Use of ligustrazine nitrone derivative in prevention or treatment of muscle strength reduction or functional loss caused by nerve injury

Abstract

The use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating muscle strength reduction or functional loss caused by nerve injury. The ligustrazine nitrone derivative has a structure as shown in the following general formula (I): (I), wherein R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or (II); R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl. The C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

Description

Application of ligustrazine nitrone derivatives in preventing or treating muscle strength loss or functional loss caused by nerve damage Technical Field

[0001] The present invention belongs to the field of biomedicine technology and relates to the use of ligustrazine nitrone derivatives or pharmaceutically acceptable salts thereof in preventing or treating muscle strength loss or function loss caused by nerve damage. Background Art

[0002] Muscle strength refers to the force that can be generated by one or more muscle groups. Muscle weakness caused by limited neuromuscular input or failure of signal transmission at the neuromuscular junction leads to many functional losses and increased mortality in motor neuron diseases. ALS is a disease characterized by progressive muscle strength loss or functional loss caused by obvious nerve damage. It usually begins with muscle twitching and weakness in the arms or legs, or slurred speech. Usually within three to five years after the onset of symptoms, the muscle capacity required to control movement, speaking, eating, and breathing is gradually lost, eventually paralyzing the muscles required for breathing, and the patient dies of respiratory failure. Throughout the course of the disease, the patient will always maintain clear consciousness and good skin sensation. This symptom is like a person being gradually frozen, and can only watch his or her body gradually die, but is powerless to do anything. Therefore, ALS is considered to be "a terminal illness more cruel than cancer."

[0003] Slowing down the progression of the disease is very important, and treatments that improve muscle function performance are also beneficial to patients. However, for muscle strength loss or functional loss caused by nerve damage (such as ALS), there are currently no drugs in clinical practice that can statistically improve the patient's muscle strength level. An article published by Mitsumoto H et al. in the top international academic journal "The Lancet Neurology" shows that in the past decade, at least 18 drugs have been tested in large-scale Phase II or Phase III clinical trials, but none of them showed positive results (Lancet Neurol. 2014 Nov; 13 (11): 1127-1138.). The reason is that at this stage we know very little about the pathogenic mechanism of this type of disease. In addition, animal models are usually difficult to simulate the patient's actual disease state. A large number of drugs that have certain efficacy in animal experiments have not shown efficacy in corresponding clinical studies, such as coenzyme Q10 (Kaufmann P, Thompson JL, Levy G, Buchsbaum R, Shefner J, Krivickas LS, Katz J, Rollins Y, Barohn RJ, Jackson CE, Tiryaki E, Lomen-Hoerth C, Armon C, Tandan R, Rudnicki SA, Rezania K, Sufit R, Pestronk A, Novella SP, Heiman-Patterson T, Kasarskis EJ, Pioro EP, Montes J, Arbing R, Vecchio D, Barsdorf A, Mitsumoto H, Levin B; QALS Study Group. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol. 2009 Aug; 66(2):235-44.); levomontracetam (Cudkowicz J). M,Genge A,Maragakis N,Petri S,van den Berg L,Aho VV,Sarapohja T, M, Garratt C, Al-Chalabi A; REFALS investigators. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2021 Oct; 20(10):821-831.), depramipexole (Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA; EMPOWER investigators. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2013 Nov; 12(11):1059-67.), pioglitazone (Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, Fischer W, Steiner F, Lindauer E, Otto M, Dreyhaupt J, Grehl T, Hermann A, Winkler AS, Bogdahn U, Benecke R, Schrank B, Wessig C, Grosskreutz J, Ludolph AC; GERP ALS Study Group. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One. 2012; 7(6):e37885.) Olanizumab (Meininger V, Genge A, van den Berg LH, Robberecht W, Ludolph A, Chio A, Kim SH, Leigh PN, Kiernan MC, Shefner JM, Desnuelle C, Morrison KE, Petri S, Boswell D, Temple J, Mohindra R, Davies M, Bullman J, Rees P, Lavrov A; NOG112264 Study Group. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017 Mar;16(3):208-216.), vitamin E (Graf M, Ecker D, Horowski R, Kramer B, Riederer P, Gerlach M, Hager C, Ludolph AC, Becker G, Osterhage J, Jost WH, Schrank B, Stein C, Kostopulos P, Lubik S, Wekwerth K, Dengler R, Troeger M, Wuerz A, Hoge A, Schrader C, Schimke N, Krampfl K, Petri S, Zierz S, Eger K, Neudecker S, Traufeller K, Sievert M,. B, Hecht M; German vitamin E / ALS Study Group. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm (Vienna). 2005 May; 112(5): 649-60.). The relevant Chinese Guidelines (2012 edition) and Expert Consensus (2022 edition) issued by the Chinese Society of Neurology clearly point out that in animal experiments, although a number of drugs have shown certain efficacy in the treatment of animal models, such as creatine, high-dose vitamin E, coenzyme Q10, lithium carbonate, ciliary neurotrophic factor, insulin-like growth factor, lamotrigine, etc., they have not been proven to be effective in clinical studies (Chinese Journal of Neurology, 2012, 45(7): 531-533; Chinese Journal of Neurology, 2022, 55(6): 581-588.).

