Pharmaceutical use for magnesium compound

Abstract

Provided is a treatment effective for skeletal muscle cramps.　The present invention relates to a pharmaceutical composition for transdermal administration that is to be used in the prevention, suppression, or treatment of muscle cramps, and that is easy and simple to employ, has superior effects, and contains a magnesium compound.

Description

Medicinal uses of magnesium compounds

[0001] This patent application claims priority under the Paris Convention and the benefit of Japanese Patent Application No. 2024-122306 (filed July 29, 2024), and priority under Article 41 of the Japanese Patent Act, the entire contents of which are incorporated herein by reference.

[0002] The present invention generally relates to the field of treatment for skeletal muscle spasms. Specifically, the present invention relates to a pharmaceutical composition for transdermal administration containing a magnesium compound, which can treat muscle spasms easily, conveniently, and effectively.

[0003] The phenomenon of muscle cramping during exercise, commonly referred to as "muscle cramps" or "muscle cramps," is a serious problem for many athletes. Muscle cramps are thought to occur when muscles continue to contract without relaxing. Possible causes of exercise-induced muscle cramps include electrolyte imbalance due to dehydration and abnormal neural control (Non-Patent Document 1). However, these mechanisms are merely hypotheses, and no clear evidence has been obtained. If the mechanism of muscle cramps is electrolyte imbalance, it is likely to cause abnormalities in muscle membrane excitability. Muscle membrane potential is determined by the ionic composition inside and outside the cell, with potassium and chloride ions playing a particularly important role in relaxation.

[0004] Magnesium has been proposed as potentially effective for exercise-induced pain. For example, Non-Patent Document 2 demonstrates the usefulness of transdermal administration of magnesium oil spray to patients with lower back pain. The formulation used here is an oil-based spray, and the target patients are those with lower back pain. Non-Patent Document 3 also demonstrates that iontophoresis of magnesium sulfate improves pain levels, range of motion in the neck, and neck function. The method used here involves forcibly administering magnesium sulfate using electromotive force, and the disease being evaluated is ultimately pain.

[0005] Maughan & Shirreffs 2019 Sports MedJournal of Cardiovascular Disease Research VOL14, ISSUE 06, 2023Journal of Taibah University Medical Sciences Volume 16, Issue 3, June 2021, Pages 369-378

[0006] The mechanism of muscle spasms is unclear, and therefore, several drug therapies for muscle spasms have been proposed. However, all of them have drawbacks, such as high drug costs and complicated administration methods. The present invention provides an effective treatment for skeletal muscle spasms.

[0007] The present inventors have conducted extensive research and have discovered a pharmaceutical agent that is easy and simple to administer and highly effective for use in the prevention, suppression or treatment of muscle spasms.

[0008] Accordingly, the present invention includes the following aspects. [1] A pharmaceutical composition for transdermal administration containing a pharmaceutically effective amount of a bioavailable magnesium compound for preventing, suppressing, or treating muscle spasms. [2] The pharmaceutical composition of [1], wherein the magnesium compound is a magnesium salt, for example, an inorganic magnesium salt and / or an organic magnesium salt, preferably an inorganic magnesium salt, more preferably magnesium chloride. [3] The pharmaceutical composition of [1] or [2], wherein the magnesium compound is magnesium chloride hexahydrate. [4] The pharmaceutical composition of any of [1] to [3], wherein the pharmaceutically effective amount of the magnesium compound is 0.5% or more and less than 99%, preferably 10% or more and less than 99%.

[0009] [5] The pharmaceutical composition according to any one of [1] to [4], for preventing, suppressing, or treating recurrent and / or idiopathic muscle cramps. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the muscle cramps include skeletal muscle cramps. [7] The pharmaceutical composition according to any one of [1] to [6], wherein the skeletal muscle cramps are cramps of the limbs, such as the legs, feet, and hands. [8] The pharmaceutical composition according to any one of [1] to [7], for increasing the muscle cramp threshold. [9] The pharmaceutical composition according to any one of [1] to [8], which is aqueous.

[10] The pharmaceutical composition according to any one of [1] to [9], further comprising water and / or ethanol.

