WO2023274117A1 - 一种药物组合物及其用途 - Google Patents
一种药物组合物及其用途 Download PDFInfo
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- WO2023274117A1 WO2023274117A1 PCT/CN2022/101423 CN2022101423W WO2023274117A1 WO 2023274117 A1 WO2023274117 A1 WO 2023274117A1 CN 2022101423 W CN2022101423 W CN 2022101423W WO 2023274117 A1 WO2023274117 A1 WO 2023274117A1
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- riluzole
- composition
- pregabalin
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- animals
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- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- 239000000203 mixture Substances 0.000 claims abstract description 126
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical group CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 124
- 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 119
- 229960004181 riluzole Drugs 0.000 claims abstract description 104
- 239000003814 drug Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 208000004296 neuralgia Diseases 0.000 claims abstract description 39
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims description 12
- 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 104
- 241001465754 Metazoa Species 0.000 description 65
- 208000000114 Pain Threshold Diseases 0.000 description 61
- 230000037040 pain threshold Effects 0.000 description 59
- 238000000034 method Methods 0.000 description 21
- 238000010171 animal model Methods 0.000 description 19
- 230000002195 synergetic effect Effects 0.000 description 18
- 210000003141 lower extremity Anatomy 0.000 description 13
- 238000004364 calculation method Methods 0.000 description 12
- 238000012453 sprague-dawley rat model Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 10
- 241000700159 Rattus Species 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000037396 body weight Effects 0.000 description 6
- 239000007928 intraperitoneal injection Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000003285 pharmacodynamic effect Effects 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 210000001032 spinal nerve Anatomy 0.000 description 5
- 230000036407 pain Effects 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229930195712 glutamate Natural products 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
- 239000000890 drug combination Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229940039024 pregabalin 25 mg Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000656 threshold model Toxicity 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
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-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
- 208000027534 Emotional disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 208000032023 Signs and Symptoms 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
- 230000000996 additive 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
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003063 anti-neuropathic 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
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 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
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 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
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 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
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000003238 somatosensory effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
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Classifications
-
- 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
-
- 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
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- the invention belongs to the field of pharmacy, and relates to a composition of (S)-3-aminomethyl-5-methylhexanoic acid and riluzole, and an application thereof in preparing medicines for treating neuropathic pain.
- Neuropathic pain is the pain caused by damage or disease of the somatosensory system. It can be divided into peripheral neuropathic pain and central neuropathic pain. Peripheral neuropathic pain is more common clinically. A European study showed that the prevalence of neuropathic pain in the general population was as high as 8.0%. Neuropathic pain is not a single disease, but a syndrome caused by different diseases and lesions, manifested by a series of symptoms and signs, which seriously affect the patient's quality of life. Postherpetic neuralgia and diabetic peripheral neuropathy are the two most common types of neuropathic pain.
- pregabalin can be used clinically for the treatment of peripheral neuralgia in adults, including diabetic peripheral neuralgia, fibromyalgia and postherpetic neuralgia Treatment is jointly recommended by multiple international guidelines as the first-line drug for the treatment of neuropathic pain.
- the mechanism of action of pregabalin is thought to modulate the voltage-gated calcium channel ⁇ 2 ⁇ subunit, reducing glutamate, norepinephrine, and substance P release.
- Pregabalin can cause adverse reactions such as dizziness and drowsiness, and its adverse reactions limit the clinical application to a certain extent.
- Riluzole (Riluzole, chemical name 2-amino-6-trifluoromethoxybenzothiazole), is a drug developed by Sanofi for the treatment of amyotrophic lateral sclerosis (ALS). In 1996, it was approved for marketing by the US FDA and the EU EMA, and it played a very important role in prolonging the survival period of ALS patients, relieving symptoms and improving the quality of life. Its mechanism of action is considered to be related to inhibiting the release of glutamate, stabilizing the inactivation state of voltage-dependent sodium channels, and interfering with intracellular events after the binding of neurotransmitters to excitatory amino acid receptors. Riluzole has a wide range of pharmacological effects, including regulating glutamate and its transporters, antidepressant, anxiolytic, antiepileptic, analgesic and neuroprotective.
- the present invention provides a pharmaceutical composition comprising (S)-3-aminomethyl-5-methylhexanoic acid and riluzole, which produces an unexpected synergistic effect when used to enhance anti-neuropathic properties Therapeutic effect on pain.
- the invention provides an application of a pharmaceutical composition in the preparation of medicines for treating neuropathic pain, the composition comprising (S)-3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof.