[0004] Summary of the invention:

[0005] In order to solve the problems in the prior art, the present invention provides the use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating muscle strength loss or function loss caused by nerve damage.

[0006] The present invention provides a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof for use in preparing a medicament and in preventing or treating muscle strength loss or functional loss caused by nerve damage; the ligustrazine nitrone derivative has the following general formula (I):

[0007] Wherein, R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl. Preferably, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

[0008] According to one embodiment of the present invention, the ligustrazine nitrone derivative is nitrone oxazine or TN-2, and the structure is as follows:

[0009] The present invention provides a method for alleviating diseases related to muscle strength decline or function loss caused by nerve damage in patients, comprising administering a therapeutically effective amount of a ligustrazine nitrone derivative (such as nitrazine or TN-2) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0010] According to one embodiment of the present invention, the muscle strength loss or function loss caused by nerve damage is the muscle strength loss or function loss caused by ALS.

[0011] According to one embodiment of the present invention, the muscles with decreased muscle strength or function loss are biceps brachii, triceps brachii, deltoid, pectoralis major, forearm flexor muscles, thenar muscles, hypothenar muscles, tongue muscles, facial muscles, laryngeal muscles, neck muscles, trapezius muscles, sternocleidomastoid muscles, extensor digitorum communis, first interosseous muscles, abductor pollicis longus, abductor pollicis brevis, extensor digitorum indexis, thoracic paraspinal muscles, respiratory muscles, etc.

[0012] According to one embodiment of the present invention, the main symptoms of muscle strength decline or function loss caused by nerve damage are decreased ability in grip strength, speech, drooling, swallowing, handwriting, cutting food and using tableware, dressing and hygiene, dyspnea, orthopnea, and impaired respiratory function.

[0013] Muscle strength refers to the maximum force that can be generated by one or more muscle groups. Upper limb grip strength is widely recognized as an indicator of muscle strength. Grip strength is directly correlated with the biceps, triceps, deltoid, pectoralis major, forearm flexors, thenar, and hypothenar muscles. Furthermore, studies have demonstrated that grip strength is significantly correlated with parameters such as lower limb strength, quadriceps torque, and gastrocnemius muscle cross-sectional area, and is linearly correlated with the ability to perform activities of daily living. A handgrip dynamometer is the most commonly used tool for measuring grip strength.

[0014] The ligustrazine nitrone derivatives of the present invention can improve, maintain or slow down the deterioration of muscle strength (e.g., grip strength, bulbar function, respiratory function, etc.) in subjects with decreased muscle strength or functional loss due to nerve damage. In some embodiments, these methods can more significantly improve the subject's upper limb strength compared to other muscle groups.

[0015] Nerve damage may cause a decline in medullary function, mainly involving the tongue muscles, trapezius muscles, sternocleidomastoid muscles, etc., which may cause speech problems and dysphagia, which directly affects the patient's quality of life.