[0010] The pharmaceutical composition for transdermal administration containing the magnesium compound of the present invention can increase maximum muscle strength. The maximum muscle strength-promoting effect of the pharmaceutical composition for transdermal administration containing the magnesium compound of the present invention is maintained even during moderate-intensity endurance exercise, allowing the patient to maintain final spurt power in athletic competitions. The pharmaceutical composition for transdermal administration containing the magnesium compound of the present invention can reduce the occurrence of exercise-associated muscle cramps, known as "cramps." Furthermore, the pharmaceutical composition for transdermal administration containing the magnesium compound of the present invention is also effective against muscle cramps associated with endurance exercise.

[0011] Figure 1A is a schematic diagram showing the drug-treated and untreated legs in an in vivo contraction model experiment. Figure 1B is a photograph of the actual treatment scene. Figure 2 shows the overall changes in torque and fade before and after fatigue induction in an in vivo contraction model experiment. Figure 2A is a graph showing the relationship between torque and stimulation frequency for the untreated (NT) and treated (T) legs before fatigue induction (Rest). Figure 2B is a graph showing the relationship between torque and stimulation frequency for the untreated (NT) and treated (T) legs immediately after fatigue induction (Fatigue). Figure 2C is a graph showing the change in fade, an index of membrane excitability, before and after fatigue induction. *P<0.05. ****P<0.0001. Figure 3 shows the overall changes in torque during fatigue induction in an in vivo contraction model experiment. Figure 3A is a graph showing torque at each time point during fatigue induction for the intact leg (NT) and the treated leg (T), and Figure 3B is the tension time integral during fatigue induction for the intact leg (NT) and the treated leg (T). ****P<0.0001. Figure 4 shows the overall change in torque before and after fatigue induction during endurance exercise. Figure 4A is a graph comparing the torque exerted by the intact leg (NT) and the treated leg (T) before fatigue induction (Rest), and Figure 4B is a graph comparing the torque exerted by the intact leg (NT) and the treated leg (T) immediately after fatigue induction (Fatigue). *P<0.05. ****P<0.0001. Figure 5 shows the overall change in torque during fatigue induction during endurance exercise. Figure 5A is a graph showing torque at each time point during fatigue induction for the intact leg (NT) and the treated leg (T), and Figure 3B is the voltage required to generate an action potential for the intact leg (NT) and the treated leg (T). AP threshold refers to the muscle action potential (threshold).

[0012] In one aspect, the present invention relates to a transdermal pharmaceutical composition containing a pharmaceutically effective amount of a bioavailable magnesium compound for preventing, suppressing, or treating muscle spasms. As mentioned above, Non-Patent Document 2 demonstrates the usefulness of transdermal administration of magnesium oil spray to patients with lower back pain, but the target patients are those with lower back pain. Furthermore, Non-Patent Document 3 demonstrates that iontophoresis of magnesium sulfate improves pain level, neck range of motion, and neck function, but the disease evaluated is pain. Thus, there has been no evidence to date that magnesium compounds are involved in muscle spasms.

[0013] In the present invention, "bioavailable magnesium compound" means any form of magnesium compound that can be absorbed through the skin into the muscles and that provides the effect of preventing, suppressing or treating muscle spasms without causing serious side effects.

[0014] As shown in the examples herein, it has been found that the magnesium compound of the present invention increases torque (contractile force) by 10% with a large electrical stimulus. A 10% increase in torque means a 10% increase in explosive power, i.e., a 10% increase in explosive athletic performance. A "10% increase in athletic performance" means, for example, running the 100-meter dash in 9 seconds instead of 10 seconds, or lifting 110 kg instead of 100 kg.

[0015] In actual sports situations, high intensity can only be sustained for a short period of time, so it is often explosive exercise, while moderate intensity can be sustained for a relatively long period of time, so it is often endurance exercise. For this reason, while top athletes are capable of high-intensity endurance exercise, it is said to be physically impossible for many people. Generally, high-intensity exercise is exercise at an intensity of at least 80%, while moderate-intensity endurance exercise refers to endurance exercise (exercise of 30 minutes or more) performed at a moderate intensity (around 60% to 80% exercise intensity).

[0016] The magnesium compound is specifically a magnesium (Mg) salt, for example, an inorganic magnesium salt and / or an organic magnesium salt. Inorganic magnesium salts include magnesium sulfate, magnesium lactate, magnesium oxide, magnesium bicarbonate, magnesium phosphate, and magnesium chloride. Preferably, the inorganic magnesium salt is magnesium chloride, more preferably magnesium chloride hexahydrate. Organic magnesium salts include magnesium aspartate, alginate, ascorbate, citrate, gluconate, lactate, picolinate, taurate, glycerophosphate, bisglycinate, malate, and picolinate.

