CN117462648A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN117462648A CN117462648A CN202210862109.0A CN202210862109A CN117462648A CN 117462648 A CN117462648 A CN 117462648A CN 202210862109 A CN202210862109 A CN 202210862109A CN 117462648 A CN117462648 A CN 117462648A
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- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical group CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 81
- 239000000203 mixture Substances 0.000 claims abstract description 79
- 208000004296 neuralgia Diseases 0.000 claims abstract description 36
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960004181 riluzole Drugs 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940002612 prodrug Drugs 0.000 claims abstract description 19
- 239000000651 prodrug Substances 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- 230000002093 peripheral effect Effects 0.000 claims description 10
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 229960001233 pregabalin Drugs 0.000 description 63
- 208000000114 Pain Threshold Diseases 0.000 description 40
- 230000037040 pain threshold Effects 0.000 description 40
- 241001465754 Metazoa Species 0.000 description 39
- YBZSGIWIPOUSHY-UHFFFAOYSA-N troriluzole Chemical compound NCC(=O)NCC(N(CC(NC=1SC2=C(N=1)C=CC(=C2)OC(F)(F)F)=O)C)=O YBZSGIWIPOUSHY-UHFFFAOYSA-N 0.000 description 38
- 229940121629 troriluzole Drugs 0.000 description 22
- 238000010171 animal model Methods 0.000 description 20
- 229940079593 drug Drugs 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 10
- 210000003141 lower extremity Anatomy 0.000 description 9
- 238000005259 measurement Methods 0.000 description 8
- 230000002980 postoperative effect Effects 0.000 description 8
- 238000012453 sprague-dawley rat model Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229930195712 glutamate Natural products 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000001032 spinal nerve Anatomy 0.000 description 5
- 230000037396 body weight Effects 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000037087 Excitatory amino acid transporters Human genes 0.000 description 1
- 108091006291 Excitatory amino acid transporters Proteins 0.000 description 1
- 241000662429 Fenerbahce Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009954 braiding Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Gastroenterology & Hepatology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a composition of (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and a riluzole prodrug, which is useful for the preparation of a medicament for the treatment of neuropathic pain.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to a composition of (S) -3-aminomethyl-5-methylhexanoic acid and a riluzole prodrug and application thereof in preparing medicines for treating neuropathic pain.
Background
Neuropathic Pain (NP) is pain caused by injury or disease of the somatosensory system, and is classified into peripheral neuropathic pain and central neuropathic pain, with clinical peripheral neuropathic pain being common. One study from europe showed a high prevalence of neuropathic pain in the general population of 8.0%. Neuropathic pain is not a single disease, but rather is a syndrome caused by different diseases and lesions, manifesting as a series of symptoms and signs, severely affecting the quality of life of the patient. Postherpetic neuralgia and diabetic peripheral neuropathy are the most common two neuropathic pain types, and long-term pain can affect the sleeping, working and living abilities of patients, and can increase the incidence of affective disorders such as depression, anxiety and the like. There are studies showing that: the quality of life score of the postherpetic neuralgia patients is only 1/2 of that of the normal population. The lack of therapeutic drugs for neuropathic pain is currently treated clinically by using calcium ion channel modulators, antidepressants, local anesthetics and the like. However, due to the complex pathogenesis, existing treatments are not satisfactory and pain in a significant portion of patients is not adequately relieved.
(S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) is clinically useful in the treatment of peripheral neuralgia in adults, including the treatment of diabetic peripheral neuralgia, fibromyalgia, and postherpetic neuralgia, and is commonly recommended by a number of international guidelines as a first-line drug for the treatment of neuropathic pain. The mechanism of action of pregabalin is thought to regulate the voltage-gated calcium channel α2δ subunit, reducing glutamate, norepinephrine and substance P release. Pregabalin causes adverse reactions such as dizziness and somnolence, and the adverse reactions limit clinical application to a certain extent.
The structural formula of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) is as follows:
(molecular formula C 8 H 17 NO 2 Molecular weight 159.23).
Riluzole (chemical name 2-amino-6-trifluoromethoxybenzothiazole), a drug developed by the company celeofilin for treating Amyotrophic Lateral Sclerosis (ALS), was approved by the us FDA and eu EMA in 1996 and has very important roles in prolonging survival of ALS patients, alleviating symptoms and improving quality of life. The mechanism of action is thought to be related to inhibition of glutamate release, stabilization of the inactive state of voltage-dependent sodium channels, and the interference of intracellular events following neurotransmitter binding to excitatory amino acid receptors. Riluzole has a wide range of pharmacological effects including regulation of glutamate and its transporters, antidepressant, anxiolytic, antiepileptic, analgesic, neuroprotective, etc.