[0016] In terms of respiratory function, forced vital capacity (FVC), dyspnea, orthopnea and respiratory function impairment scores can be used to monitor the response of patients and / or subjects to treatment with decreased muscle strength or functional loss caused by nerve damage. The ligustrazine nitrone derivatives of the present invention can be used for the degeneration of respiratory muscle strength and / or deterioration of lung function caused by nerve damage. The method provided by the present invention can improve or maintain the respiratory muscle and / or lung function of the subject, or slow down the deterioration of the respiratory muscle and / or lung function of the subject. The respiratory muscle and / or lung function of the subject can be evaluated by any suitable method described herein or known in the art. For example, respiratory function scores (dyspnea, orthopnea, respiratory function impairment) and medullary function scores (speech, swallowing, drooling) can be assessed by the ALSFRS-R scale. ALSFRS-R is a scale for assessing ALS (rating 0-4) well known in the art, which is used to determine the subject's assessment of their ability and independence in their functional activities.

[0017] The present invention relates to the use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical preparation for preventing or treating decreased muscle strength or loss of function, characterized in that an oral preparation mainly composed of a ligustrazine nitrone derivative is administered in the form of a unit dose, and the amount of the ligustrazine nitrone derivative contained in the preparation can effectively treat, prevent, and prevent loss of muscle strength or function, reduce its risk, delay its occurrence and / or delay its progression, and the range is about 100-5000 mg of ligustrazine nitrone derivative per day, such as about 300-4000 mg of ligustrazine nitrone derivative per day, about 600-3000 mg of ligustrazine nitrone derivative per day, and about 1200-2400 mg of ligustrazine nitrone derivative per day.

[0018] According to one embodiment of the present invention, the pharmaceutically acceptable salt of the present invention can be a salt of a ligustrazine nitrone derivative formed with an acid, such as a salt formed with the following acid: hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecyl sulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

[0019] According to one embodiment of the present invention, the ligustrazine nitrone derivative (such as nitrone nitrone or TN-2) as an active pharmaceutical ingredient can be formulated into a pharmaceutical composition (pharmaceutical preparation) using a pharmaceutically acceptable carrier.

[0020] According to one embodiment of the present invention, the pharmaceutical composition is in any form suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration. Oral administration is preferred.

[0021] According to one embodiment of the present invention, the "acceptable carrier" is intended to be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

[0022] If appropriate, the formulation is preferably in discrete dosage units and can be prepared by any method well known in the pharmaceutical art. All methods comprise the steps of mixing the active ingredient with one or more pharmaceutically acceptable carriers and then, if necessary, forming the product into the desired formulation. The pharmaceutical composition can be formulated into the following dosage forms: tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, chewable tablets, sugar-coated tablets, effervescent tablets, drops, suspensions, rapidly dissolving tablets, rapidly dispersible orally tablets, sustained-release tablets, sustained-release capsules, enteric-coated tablets or capsules, etc.

[0023] According to one embodiment of the present invention, the desired dose of the oral pharmaceutical formulation of the present invention may be conveniently provided as a single dose per day or as divided doses administered at appropriate intervals (eg, two, three or more doses per day).

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not limiting.

[0025] As used herein, the terms "subject" and "patient" are used interchangeably. A subject or patient is a human patient or human subject. The terms "for example" and "such as" and their grammatical equivalents, unless expressly stated otherwise, should be understood to follow the phrase "without limitation" or "without limitation."

[0026] As used herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to that amount of an active compound or agent that elicits in a human the medical response that a physician or other clinician is seeking. A therapeutically or pharmaceutically effective amount of a compound is at least the minimum amount necessary to ameliorate, alleviate, palliate, delay, reduce, relieve, or cure a disease, disorder, or syndrome, or one or more of its symptoms, signs, or causes.

[0027] The term "treatment" encompasses therapeutic treatment of a patient already experiencing the condition in question. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of the specific indication, or causal treatment to reverse or partially reverse the condition of the indication or to halt or slow disease progression. Thus, the compositions and methods of the present invention can be used, for example, as therapeutic treatment over a period of time as well as for chronic treatment.

[0028] The terms "prophylactic treatment," "preventative therapy," and "prevention" are used interchangeably and include treating a patient at risk of developing the conditions described above, thereby reducing the risk. As used herein, the term "treating" also refers to delaying, ameliorating, or preventing the progression (i.e., the known or expected progression), severity, and / or duration of a disease due to the administration of one or more therapies; or delaying, ameliorating, or preventing the progression of one or more symptoms, clinical manifestations, observations, or measurements; or preventing or slowing a negative progression of a pathological assessment (i.e., "managing" rather than "curing" a condition). DETAILED DESCRIPTION

[0029] The present invention is described in detail below by way of specific examples. It is noted that the following examples are intended only to further illustrate the present invention and are not to be construed as limiting the scope of the present invention. Unless otherwise specified, all parts and percentages are by weight. In the examples of the present invention, n represents the number of subjects participating in the experiment.