[0017] The pharmaceutically effective amount of the magnesium compound in the pharmaceutical composition is sufficient if it is 0.5% by weight or more, preferably 3% by weight or more, for example, 0.5% by weight or more but less than 99% by weight, preferably 10% by weight or more but less than 99% by weight, more specifically, 20% by weight or more but less than 80% by weight, for example, 30% by weight or more but less than 70% by weight, 40% by weight or more but less than 60% by weight, or 45% by weight or more but less than 55% by weight. When the pharmaceutical composition of the present invention is in the form of a patch or a poultice, the pharmaceutically effective amount of the magnesium compound in the pharmaceutical composition is preferably 0.5% by weight or more but less than 5% by weight.

[0018] In the present invention, "muscle cramp" refers to a spasm of a skeletal muscle, and can occur, for example, throughout the body, e.g., in the limbs, including the hands, feet, arms, and legs. In one embodiment, the pharmaceutical composition of the present invention is used to suppress or treat recurrent and / or sudden muscle cramps. In the present invention, "recurrent muscle cramp" refers to muscle cramps that occur frequently, e.g., at least three times a month, at least once a week, or even more frequently, e.g., nearly every day or nearly every night. Suppression or treatment in this embodiment involves regular administration, which can prevent or at least significantly suppress the occurrence of recurrent muscle cramps. In the present invention, "spontaneous muscle cramp" refers to muscle cramps that suddenly occur during exercise or during normal activity. In the present invention, sudden muscle cramps during exercise are particularly effective.

[0019] In the present invention, "preventing, suppressing, or treating muscle cramps" preferably means "increasing the muscle cramp threshold." In the present invention, "increasing the muscle cramp threshold" means that muscles have a certain threshold at which they will cramp when stimulated, that is, a value below which stimulation will not cause muscle cramps, and by increasing this threshold, the frequency of muscle cramp induction is reduced. This can result in the prevention and / or suppression of muscle cramps.

[0020] As used herein, "prevention" refers to any action taken to prevent, i.e., avoid, the onset of a muscle spasm or condition, and any action taken to counteract or prevent its onset. As used herein, "treatment" refers to a method or process intended to (1) delay the onset of a muscle spasm or condition; (2) slow or stop the progression, worsening, or deterioration of the symptoms of a muscle spasm or condition; (3) bring about the amelioration of the symptoms of a muscle spasm or condition; or (4) cure a muscle spasm or condition. Treatment may be administered prior to the onset of a muscle spasm or condition as a preventative measure, or alternatively, treatment may be administered after the onset of a muscle spasm.

[0021] In one embodiment, the pharmaceutical composition of the present invention is for transdermal administration. "Transdermal administration" refers to the application of a composition containing a suitable compound for preventing, suppressing, or treating muscle spasms to the skin, allowing the compound to reach the skeletal muscle. "Subcutaneous" refers to the application of a composition containing a suitable compound to the epidermis and the layer below the dermis. "Intradermal" refers to the application of a composition containing a suitable compound in the dermis or subcutaneous layer. In cases where muscle spasms are severe, it may be envisioned to inject a composition containing a suitable compound into the affected area where the spasms are severe.

[0022] In another embodiment, the pharmaceutical composition of the present invention is aqueous. "Aqueous" means a state in which the ingredients are dissolved or suspended in an aqueous medium such as an aqueous solution containing water, methanol, ethanol, polyethylene glycol, sugars, etc. The aqueous medium may generally contain, in addition to pure water, saline, an aqueous buffer solution, a small amount of lower alcohols, antioxidants, preservatives, etc. as needed. In other words, the present invention relates to an aqueous pharmaceutical composition for transdermal administration.

[0023] Specific examples of dosage forms of pharmaceutical compositions for transdermal administration include, but are not limited to, solutions, suspensions, patches, poultices, and injections. These preparations can be manufactured by known methods using additives commonly used as pharmaceutical additives. These additives can include solubilizers, solubilizers, thickeners, dispersants, stabilizers, and the like, depending on the purpose. Preferably, the formulation can further contain water, physiological saline, Ringer's solution, and / or ethanol.