Troriluzole is a prodrug molecule of riluzole, also known as Trigriluzole, BHV-4157, and FC-4157, troriluzole is a novel chemical molecule that regulates glutamate, which is the most excitatory neurotransmitter in humans. The main mechanism of action of Troriluzole is the reduction of glutamate in the nerve synapses. Troriluzole increases glutamate uptake by increasing expression and function of excitatory amino acid transporters located on glial cells (e.g., EAAT 2), the structure of Troriluzole is as follows:
(molecular formula C 15 H 16 F 3 N 5 O 4 S, molecular weight 419.38).
Disclosure of Invention
The technical problems to be solved are as follows: the invention provides a pharmaceutical composition comprising (S) -3-aminomethyl-5-methylhexanoic acid and a riluzole prodrug, which produces unexpected synergistic effects when used, and can enhance the therapeutic effect against neuropathic pain.
The technical scheme is as follows: a composition for use in the preparation of a medicament for the treatment of neuropathic pain, said composition comprising (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and a riluzole prodrug or a pharmaceutically acceptable salt thereof, said riluzole prodrug having the structure:
。
the composition is characterized in that the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 16:1-1:60 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 8:1-1:30 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 4:1-1:30 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 4:1-1:12 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 3:1-1:6 in terms of free acid or alkali form.
The pharmaceutical composition of the invention can be used for preparing medicines for treating neuropathic pain, wherein the neuropathic pain is preferably peripheral neuropathic pain.
More preferably, the peripheral neuropathic pain is postherpetic neuralgia and neuralgia associated with diabetic peripheral neuropathy.
The beneficial effects are that:
the animal efficacy experiment result shows that the pharmaceutical composition containing the (S) -3-aminomethyl-5-methylhexanoic acid and the riluzole prodrug can play a synergistic role and enhance the treatment effect of resisting peripheral neuropathic pain.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the invention, but are not intended to limit the invention in any way.
EXAMPLE 1 pharmacodynamic effects of pregabalin, troriluzole compositions on neuropathic pain study 1
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
| Medicine name | Manufacturer' s |
| Pregabalin | Adamas Reagent, Ltd |
The Troriluzole laboratory is synthesized and self-made.
1.3 Experimental method
1.3.1 Preparation of neuropathic pain animal models
The experiments used a model of neuropathic pain induced by ligation of the L5 Spinal Nerve (SNL) alone. Animals were anesthetized with 7% chloral hydrate (420 mg/kg, intraperitoneal injection), rat limbs were fixed prone, placed under an dissecting microscope, back hair removed, and alcohol swabs sterilized. A long incision of about 2-3 cm is cut on the right side of the back vertebra, two spinal nerves L4 and L5 are exposed, the spinal nerves L5 are gently ligated by using a 6-0 number braiding wire, and the adjacent spinal nerves are prevented from being damaged. Double-layer suturing the back incision of the experimental animal, sterilizing with iodophor, and lightly placing into a raising cage to freely move food and drink water.
1.3.2 Method for measuring mechanical pain threshold
All experimental animals were tested for mechanical withdrawal threshold (mechanical withdrawal threshold, MWT) using a mechanical automatic stabbing needle. Placing the experimental animal in a transparent organic glass box with a wire netting at the bottom, applying force to stimulate the hind limb plantar of the experimental animal at a constant speed by using a stabbing needle after the experimental animal is adapted to the experimental animal for 30 min, and recording a reflection threshold (MWT) when the rapid foot shrinkage or the foot throwing reaction of the rat occurs, namely the mechanical pain threshold of the animal.
1.3.3 Measurement and calculation of basic pain threshold of animals
Each experimental animal was measured for a 2-day basal mechanical pain threshold after molding, and the basal mechanical pain threshold of the experimental animal was the average of two times.
1.4 Animal grouping and experimental procedure
The experimental animals were randomly divided into 7 groups, namely, a model control group, a pregabalin group (32 mg/kg), a pregabalin group (0.5 mg/kg), a Troriluzole group (30 mg/kg), a Troriluzole group (2 mg/kg), a pregabalin and Troriluzole composition 16:1 group (pregabalin 32 mg/kg+troriluzole 2 mg/kg), and a pregabalin and Troriluzole composition 1:60 group (pregabalin 0.5 mg/kg+riluzole 30 mg/kg). And the pregabalin and the troilizole are both administrated through oral gastric administration, 10-12 animals are in each group, and the corresponding blank solvent is administrated in a model control group.