[0030] Example 1 Clinical Trial

[0031] The present invention adopts a multi-center, randomized, double-blind, placebo parallel controlled design.

[0032] Test subjects: Patients who have been diagnosed with ALS (all signed informed consent forms).

[0033] Participants were randomly assigned (1:1:1) to receive nitrofentanolamine 600 mg, 1200 mg, or placebo twice daily for 180 days. A total of 148 subjects were included in the FAS set, of which 50 received placebo, 46 ​​received nitrofentanolamine 600 mg twice daily, and 52 received nitrofentanolamine 1200 mg twice daily.

[0034] The subjects' maximum grip strength was tested using an electronic handgrip dynamometer. The results showed that nitrazepam significantly improved grip strength in the subjects. The placebo group had a baseline of 16.13 kg, and after 180 days of treatment, the relative change was -7.60 kg. The 600 mg group had a baseline of 14.53 kg, and after 180 days of treatment, the relative change was -6.53 kg, a 13.95% improvement in the difference in the placebo group. The 1200 mg group had a baseline of 16.51 kg, and after 180 days of treatment, the relative change was -5.14 kg, a 32.37% improvement in the difference in the placebo group (p = 0.037).

[0035] In addition, trial results showed that nitrazepam also improved medullary and respiratory function in participants. For example, in the 1200mg group, the baseline medullary function score was 11.0 points in the placebo group, and the change from baseline after 180 days of treatment was -1.26 points. In the 1200mg group, the baseline was 11.4 points, and the change from baseline after 180 days of treatment was -1.12 points, an 11.11% improvement in the difference in change rate relative to the placebo group. In the respiratory function score, the baseline was 12.00 points in the placebo group, and the change from baseline after 180 days of treatment was -1.21 points. In the 1200mg group, the baseline was 12.00 points, and the change from baseline after 180 days of treatment was -0.96 points, an 20.66% improvement in the difference in change rate relative to the placebo group.

[0036] In the clinical trial, during the 12-week observation period before randomization, all subjects aged less than 65 years and whose ALSFRS-R score decreased by 1-2 points (≥1 and ≤2) had ALSFRS-R scores, forced vital capacity (%FVC), and muscle strength (grip strength) after 180 days of treatment as shown in Table 1 below, and bulbar function scores and respiratory function scores as shown in Table 2 below.

[0037] Table 1. ALSFRS-R score, forced vital capacity (%FVC) and muscle strength (grip strength)

[0038] As can be clearly seen in Table 1, nitrazepam significantly improved the subjects' ALSFRS-R scores, forced vital capacity (%FVC), and decreased muscle strength. Regarding the ALSFRS-R score, the placebo group had a baseline score of 42.11, with a change of -5.72 points relative to baseline after 180 days of treatment. The 600 mg group had a baseline score of 42.40, with a change of -5.04 points relative to baseline after 180 days of treatment, an 11.89% improvement in the difference in the rate of change relative to the placebo group. The 1200 mg group had a baseline score of 42.30, with a change of -4.42 points relative to baseline after 180 days of treatment, an 22.90% improvement in the difference in the rate of change relative to the placebo group. In terms of forced vital capacity (%FVC), the baseline value of the placebo group was 99.48%, and the relative change from baseline after 180 days of treatment was -14.46%; the baseline value of the 600 mg group was 98.34%, and the relative change from baseline after 180 days of treatment was -10.16%, and the difference change rate relative to the placebo group increased by 29.67%; the baseline value of the 1200 mg group was 98.43%, and the relative change from baseline after 180 days of treatment was -9.06%, and the difference change rate relative to the placebo group increased by 37.25%. In terms of muscle strength (grip strength), the baseline value of the placebo group was 18.51 kg, and the relative change after 180 days of treatment was -7.24 kg; the baseline value of the 600 mg group was 17.03 kg, and the relative change after 180 days of treatment was -4.74 kg, and the difference change rate relative to the placebo group was increased by 34.67%; the baseline value of the 1200 mg group was 20.28 kg, and the relative change after 180 days of treatment was -3.62 kg, and the difference change rate relative to the placebo group was increased by 50.14% (p=0.011).