[0024] In another aspect, the present invention relates to a method for preventing, suppressing, or treating muscle spasms, comprising administering a pharmaceutically effective amount of a bioavailable magnesium compound to a subject in need of such treatment. In yet another aspect, the present invention relates to a pharmaceutically effective amount of a bioavailable magnesium compound for preventing, suppressing, or treating muscle spasms. In yet another aspect, the present invention relates to the use of a pharmaceutically effective amount of a bioavailable magnesium compound for the manufacture of a medicament for preventing, suppressing, or treating muscle spasms.

[0025] The present invention will be described in detail below with reference to examples. However, it should be noted that these examples do not limit the scope of the present invention and are merely illustrative.

[0026] The present invention will be described in detail below with reference to examples. However, it should be noted that these examples do not limit the scope of the present invention and are merely illustrative.

[0027] Example 1 Preparation of magnesium chloride aqueous solution 50 g of magnesium chloride hexahydrate (Kishida Chemical) was dissolved in purified water, and the solution was diluted to 100 mL to prepare a 50% magnesium chloride aqueous solution.

[0028] Example 2 Effect of magnesium chloride aqueous solution on exercise-induced muscle spasm An in vivo contraction model experiment was carried out using 12-week-old male Wistar rats (CLEA Japan) as test animals.

[0029] 2-1: Experimental Protocol: 1) Under anesthesia, rats were shaved around the triceps surae muscle and wiped with alcohol. One leg of each rat was immersed in the 50% magnesium chloride aqueous solution prepared in Example 1 (treated leg (T)), and the other leg was immersed in MilliQ water (untreated leg (NT)). The treated leg was determined randomly. There were six rats per group. 2) After 30 minutes of rest, surface electrodes were attached to each leg. 3) Electrical stimulation was applied to the leg immersed in the 50% magnesium chloride aqueous solution (treated leg (T)) and the other leg immersed in MilliQ water (untreated leg (NT)). Muscle contraction force (torque) and fade at maximum contraction (an index of membrane excitability) were measured at each stimulation frequency. 4) Both legs were subjected to fatigue contractions to induce muscle fatigue. 5) Immediately after fatigue induction, measurements in 3) were repeated.

[0030] 2-2: Electrical stimulation protocol: 1) Muscle contraction force (torque) at each stimulation frequency. Each stimulation frequency: Instructed Hz, 1 ms pulse width, 1.5 s contraction, 50 V. 2) Fatigue contraction: 100 Hz, 0.5 ms pulse width, 0.35 s contraction, every 1 s, 50 V, 5 min. 3) Fade: 100 Hz, 5 ms pulse width, 3 s contraction, 50 V. The decrease in tension from 0.5 s to 2.5 s after the start of contraction was calculated as the value divided by the maximum tension.

[0031] Figure 2 shows the changes in torque and fade before and after fatigue induction. Figure 2A shows the difference in torque before fatigue induction (Rest), and Figure 2B shows the difference in torque immediately after fatigue induction (Fatigue). The torques in the untreated leg (NT) and the treated leg (T) are indicated by "open circles" and "black circles," respectively, when small stimuli ranging from 1 Hz to large stimuli of 100 Hz are applied. Differences between the untreated and treated groups at each Hz are evident. In both Figures 2A and 2B, significant differences are observed with increasing stimuli (Hz) up to approximately 60 Hz. Specifically, Figures 2A and 2B show that torque (contractile force) plateaus near 60 Hz, indicating that maximum muscle force is reached at approximately 60 Hz. Figure 2A shows that the torque of the treated leg (T) increased by 13.0% at 60 Hz, 12.9% at 80 Hz, and 11.7% at 100 Hz compared to the torque of the untreated leg (NT) (percentages are averages for six animals). Generally, treatment increased torque (contractile force) by more than 10%. A 10% increase in torque corresponds to a 10% increase in explosive power, i.e., a 10% increase in explosive motor performance. Compared to the untreated group, the treated group exhibited greater instantaneous muscle contraction torque (contractile force), suggesting improved short-term motor performance.