SD rats of appropriate body weight were selected to prepare L5-SNL models, and post-operative mechanical pain threshold measurements were initiated at least 7 days after modeling. Animals with significantly reduced postoperative right hind limb pain threshold compared to contralateral hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at a time point of 2h after the administration.
1.5 Composition synergy analysis
Evaluation of the synergy of pregabalin and Troriluzole in the composition according to the golden average formula q=e (a+b)/(ea+eb-ea×eb)
Acting as a medicine. Wherein E (a+b) is the improvement rate of the combination drug, ea and Eb are the improvement rates of the drug A (pregabalin) and the drug B (Troriluzole) which are used independently. E= (pain threshold after administration-model value)/(basal value-model value). If the q value is in the range of 0.85-1.15, the two medicines are combined and simply added, and the q value is more than 1.15 and is synergistic, and if the q value is less than 0.85, the two medicines are combined and have antagonism.
1.6 Data statistics
Experimental data are expressed as Mean ± standard error (Mean ± SEM). Differences among groups are analyzed by adopting single factor variance analysis, and groups are separated
Comparison was tested using LSD method, P <0.05 defined as significant difference.
2. Results
The experimental results are shown in Table 1. The mechanical pain threshold of animals (P <0.0001 ) can be significantly improved by pregabalin 32 mg/kg, troriluzole, 30 mg/kg, composition 16:1, and composition 1:60 at 2h after administration. The synergy calculation results show that: the q value of composition 16:1 at 2h post-dose was 1.030 and the q value of composition 1:60 at 2h post-dose was 1.020, indicating no synergy for both composition 16:1 and composition 1:60 at 2h post-dose.
Table 1 mechanical pain threshold (unit: g) for each group of animals
| Group of | Number of animals | Basic value | Model value | Pain threshold 2h after administration |
| Model control group | 10 | 28.32±1.42 | 14.07±0.48 | 14.90±0.86 |
| Pregabalin group (32 mg/kg) | 11 | 28.59±1.26 | 13.78±0.83 | 25.81±1.05**** |
| Pregabalin group (0.5 mg/kg) | 11 | 29.14±1.17 | 14.83±0.93 | 14.99±0.74 |
| Troriluzole group (2 mg/kg) | 12 | 28.34±0.73 | 13.75±0.59 | 13.89±1.02 |
| Troriluzole group (30 mg/kg) | 12 | 29.06±1.23 | 13.84±0.60 | 23.37±0.90**** |
| Composition 16:1 group | 11 | 28.29±1.21 | 13.59±0.91 | 25.92±1.09**** |
| Composition 1:60 group | 12 | 28.52±1.37 | 14.02±0.69 | 23.34±1.23**** |
Data are expressed as mean ± standard error, P <0.0001, compared to model control.
EXAMPLE 2 pharmacodynamic effects of pregabalin, troriluzole compositions on neuropathic pain study 2
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and troiliuzole are as in example 1.
1.3 Experimental method
The preparation of neuropathic pain animal models, the determination of mechanical pain threshold and the measurement and calculation of basic pain threshold of animals are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental animals were randomly divided into 7 groups, namely, a model control group, a pregabalin group (32 mg/kg), a pregabalin group (1 mg/kg), a Troriluzole group (30 mg/kg), a Troriluzole group (4 mg/kg), a pregabalin and Troriluzole composition 8:1 group (pregabalin 32 mg/kg+troriluzole 4 mg/kg), and a pregabalin and Troriluzole composition 1:30 group (pregabalin 1 mg/kg+riluzole 30 mg/kg). And the pregabalin and the troilizole are both administrated through oral gastric administration, 10-12 animals are in each group, and the corresponding blank solvent is administrated in a model control group.
SD rats of appropriate body weight were selected to prepare L5-SNL models, and post-operative mechanical pain threshold measurements were initiated at least 7 days after modeling. Animals with significantly reduced postoperative right hind limb pain threshold compared to contralateral hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at a time point of 2h after the administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 2. The mechanical pain threshold of animals can be significantly improved by pregabalin 32 mg/kg, troriluzole 30 mg/kg, composition 8:1, composition 1:30 at 2h post-administration compared to vehicle control group (P <0.0001 ). The synergy calculation results show that: the q value of composition 8:1 at 2h post-dose was 1.174 and the q value of composition 1:30 at 2h post-dose was 1.162, indicating that both composition 8:1 and composition 1:30 had a synergistic effect at 2h post-dose.