- the (S)-3-aminomethyl-5-methylhexanoic acid or its pharmaceutically acceptable salt riluzole or its pharmaceutically acceptable salt, in the form of free acid or base
- the mass ratio of the meter is 20:1 ⁇ 1:10.
- the (S)-3-aminomethyl-5-methylhexanoic acid or its pharmaceutically acceptable salt riluzole or its pharmaceutically acceptable salt, in the form of free acid or base
- the mass ratio of the meter is 20:1 ⁇ 1:4.
- the (S)-3-aminomethyl-5-methylhexanoic acid or its pharmaceutically acceptable salt riluzole or its pharmaceutically acceptable salt, in the form of free acid or base
- the mass ratio of the meter is 10:1 ⁇ 1:4.
- the (S)-3-aminomethyl-5-methylhexanoic acid or its pharmaceutically acceptable salt riluzole or its pharmaceutically acceptable salt, in the form of free acid or base
- the mass ratio of the meter is 6:1 ⁇ 1:4.
- the (S)-3-aminomethyl-5-methylhexanoic acid or its pharmaceutically acceptable salt riluzole or its pharmaceutically acceptable salt, in the form of free acid or base
- the mass ratio of the meter is 3:1 ⁇ 1:2.
- the pharmaceutical composition of the present invention can be used to prepare medicines for treating neuropathic pain, wherein the neuropathic pain is preferably peripheral neuropathic pain.
- the peripheral neuropathic pain is postherpetic neuralgia and diabetic peripheral neuropathy.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (S)-3-aminomethyl-5-methylhexanoic acid and riluzole.
- the results of animal efficacy experiments show that the pharmaceutical composition can exert a synergistic effect and enhance anti-inflammatory effects.
- Therapeutic effects in peripheral neuropathic pain are shown.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Drug Name factory batch number Pregabalin Adamas Reagent,Ltd P1472904 Riluzole Shanghai Aladdin Biochemical Technology Co., Ltd. F1502089
- a neuropathic pain model was induced by ligating the L5 spinal nerve (SNL) alone.
- the animal was anesthetized with 7% chloral hydrate (420 mg/kg, intraperitoneal injection), the limbs of the rat were fixed in prone position, placed under a dissecting microscope, the back hair was removed, and wiped with alcohol for disinfection. Cut an incision about 2-3 cm long on the right side of the dorsal spine to expose the two spinal nerves L4 and L5, and gently ligate the L5 spinal nerve with a 6-0 braided wire, avoiding damage to the adjacent spinal nerves.
- the incision on the back of the experimental animal was sutured in double layers, disinfected with povidone iodine, gently placed in a breeding cage, and free to move about, eat and drink.
- the basic mechanical pain threshold of each experimental animal was measured 2 days after modeling, and the basic mechanical pain threshold of the experimental animals was the average value of two times.
- Experimental model animals were randomly divided into 7 groups, namely model control group, pregabalin group (25mg/kg), pregabalin group (0.5mg/kg), riluzole group (10mg/kg), riluzole group ( 0.5mg/kg), pregabalin and riluzole composition 50:1 group (pregabalin 25mg/kg+riluzole 0.5mg/kg), pregabalin and riluzole composition 1:20 group (pregabalin Regabalin 0.5mg/kg+ Riluzole 10mg/kg).
- Pregabalin and riluzole were administered by intraperitoneal injection, with 11 to 12 animals in each group, and the corresponding blank vehicle was given to the model control group.
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given the corresponding drug or vehicle, and the mechanical pain threshold of the animals was measured at the time points of 0.5h and 3h after administration.
- E(a+b) is the improvement rate of drug combination
- Ea and Eb are the improvement rates of drug A (pregabalin) and drug B (riluzole) alone, respectively.
- E (post-dose pain threshold-model value)/(basal value-model value).
- the q value is in the range of 0.85 to 1.15, it is simple addition of the combination of the two drugs, if the q value > 1.15 is synergistic, and if the q value ⁇ 0.85, it means that the combination of the two drugs has an antagonistic effect.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, ***P ⁇ 0.001, ****P ⁇ 0.0001, compared with the model control group.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Pregabalin and riluzole are the same as in Example 1.
- Example 1 The preparation of the animal model of neuropathic pain, the method of measuring the mechanical pain threshold, and the measurement and calculation of the animal's basic pain threshold are the same as in Example 1.
- Experimental model animals were randomly divided into 7 groups, namely model control group, pregabalin group (20mg/kg), pregabalin group (1mg/kg), riluzole group (10mg/kg), riluzole group (1mg /kg), pregabalin and riluzole composition 20:1 group (pregabalin 20mg/kg+riluzole 1mg/kg), pregabalin and riluzole composition 1:10 group (pregabalin 1mg /kg+riluzole 10mg/kg).