[0032] Figure 2C shows the change in fade, an index of membrane excitability, before and after fatigue induction. Fade is the rate of torque decline during strong contractions. At fatigue, fade tended to be lower in the T-leg, i.e., a decline in fade was observed. Fade is a decrease in muscle contraction torque, or attenuation of force, due to fatigue. In other words, the "decrease in fade" observed here means that the torque of muscle contraction is maintained (not decreased) and is not attenuated. This indicates that attenuation of muscle contraction is less likely to occur in the T-leg, even during cramps with continued muscle contraction.

[0033] Figure 3 shows the change in torque during fatigue induction. Figure 3A shows that the T-leg exhibited higher torque than the NT-leg 1 second after the onset of contraction, but no change was observed after 10 seconds. Figure 3A shows that the initial effect of contraction onset is lost over time. Figure 3B shows the tension-time integral (impulse: area under the curve) during fatigue induction. Impulse reflects the amount of work performed during fatigue induction, and the T-leg was able to perform more work. This suggests that, when applied to sports situations, treatment can enable a higher exercise volume to be achieved within the same exercise duration.

[0034] Considering that maximal muscle force exertion results in a high neural firing rate, an increase in high-frequency evoked torque corresponds to an increase in maximal muscle force. The significant increase in high-frequency evoked torque at 40 Hz to 100 Hz at rest in the T-leg (Figure 2A) suggests that 50% magnesium chloride solution is effective in enhancing maximal muscle force at rest. However, no change was observed in torque evoked by low-frequency stimulation at 1 Hz or 10 Hz (low-frequency evoked torque) (Figure 2A, B). This suggests that the treatment may not be effective during submaximal muscle force exertion. Fade, an index of membrane excitability, tended to increase after fatigue with 50% magnesium chloride solution treatment. In an inappropriate experimental system, fade may not increase after fatigue, meaning that the duration of muscle contraction cannot be measured. However, the significant increase in fade after fatigue with this method suggests that there are no major problems with the measurement method itself. The lack of a statistically significant difference may be due to insufficient changes in membrane excitability to be detected by this method. Fatigue induction abolished the effect of treatment with 50% magnesium chloride solution on the high-frequency-induced torque increase (Figure 2B). In other words, while a difference between NT and T was observed at 40 Hz–100 Hz in Figure 2A, this difference disappeared in Figure 2B. This suggests that the effect of 50% magnesium chloride solution is lost during intense exercise. Results may differ depending on whether the fatigue contraction protocol is changed to an endurance exercise format. The increase in muscle force at the beginning of the fatigue contraction increased impulse during fatigue induction (Figure 3B). This indicates that application of 50% magnesium chloride solution increased exercise volume and thus improved overall exercise performance.

[0035] In conclusion, treatment with 50% magnesium chloride solution can increase maximal muscle strength, likely through increased membrane excitability, but this improvement is lost during strenuous exercise.

[0036] Example 3: Effect of magnesium chloride solution on endurance exercise-induced muscle spasms. Similar to Example 2, 12-week-old male Wistar rats (CLEA Japan) were used as test animals. An in vivo contraction model experiment was conducted using a fatigue stimulus at a frequency of 40 Hz for 30 minutes. 3-1: Experimental Protocol: 1) Under anesthesia, one leg of the rat was shaved, wiped with alcohol, and immersed in 50% magnesium chloride solution. The contralateral leg served as a control. Each group consisted of nine rats. 2) After 30 minutes of immersion under rest, surface electrodes were attached to each leg. 3) Electrical stimulation was applied to the 50% magnesium chloride solution-immersed leg or the control leg, and muscle contraction force was measured at each stimulation frequency. 4) The action potential generation threshold was measured. 5) A fatigue contraction was applied to induce muscle fatigue. 6) Immediately after fatigue, measurements in 3) were repeated.

[0037] 3-2: Electrical stimulation protocol: 1) Muscle contraction force (torque) at each stimulation frequency: Each stimulation frequency: Instructed Hz, 1 ms pulse width, 1.5 s contraction, 50 V. 2) Fatigue contraction: 40 Hz, 0.5 ms pulse width, 0.35 s contraction, every 5 s, 50 V, 30 min. 3) Action potential generation threshold: Stimulation was performed at 1 Hz, 1 ms pulse width, and the minimum voltage required for contraction was measured.

[0038] The changes in torque before and after fatigue induction during endurance exercise are shown in Figure 4. Figure 4 shows that the high-frequency induced torque increased in the treated leg (T) compared with the intact leg (NT), and this effect was maintained even after the fatigue contraction.