TABLE 2 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold 2h after administration |
| Model control group | 10 | 29.64±1.31 | 14.91±0.64 | 15.02±0.77 |
| Pregabalin group (32 mg/kg) | 10 | 28.60±1.38 | 14.39±0.97 | 25.65±0.85**** |
| Pregabalin group (1 mg/kg) | 10 | 29.03±0.85 | 14.74±0.98 | 14.92±0.89 |
| Troriluzole group (4 mg/kg) | 12 | 28.49±1.34 | 13.53±1.02 | 14.04±1.27 |
| Troriluzole group (30 mg/kg) | 12 | 28.52±1.07 | 13.55±0.79 | 22.88±0.84**** |
| Composition 8:1 group | 12 | 28.94±1.32 | 14.26±0.58 | 28.04±1.11**** |
| Composition 1:30 group | 12 | 29.31±1.27 | 14.96±0.85 | 25.43±1.38**** |
Data are expressed as mean ± standard error, P <0.0001, compared to model control.
EXAMPLE 3 pharmacodynamic effects of pregabalin, troriluzole compositions on neuropathic pain study 3
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and troiliuzole are as in example 1.
1.3 Experimental method
The preparation of neuropathic pain animal models, the determination of mechanical pain threshold and the measurement and calculation of basic pain threshold of animals are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental animals were randomly assigned to 11 groups, namely, the model control group, the pregabalin group (16 mg/kg), the pregabalin group (12 mg/kg), the pregabalin group (2 mg/kg), the troilezole group (24 mg/kg), the troilezole group (12 mg/kg), the troilezole group (4 mg/kg), the pregabalin and troilezole composition 4:1 group (pregabalin 16 mg/kg+troile4 mg/kg), the pregabalin and troilezole composition 3:1 group (pregabalin 12 mg/kg+troilezole 4 mg/kg), the pregabalin and troilezole composition 1:12 group (pregabalin 2 mg/kg+troile24 mg/kg), and the pregabalin and troilezole composition 1:6 group (pregabalin 2 kg+troileole 4/mg/kg). And the pregabalin and the troilizole are both administrated through oral gastric administration, 8-10 animals are in each group, and the corresponding blank solvent is administrated in a model control group.
SD rats of appropriate body weight were selected to prepare L5-SNL models, and post-operative mechanical pain threshold measurements were initiated at least 7 days after modeling. Animals with significantly reduced postoperative right hind limb pain threshold compared to contralateral hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at a time point of 2h after the administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 3. Pregabalin 16 mg/kg, pregabalin 12 mg/kg, troriluzole 24 mg/kg, composition 4:1, composition 3:1, composition 1:12, composition 1:6 all significantly increased the mechanical pain threshold of animals 2h post-dosing compared to vehicle control (P <0.0001, p=0.0001, p=0.0002, P <0.0001, p=0.0066). The synergy calculation results show that: the q value of composition 4:1 at 2h post-dose was 1.209, the q value of composition 3:1 at 2h post-dose was 1.213, the q value of composition 1:12 at 2h post-dose was 1.200, and the q value of composition 1:6 at 2h post-dose was 1.280, indicating that composition 4:1, composition 3:1, composition 1:12, composition 1:6 all have synergy at 2h post-dose.
TABLE 3 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold 2h after administration |
| Model control group | 8 | 29.26±1.15 | 15.43±0.57 | 15.35±0.92 |
| Pregabalin group (16 mg/kg) | 8 | 27.58±1.28 | 14.37±0.93 | 22.74±0.85**** |
| Pregabalin group (12 mg/kg) | 8 | 28.43±0.73 | 15.44±0.79 | 21.84±0.98*** |
| Pregabalin group (2 mg/kg) | 8 | 28.32±1.29 | 15.11±0.73 | 15.15±0.86 |
| Troriluzole group (24 mg/kg) | 10 | 28.57±1.04 | 13.93±1.12 | 21.39±0.73*** |
| Troriluzole group (12 mg/kg) | 10 | 29.41±1.29 | 14.39±1.22 | 18.32±1.03 |
| Troriluzole group (4 mg/kg) | 10 | 28.91±0.96 | 13.52±0.75 | 14.33±1.18 |
| Composition 4:1 group | 10 | 27.87±1.04 | 13.54±0.89 | 24.85±1.41**** |
| Composition 3:1 group | 10 | 29.66±0.83 | 15.17±0.63 | 24.30±1.22**** |
| Composition 1:12 group | 10 | 28.29±1.19 | 13.86±1.17 | 22.71±0.90**** |
| Composition 1:6 group | 9 | 29.16±1.08 | 14.98±0.91 | 19.77±1.32** |
Data are expressed as mean ± standard error, P <0.01, P <0.001, P <0.0001, compared to model control.