- Pregabalin and riluzole were administered by intraperitoneal injection, 12 animals in each group, and the corresponding blank vehicle was given to the model control group.
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given the corresponding drug or vehicle, and the mechanical pain threshold of the animals was measured at the time points of 0.5h and 3h after administration.
- Composition synergy analysis is the same as in Example 1.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, ****P ⁇ 0.0001, compared with the model control group.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Pregabalin and riluzole are the same as in Example 1.
- Example 1 The preparation of the animal model of neuropathic pain, the method of measuring the mechanical pain threshold, and the measurement and calculation of the animal's basic pain threshold are the same as in Example 1.
- Experimental model animals were randomly divided into 9 groups, namely model control group, pregabalin group (30mg/kg), pregabalin group (18mg/kg), pregabalin group (3mg/kg), riluzole group (12mg /kg), riluzole group (3mg/kg), pregabalin and riluzole combination 10:1 group (pregabalin 30mg/kg+riluzole 3mg/kg), pregabalin and riluzole combination Composition 1:4 group (pregabalin 3mg/kg+riluzole 12mg/kg), pregabalin and riluzole composition 6:1 group (pregabalin 18mg/kg+riluzole 3mg/kg).
- Pregabalin and riluzole were administered by intraperitoneal injection, with 10-12 animals in each group, and the corresponding blank vehicle was given to the model control group.
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given the corresponding drug or vehicle, and the mechanical pain threshold of the animals was measured at the time points of 0.5h and 3h after administration.
- Composition synergy analysis is the same as in Example 1.
- composition 10:1 at 0.5h and 3h after administration were 1.273 and 1.182, respectively, and the q values of composition 1:4 at 0.5h and 3h after administration were 1.210 and 1.211, respectively.
- the q values of composition 6:1 at 0.5h and 3h after administration were 1.222 and 1.269, respectively, which indicated that composition 10:1, composition 1:4 and composition 6:1 were at 0.5h and 3h after administration All have a synergistic effect.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001, compared with the model control group.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Pregabalin and riluzole are the same as in Example 1.
- Example 1 The preparation of the animal model of neuropathic pain, the method of measuring the mechanical pain threshold, and the measurement and calculation of the animal's basic pain threshold are the same as in Example 1.
- model control group pregabalin group (18mg/kg), pregabalin group (9mg/kg), pregabalin group (3mg/kg), riluzole group (12mg /kg), riluzole group (6mg/kg), riluzole group (3mg/kg), pregabalin and riluzole composition 6:1 group (pregabalin 18mg/kg+ riluzole 3mg/kg ), the combination of pregabalin and riluzole 3:1 group (pregabalin 9mg/kg+riluzole 3mg/kg), the combination of pregabalin and riluzole 1:4 group (pregabalin 3mg/kg+ Riluzole 12mg/kg), pregabalin and riluzole combination 1:2 group (pregabalin 3mg/kg+riluzole 6mg/kg).
- Pregabalin and riluzole were
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given the corresponding drug or vehicle, and the mechanical pain threshold of the animals was measured at the time points of 0.5h and 3h after administration.
- Composition synergy analysis is the same as in Example 1.
- composition 6:1 at 0.5h and 3h after administration were 1.250 and 1.248 respectively, and the q values of composition 3:1 at 0.5h and 3h after administration were 1.389 and 1.391, respectively
- the q values of composition 1:4 at 0.5h and 3h after administration were 1.235 and 1.294, respectively, and the q values of composition 1:2 at 0.5h and 3h after administration were 1.320 and 1.384, respectively, which indicated that composition 6 :1, composition 3:1, composition 1:4, and composition 1:2 all had synergistic effect at 0.5h and 3h after administration.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, **P ⁇ 0.01, ****P ⁇ 0.0001, compared with the model control group.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Pregabalin and riluzole are the same as in Example 1.
- Example 1 The preparation of the animal model of neuropathic pain, the method of measuring the mechanical pain threshold, and the measurement and calculation of the animal's basic pain threshold are the same as in Example 1.
- Experimental model animals were randomly divided into 9 groups, namely model control group, pregabalin group (9mg/kg), pregabalin group (6mg/kg), pregabalin group (3mg/kg), riluzole group (6mg/kg) /kg), riluzole group (3mg/kg), pregabalin and riluzole combination 3:1 group (pregabalin 9mg/kg+riluzole 3mg/kg), pregabalin and riluzole combination Composition 1:2 group (pregabalin 3mg/kg+riluzole 6mg/kg), pregabalin and riluzole composition 1:1 group (pregabalin 6mg/kg+riluzole 6mg/kg).
