5th day after nerve injury to collect the trigeminal ganglion. As a result, botulinum toxin type E was found to significantly inhibit NLRP3 expression in the trigeminal ganglion, which was increased due to nerve injury (P<0.05, Fig. 10).

[0109]

[0110] Example 5-2. Confirmation of Decrease in Cytokines in Trigeminal Ganglion After Administration of Botulinum Toxin Type E (BoNT-E)

[0111] Botulinum toxin type E (10 U / kg) was administered on the 3rd day after nerve injury, and on the 5th day after nerve injury, the experimental animals were anesthetized and the trigeminal ganglion area was collected and various cytokine concentrations were analyzed.

[0112] As a result, administration of botulinum toxin type E was found to significantly inhibit the concentrations of IL-1β, IL-6, IL-18, and TNF-α in the trigeminal ganglion, which were increased due to nerve damage (P<0.05, Fig. 11).

[0113]

[0114] Example 5-3. Evaluation of HIF-1α changes in the trigeminal ganglion after administration of botulinum toxin type E (BoNT-E).

[0115] Botulinum toxin type E (10 U / kg) was administered on the 3rd day after nerve injury, and on the 5th day after nerve injury, the experimental animals were anesthetized and the trigeminal ganglion area was collected to analyze HIF-1α expression.

[0116] As a result, administration of botulinum toxin type E was found to significantly suppress HIF-1α expression in the trigeminal ganglion, which is increased due to nerve damage (P<0.05, Fig. 12).

[0117]

[0118] Example 6. Correlation between changes in HIF-1α and cytokine secretion after nerve injury

[0119]

[0120] Example 6-1. Confirmation of regulation of NLRP3 after neurological injury by HIF-1α, which increases due to neurological injury

[0121] On the 5th day after nerve injury, PX-478, a HIF-1α inhibitor, was administered to the facial subcutaneous tissue to observe changes in mechanical allodynia.

[0122] As a result of administering PX-478 (0.5 or 1 μg / 3 uL), mechanical allodynia was significantly suppressed (F(2,16)=4664.481, P<0.05, Fig. 13).

[0123] The analgesic effect began to appear about 4 hours after administration of PX-478, and when administered at a concentration of 1 μg / 3 uL, the analgesic effect lasted for up to 8 hours after administration and then disappeared after 24 hours.

[0124] Trigeminal ganglion samples were collected within 5 hours of administering PX-478 (1 μg / 3 uL) and NLRP3 expression was analyzed.

[0125] When PX-478 (1 μg / 3 uL) was administered on day 5 after nerve injury and the trigeminal ganglion was collected 5 hours later, it was confirmed that PX-478 significantly inhibited NLRP3 expression, which was increased due to nerve injury (P<0.05, Fig. 14).

[0126]

[0127] Example 6-2. Confirmation of HIF-1α regulation of cytokine concentration after neurological injury

[0128] PX-478 (1 μg / 3 uL) was administered on the 5th day after nerve injury, and the trigeminal ganglion area was collected 5 hours later to analyze cytokine concentration.

[0129] PX-478 administration was found to significantly inhibit the expression of IL-1β, IL-6, IL-18, and TNF-α, which are increased due to nerve damage (P<0.05, Fig. 15).

[0130]

[0131] The botulinum toxin type E (BoNT-E) of the present invention has been confirmed to exhibit analgesic effects by significantly suppressing neuropathic pain and to effectively regulate inflammatory and molecular changes such as NLRP3, cytokine, and HIF-1α after nerve injury.

[0132]

[0133] Comparative Example 1. Confirmation of the analgesic effect of botulinum toxin type A (BoNT-A)

[0134]

[0135] Comparative Example 1-1. Confirmation of the onset and duration of analgesic action of Botulinum Toxin Type A (BoNT-A)

[0136] Figure 16 shows the change in mechanical allodynia over time after administering botulinum toxin type A on the 3rd day after nerve injury.

[0137] When botulinum toxin type A was administered at concentrations of 2, 6, and 10 U / kg, no analgesic effect was observed at a concentration of 2 U / kg, but significant analgesic effects were confirmed at concentrations of 6 U / kg and 10 U / kg (F(3,24)=8569.1, P<0.05).

[0138] In particular, when administered at a concentration of 10 U / kg, the analgesic effect tended to last longer.

[0139] When botulinum toxin type A was administered at a concentration of 10 U / kg, the analgesic effect began to appear about 8 hours after administration, and the duration of the effect lasted up to 192 hours after administration.

[0140] On average, the duration of the analgesic action of botulinum toxin type A was observed to be about 180 hours. The duration of the analgesic effect of botulinum toxin type A was longer compared to botulinum toxin type E, but the time to onset of effect was found to be similar.