EXAMPLE 4 pharmacodynamic effects of pregabalin, troriluzole compositions on neuropathic pain study 4
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and troiliuzole are as in example 1.
1.3 Experimental method
The preparation of neuropathic pain animal models, the determination of mechanical pain threshold and the measurement and calculation of basic pain threshold of animals are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental animals were randomly divided into 8 groups, namely, a model control group, a pregabalin group (12 mg/kg), a pregabalin group (2 mg/kg), a troilizole group (12 mg/kg), a troilizole group (4 mg/kg), a pregabalin and troilizole composition 3:1 group (pregabalin 12 mg/kg+troilizole 4 mg/kg), a pregabalin and troilizole composition 1:6 group (pregabalin 2 mg/kg+troilizole 12 mg/kg), a pregabalin and troilizole composition 1:1 group (pregabalin 12 mg/kg+troilizole 12 mg/kg). And the pregabalin and the troilizole are both administrated through oral gastric administration, 8-10 animals are in each group, and the corresponding blank solvent is administrated in a model control group.
SD rats of appropriate body weight were selected to prepare L5-SNL models, and post-operative mechanical pain threshold measurements were initiated at least 7 days after modeling. Animals with significantly reduced postoperative right hind limb pain threshold compared to contralateral hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at a time point of 2h after the administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 4. Pregabalin 12 mg/kg, troriluzole 12 mg/kg, composition 3:1, composition 1:6, composition 1:1 all significantly increased the mechanical pain threshold (P <0.0001, p=0.0099, P < 0.0001) of animals at 2h post-dose compared to vehicle control. The synergy calculation results show that: the q value of composition 3:1 at 2h post-dose was 1.275, the q value of composition 1:6 at 2h post-dose was 1.297, and the q value of composition 1:1 at 2h post-dose was 1.343, indicating that composition 3:1, composition 1:6, and composition 1:1 all have synergy at 2h post-dose.
TABLE 4 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold 2h after administration |
| Model control group | 8 | 28.38±1.44 | 13.26±0.96 | 13.94±1.21 |
| Pregabalin group (12 mg/kg) | 8 | 30.17±0.91 | 14.11±0.72 | 21.97±0.88**** |
| Pregabalin group (2 mg/kg) | 8 | 28.85±1.16 | 13.29±0.99 | 14.01±0.73 |
| Troriluzole group (12 mg/kg) | 10 | 29.46±1.27 | 13.87±1.14 | 17.93±1.20** |
| Troriluzole group (4 mg/kg) | 10 | 28.49±0.86 | 14.35±0.79 | 14.37±1.25 |
| Composition 3:1 group | 10 | 29.74±0.84 | 14.73±0.92 | 24.11±0.75**** |
| Composition 1:6 group | 10 | 28.65±1.24 | 15.02±1.05 | 20.23±0.87**** |
| Composition 1:1 group | 10 | 30.16±1.22 | 14.97±1.25 | 27.67±1.14**** |
Data are expressed as mean ± standard error, P <0.01, P <0.0001, compared to model control.
Claims (9)
1. A composition for use in the preparation of a medicament for the treatment of neuropathic pain, said composition comprising (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and a riluzole prodrug or a pharmaceutically acceptable salt thereof, said riluzole prodrug having the structure:
。
2. use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 16:1-1:60 in terms of free acid or alkali form.
3. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 8:1-1:30 in terms of free acid or alkali form.
4. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 4:1-1:30 in terms of free acid or alkali form.
5. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 4:1-1:12 in terms of free acid or alkali form.
6. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: the riluzole prodrug or the pharmaceutically acceptable salt thereof has a mass ratio of 3:1-1:6 in terms of free acid or alkali form.
7. Use according to claims 1-6, characterized in that the neuropathic pain is peripheral neuropathic pain.
8. Use according to claims 1-7, characterized in that the peripheral neuropathic pain is postherpetic neuralgia.
9. Use according to claims 1-7, characterized in that the peripheral neuropathic pain is diabetic peripheral neuropathy.
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