- Pregabalin and riluzole were administered by intraperitoneal injection, with 10-11 animals in each group, and the corresponding blank vehicle was given to the model control group.
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given the corresponding drug or vehicle, and the mechanical pain threshold of the animals was measured at the time points of 0.5h and 3h after administration.
- Composition synergy analysis is the same as in Example 1.
- composition 3:1 at 0.5h and 3h after administration were 1.362 and 1.384, respectively, and the q values of composition 1:2 at 0.5h and 3h after administration were 1.330 and 1.361, respectively.
- the q values of composition 1:1 at 0.5h and 3h after administration were 1.453 and 1.501 respectively, which indicated that composition 3:1, composition 1:2 and composition 1:1 were at 0.5h and 3h after administration All have a synergistic effect.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001, compared with the model control group.
- Sprague-Dawley (SD) rats male, SPF grade, body weight 150-200g.
- Pregabalin and riluzole are the same as in Example 1.
- Example 1 The preparation of the animal model of neuropathic pain, the method of measuring the mechanical pain threshold, and the measurement and calculation of the animal's basic pain threshold are the same as in Example 1.
- model control group pregabalin group (30mg/kg), pregabalin group (20mg/kg), pregabalin group (6mg/kg), riluzole group (10mg/kg) /kg), riluzole group (7.5mg/kg), riluzole group (6mg/kg), pregabalin and riluzole composition 1:1 group (pregabalin 6mg/kg+ riluzole 6mg/ kg), pregabalin and riluzole composition 2:1 group (pregabalin 20mg/kg+riluzole 10mg/kg), pregabalin and riluzole composition 3:1 group (pregabalin 30mg/kg kg+riluzole 10mg/kg), pregabalin and riluzole combination 4:1 group (pregabalin 30mg/kg+riluzole 7.5mg/kg), pregabalin and riluzole combination 5:1
- SD rats of appropriate weight were selected to prepare the L5-SNL model, and the postoperative mechanical pain threshold was measured at least 7 days after the model was established. Animals whose right hindlimb pain threshold was significantly lower than the contralateral hindlimb pain threshold after operation were selected for all subsequent drug efficacy tests.
- the experimental model animals were given corresponding drugs or vehicles, and the mechanical pain thresholds of the animals were measured at the time points of 0.5h, 3h, 6h, and 8h after administration.
- the q value is in the range of 0.85 to 1.15, it is simple addition of the combination of the two drugs, if the q value > 1.15 is synergistic, and if the q value ⁇ 0.85, it means that the combination of the two drugs has an antagonistic effect.
- the formula for calculating the improvement rate of the drug group is: (AUC 0-8h - model value * 8h)/(basic value * 8h - model value * 8h).
- the calculation results of Kim Jong-kyun’s formula showed that the q value of composition 1:1 was 1.296 3 hours after administration, the q value of composition 2:1 was 1.258 3 hours after administration, and the q value of composition 3:1 was 1.258 after administration.
- the q value of 3h is 1.266, and the q value of composition 4:1 3h after administration is 1.319, and the q value of composition 5:1 3h after administration is 1.264, and this shows that composition 1:1, composition 2:1, composition 3:1, composition 4:1, and composition 5:1 all had synergistic effects 3 hours after administration;
- CompuSyn software analysis showed that the CI value of AUC for composition 1:1 after administration was 0.634, the CI value of AUC after administration of composition 2:1 was 0.364, the CI value of AUC of composition 3:1 after administration was 0.349, and the CI value of AUC of composition 4:1 after administration was 0.328,
- the CI value of the AUC of the composition 5:1 after administration was 0.349, which indicated that the composition 1:1, the composition 2:1, the composition 3:1, the composition 4:1, and the composition 5:1 had There is a synergistic effect 0-8h after the drug.
- the data are expressed as mean ⁇ standard error, *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, ****P ⁇ 0.0001, compared with the model control group.