[0141]

[0142] Comparative Example 1-2. Confirmation of the long-term analgesic effect of botulinum toxin type A (BoNT-A) and its influence on pain recovery

[0143] Long-term observation was conducted to evaluate whether the analgesic effect resulting from the administration of botulinum toxin type A at a concentration of 10 U / kg affects the time to recover from pain.

[0144] As a result, it was confirmed that botulinum toxin type A did not show additional analgesic effects in long-term observation and did not have a significant effect on pain recovery time (Fig. 17).

[0145]

[0146] Comparative Example 2. Confirmation of analgesic effect according to existing drugs

[0147]

[0148] Comparative Example 2-1. Evaluation of the pain-inhibiting effect of Gabapentin

[0149] Changes in neuropathic pain were observed after administering Gabapentin, known as a neuropathic pain suppressant, on the 3rd day after nerve injury (F(2,18)=173.2, P<0.05, Fig. 18). Gabapentin was administered intraperitoneally at concentrations of 30 mg / kg and 100 mg / kg, and an analgesic effect was confirmed at both concentrations.

[0150] When administered at a concentration of 30 mg / kg, the analgesic effect began to appear approximately 2 hours after administration and subsided after about 6 hours. When administered at a concentration of 100 mg / kg, the analgesic effect appeared approximately 2 hours after administration and lasted for about 8 hours. It also exhibited a stronger analgesic effect than the 30 mg / kg concentration.

[0151] Compared to botulinum toxin type E, Gabapentin was evaluated as having relatively lower efficiency due to the short duration of its analgesic effect after a single administration.

[0152]

[0153] Comparative Example 2-2. Confirmation of the long-term analgesic effect of Gabapentin and its influence on pain recovery

[0154] A long-term observation was conducted to evaluate whether the analgesic effect of Gabapentin affects the time to recover from pain. The results of the observation confirmed that Gabapentin did not have a significant effect on the time to recover from pain (Fig. 19).

[0155]

[0156] Foregoing, specific parts of the present invention have been described in detail. It will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for the prevention or treatment of neuropathic pain comprising botulinum toxin type E (BoNT-E) as an active ingredient, wherein the composition is characterized by having a shorter duration of effect compared to that comprising botulinum toxin type A (BoNT-A).

2. In Paragraph 1, The above pharmaceutical composition is characterized by being administered to an individual.

3. In Paragraph 2, A pharmaceutical composition characterized in that the above administration is parenteral administration.

4. In Paragraph 2, A pharmaceutical composition characterized by administering the above-mentioned administration to one or more selected from the group consisting of subcutaneous, intramuscular, intradermal, and transdermal.

5. In Paragraph 4, A pharmaceutical composition characterized by the above administration being administered subcutaneously.

6. In Paragraph 5, A pharmaceutical composition characterized by the above administration being administered subcutaneously to the facial area.

7. In Paragraph 2, A pharmaceutical composition characterized in that the above administration is performed by injection.

8. In Paragraph 1, A pharmaceutical composition characterized by having a shorter duration of effect at a ratio of 1:2 to 1:3 compared to a composition containing botulinum toxin type A.

9. In Paragraph 1, A pharmaceutical composition characterized by the above-mentioned duration of effect being calculated from the time of effect manifestation.

10. In Paragraph 1, A pharmaceutical composition characterized in that the above-mentioned neuropathic pain is peripheral neuropathic pain or central neuropathic pain.

11. In Paragraph 1, A pharmaceutical composition characterized in that the above-mentioned neuropathic pain is acute pain or chronic pain.

12. In Paragraph 1, A pharmaceutical composition characterized by the above-mentioned neuropathic pain being caused by damage to the inferior alveolar nerve.

13. In Paragraph 1, A pharmaceutical composition characterized by containing the above-mentioned botulinum toxin type E at a concentration of 1 to 10 U / kg.

14. In Paragraph 1, A pharmaceutical composition characterized by the above botulinum toxin type E inhibiting the expression of one or more selected from the group consisting of NLRP3, IL-1β, IL-6, IL-18, TNF-α, and HIF-1α.

15. In Paragraph 14, A pharmaceutical composition characterized by the above expression increasing due to nerve damage in the trigeminal ganglion.

16. A surgical analgesic containing botulinum toxin type E (BoNT-E) as an active ingredient, characterized by a shorter duration of effect compared to botulinum toxin type A (BoNT-A).

17. In Paragraph 16, The above analgesic is characterized by having a shorter duration of effect at a ratio of 1:2 to 1:3 compared to botulinum toxin type A.

18. In Paragraph 16, An analgesic characterized by containing the above-mentioned botulinum toxin type E at a concentration of 1 to 10 U / kg.

19. In Paragraph 16, The above effect is an analgesic characterized by reducing neuropathic pain.

20. In Paragraph 16, An analgesic characterized by the above-mentioned duration of effect being calculated from the time of effect manifestation.

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