[0039] Table 2. Myelobulbar function score and respiratory function score

[0040] As can be clearly seen in Table 2, nitrazepam significantly improved the subjects' bulbar function and respiratory function scores. Regarding bulbar function, the placebo group had a baseline score of 11.0 points, and after 180 days of treatment, the relative change was -1.02 points. The 600 mg group had a baseline score of 11.1 points, and after 180 days of treatment, the relative change was -0.67 points, a 35.29% improvement in the difference between the two groups. The 1200 mg group had a baseline score of 11.4 points, and after 180 days of treatment, the relative change was -0.36 points, a 64.71% improvement in the difference between the two groups (p = 0.040). In terms of respiratory function, the baseline score of the placebo group was 12.00 points, and the relative change after 180 days of treatment was -0.71 points; the baseline score of the 600 mg group was 12.00 points, and the relative change after 180 days of treatment was -0.17 points, and the difference change rate compared with the placebo group increased by 76.06% (p = 0.040); the baseline score of the 1200 mg group was 12.00 points, and the relative change after 180 days of treatment was -0.11 points, and the difference change rate compared with the placebo group increased by 85.92% (p = 0.021).

[0041] In addition, compared to the placebo group, participants' writing and tableware use abilities also improved significantly. For example, the 1200mg group had a baseline score of 3.27 points in the placebo group, and a change of -0.61 points relative to baseline after 180 days of treatment. The 1200mg group had a baseline score of 3.38 points, and a change of -0.39 points relative to baseline after 180 days of treatment, representing a 36.07% improvement in the difference in change rate relative to the placebo group. Regarding food cutting and tableware use, the placebo group had a baseline score of 3.04 points, and a change of -0.94 points relative to baseline after 180 days of treatment. The 1200mg group had a baseline score of 3.04 points, and a change of -0.33 points relative to baseline after 180 days of treatment, representing a 35.11% improvement in the difference in change rate relative to the placebo group. In terms of clothing and personal hygiene, the baseline score of the placebo group was 3.00 points, and the relative change after 180 days of treatment was -0.87 points; the baseline score of the 1200mg group was 2.92 points, and the relative change after 180 days of treatment was -0.75 points, and the difference change rate increased by 13.79% compared with the placebo group.

Claims

1. Use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating muscle strength loss or functional loss caused by nerve damage; the ligustrazine nitrone derivative has the following general formula (I): in, R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

2. The use according to claim 1, wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

3. The use according to claim 1, characterized in that The ligustrazine nitrone derivative is nitrone oxadiazine or TN-2, and the specific structure is as follows:

4. The use according to any one of claims 1 to 3, characterized in that: The muscle strength loss or function loss caused by nerve damage is the muscle strength loss or function loss caused by ALS.

5. The use according to any one of claims 1 to 3, characterized in that: The muscles with decreased muscle strength or function loss are one or more of the biceps brachii, triceps brachii, deltoid, pectoralis major, forearm flexors, thenar muscles, hypothenar muscles, tongue muscles, facial muscles, laryngeal muscles, neck muscles, trapezius muscles, sternocleidomastoid muscles, extensor digitorum common, first interosseous muscles, abductor pollicis longus, abductor pollicis brevis, extensor index digitorum, thoracic paraspinal muscles, and respiratory muscles.

6. The use according to any one of claims 1 to 3, characterized in that: The application is to improve one or more symptoms of the patient's grip strength, speech, drooling, swallowing, handwriting, cutting food and using tableware, dressing and hygiene, dyspnea, orthopnea, and impaired respiratory function.

7. The use according to any one of claims 1 to 3, characterized in that: The application is to administer a preparation containing a ligustrazine nitrone derivative in a unit dosage form, wherein the preparation contains a ligustrazine nitrone derivative that is effective in treating, preventing, and preventing muscle strength decline or function loss, reducing its risk, delaying its occurrence, and / or delaying its progression.

8. The use according to claim 7, characterized in that The application is to administer 100-5000 mg of ligustrazine nitrone derivatives every day.

9. The use according to any one of claims 1 to 3, characterized in that: The pharmaceutically acceptable salt is a salt formed by a ligustrazine nitrone derivative and an acid, wherein the acid is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecyl sulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

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