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Abstract
Description
药品名称 | 厂家 | 批号 |
普瑞巴林 | Adamas Reagent,Ltd | P1472904 |
利鲁唑 | 上海阿拉丁生化科技股份有限公司 | F1502089 |
Claims (11)
- 一种用于制备治疗神经病理性疼痛药物的组合物,所述组合物包括(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐和利鲁唑或其在药学上可接受的盐。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为50:1~1:20。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为20:1~1:10。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为20:1~1:4。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为10:1~1:4。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为6:1~1:4。
- 根据权利要求1所述的组合物,其特征在于,所述(S)-3-氨甲基-5-甲基己酸或其在药学上可接受的盐:利鲁唑或其在药学上可接受的盐,以游离酸或碱形式计的质量比为3:1~1:2。
- 权利要求1~7任意一项所述的组合物在制备治疗神经病理性疼痛药物中的应用。
- 根据权利要求8所述的应用,其特征在于,所述神经病理性疼痛为周围神经病理性疼痛。
- 根据权利要求9所述的应用,其特征在于,所述周围神经病理性疼痛为带状疱疹后神经痛。
- 根据权利要求9所述的应用,其特征在于,所述周围神经病理性疼痛 为糖尿病性周围神经病变。
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AU2022301410A AU2022301410A1 (en) | 2021-07-01 | 2022-06-27 | Pharmaceutical composition and use thereof |
KR1020247003305A KR20240027095A (ko) | 2021-07-01 | 2022-06-27 | 약학 조성물 및 이의 용도 |
CA3225644A CA3225644A1 (en) | 2021-07-01 | 2022-06-27 | Pharmaceutical composition and use thereof |
EP22831931.5A EP4364735A1 (en) | 2021-07-01 | 2022-06-27 | Pharmaceutical composition and use thereof |
CN202280047401.5A CN117642162A (zh) | 2021-07-01 | 2022-06-27 | 一种药物组合物及其用途 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102648915A (zh) * | 2011-02-28 | 2012-08-29 | 鲁南制药集团股份有限公司 | 一种治疗或预防神经病理性疼痛的药物组合物 |
CN103169716A (zh) * | 2011-12-26 | 2013-06-26 | 昆明贝克诺顿制药有限公司 | 用于治疗疼痛的复方药物组合 |
-
2021
- 2021-07-01 CN CN202110742036.7A patent/CN115554293A/zh not_active Withdrawn
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- 2022-06-27 CN CN202280047401.5A patent/CN117642162A/zh active Pending
- 2022-06-27 AU AU2022301410A patent/AU2022301410A1/en active Pending
- 2022-06-27 CA CA3225644A patent/CA3225644A1/en active Pending
- 2022-06-27 KR KR1020247003305A patent/KR20240027095A/ko unknown
- 2022-06-27 WO PCT/CN2022/101423 patent/WO2023274117A1/zh active Application Filing
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102648915A (zh) * | 2011-02-28 | 2012-08-29 | 鲁南制药集团股份有限公司 | 一种治疗或预防神经病理性疼痛的药物组合物 |
CN103169716A (zh) * | 2011-12-26 | 2013-06-26 | 昆明贝克诺顿制药有限公司 | 用于治疗疼痛的复方药物组合 |
Non-Patent Citations (3)
Title |
---|
FAN BIFA: "Chinese Expert Consensus on Diagnosis and Treatment of Peripheral Neuropathic Pain", CHINESE JOURNAL OF PAIN MEDICINE, vol. 26, no. 5, 15 May 2020 (2020-05-15), pages 321 - 328, XP093018111, ISSN: 1006-9852, DOI: 10.3969/j.issn.1006-9852.2020.05.001 * |
LIU LIU, WANG QING-CHUAN;GAI DONG-WEI;XU XIAO-KANG;XU QIANG-QIANG;HE CONG;CHEN WEI;MEI QI-BING;WU XIANG-LONG: "Research Progress of Riluzole in Neuroprotection, Analgesia and Antidepressant", CHEMISTRY & BIOENGINEERING - HUAXUE YU SHENGWU GONGCHENG, HUBEI SHENG HUAXUE GONGYE YANJIU SHEJIYUAN, CN, vol. 34, no. 2, 19 January 2017 (2017-01-19), CN , pages 6 - 9, XP093018118, ISSN: 1672-5425, DOI: 10.3969/j.issn.1672-5425.2017.02.002 * |
MIAO BEI, YUE YIN, TIAN-TIAN ZHOU, CUI-JIE SHAO, JUN-LI CAO: "Effects of Riluzole on Expression of Nav1.7 in Dorsal Root Ganglia of Rats with Diabetic Neuropathic Pain", CHINESE JOURNAL OF PAIN MEDICINE, vol. 20, no. 4, 15 April 2014 (2014-04-15), pages 203 - 207, XP093018115, ISSN: 1006-9852, DOI: 10.3969/j.issn.1006-9852.2014.04.004 * |
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EP4364735A1 (en) | 2024-05-08 |
KR20240027095A (ko) | 2024-02-29 |
CN117642162A (zh) | 2024-03-01 |
CN115554293A (zh) | 2023-01-03 |
AU2022301410A1 (en) | 2024-02-01 |
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