[0039] Figure 5 shows the torque changes during fatigue induction during endurance exercise. Figure 5 shows that there was no difference in torque changes during fatigue contractions between the NT and T legs. However, the voltage required to generate an action potential increased in the T leg (Figure 5B). This suggests that the T leg requires a higher voltage to generate an action potential.

[0040] In Example 2, during high-intensity exercise for approximately 5 minutes (2-2: Electrical Stimulation Protocol: 2) fatigue contraction, 100 Hz, 0.5 ms pulse interval, 0.35-second contraction, every 1 second, 50 V, 5 minutes), the effect of 50% magnesium chloride solution, i.e., the increase in high-frequency (60-100 Hz) induced torque, was lost upon fatigue. Generally, high-intensity exercise is defined as exercise at an intensity of at least 80%. In this case, the torque exerted at 100 Hz was classified as high-intensity exercise because it was nearly 100% of maximum muscle strength. In this experiment, moderate-intensity endurance exercise was examined, and the results showed that the effect of 50% magnesium chloride solution was maintained (Figures 4A and 4B). Moderate-intensity endurance exercise refers to endurance exercise (exercise of 30 minutes or more) performed at a moderate intensity (approximately 60-80% exercise intensity). Therefore, the effect of 50% magnesium chloride solution was not lost for at least 30 minutes (3-2: Electrical Stimulation Protocol: 2) Fatigue Contraction 40 Hz, 0.5 ms interpulse interval, 0.35 sec contraction, 5 sec per contraction, 50V, 30 minutes) unless contractions were repeated at maximum force (Fig. 4B). In actual sports situations, this would be effective in the final sprint.

[0041] Furthermore, the results of this study revealed that the voltage required to generate an action potential increased in the 50% magnesium chloride aqueous solution-treated leg (Figure 5B). This suggests that treatment with 50% magnesium chloride aqueous solution stabilizes the membrane and prevents excessive contraction. In other words, muscle contraction begins with the generation of an action potential. The increase in voltage required to generate an action potential, as observed in the T-leg in this study, suggests that a stronger membrane depolarization is required. This means that even a weak depolarization will not generate an action potential and the muscle will not contract. It is believed that excessive contraction is due in part to the generation of an action potential in response to a weak depolarization. In the T-leg, such weak depolarizations are ignored, and the muscle responds only to strong depolarizations, preventing excessive contraction. This leads to the prevention of excessive muscle cramps. Applied to sports, this suggests that 50% magnesium chloride aqueous solution reduces the occurrence of exercise-associated muscle cramps.

[0042] In conclusion, the maximal muscle strength-promoting effect of 50% magnesium chloride solution is maintained even during moderate-intensity endurance exercise. Applied to athletic situations, this means that 50% magnesium chloride solution can maintain final spurt power. 50% magnesium chloride solution has the effect of stabilizing membranes and requiring stronger depolarization for membrane action potential generation. It is unclear whether this effect is the cause of increased maximal muscle strength, but it may be effective against muscle cramps associated with endurance exercise.

Claims

1. A pharmaceutical composition for transdermal administration containing a pharmaceutically effective amount of a bioavailable magnesium compound for preventing, suppressing or treating muscle spasms.

2. A pharmaceutical composition according to claim 1, wherein the magnesium compound is a magnesium salt, such as an inorganic magnesium salt and / or an organic magnesium salt, preferably an inorganic magnesium salt, more preferably magnesium chloride.

3. The pharmaceutical composition according to claim 2, wherein the magnesium compound is magnesium chloride hexahydrate.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically effective amount of the magnesium compound is 0.5% by weight or more but less than 99% by weight.

5. A pharmaceutical composition according to claim 1 for preventing, suppressing or treating recurrent and / or idiopathic muscle spasms.

6. The pharmaceutical composition of claim 1, wherein the muscle spasm includes skeletal muscle spasm.

7. The pharmaceutical composition of claim 6, wherein the skeletal muscle spasms are spasms of the extremities, such as legs, feet, and hands.

8. The pharmaceutical composition according to claim 1 for increasing the muscle spasm threshold.

9. The pharmaceutical composition of claim 1, which is aqueous.

10. The pharmaceutical composition of claim 1, further comprising water and / or ethanol.

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