JP2007112735A - Analgesic composition - Google Patents

Abstract

[PROBLEMS] To develop a therapeutic agent for intractable pain that has been difficult to treat by a known mechanism of action, and for side effects such as drug tolerance, drug dependence, and gastrointestinal disorders observed in antipyretic analgesics. Providing a safe and effective analgesic composition having a new mechanism of action without problems.
An analgesic composition comprising, as an active ingredient, a component that inhibits, suppresses or reduces the production of hydrogen sulfide in a living body, and particularly DL-propargylglycine (PAG) and β-cyanoalanine ( An analgesic composition containing a cystathionine γ-lyase (CSE) inhibitor such as BCA) as an active ingredient.
[Selection figure] None

Description

  The present invention relates to an analgesic composition containing, as an active ingredient, a component that inhibits, suppresses or reduces the production of hydrogen sulfide in vivo.

  Pain is broadly divided into somatic pain that occurs from skin, subcutaneous tissue, skeletal muscle, joints and blood vessels distributed in them, and visceral pain that is pain from various organs such as the stomach, small intestine, large intestine, and gallbladder. . These pains are caused by nociceptive stimulation by releasing pain-generating substances such as acetylcholine, histamine, serotonin, prazikinin, and substance P into the living body and acting on sensory nerve receptors. It is known that it is often enhanced by prostaglandins.

In order to relieve or eliminate pain, the impulse generated from the sensory nerve terminal is transmitted to the pain conduction pathway consisting of spinal cord-axon-cerebral cortex. One of the measures is to suppress the production of impulses at sensory nerve terminals by suppressing the production of prostaglandins that cause increased sensitivity of sensory nerves. In general, these drugs aimed at relieving or eliminating pain include narcotic analgesics that act on the cerebral cortex, medulla or spinal cord, local anesthetics that act on the endings of sensory nerves, and the cerebrum, hypothalamus, or local areas of inflammation. It is roughly divided into antipyretic analgesics that suppress the production of prostaglandins.

  Representative narcotic analgesics include opium alkaloids such as morphine and codeine, morphinan derivatives, phenylpyridine derivatives, benzomorphan derivatives, opioid peptides, and the like.

  Representative antipyretic analgesics include salicylic acid derivatives such as sodium salicylate and aspirin, aniline derivatives such as acetaminophen and phenacetin, and virazolone derivatives such as antipyrine and aminopyrine.

  Thus, narcotic analgesics such as morphine, which act on the central nervous system and show a powerful analgesic action against the relief or disappearance of strong pain due to cancer, are widely used, but there are problems such as drug dependence and drug resistance. appear. In addition, antipyretic analgesics have a weak analgesic effect compared to the above-mentioned narcotic analgesics and do not show an effect on cancer pain or visceral pain. Furthermore, antipyretic analgesics frequently have side effects such as gastrointestinal disorders. Therefore, patients with chronic and acute pain and physicians have pain relief and treatment that effectively relieves or eliminates pain through a novel mechanism of action that is different from these narcotic and antipyretic analgesics. Drug development was desired.

On the other hand, hydrogen sulfide (H ₂ S) is generally known as a toxic gas, and most studies on H ₂ S concentrate on its toxic effects (Reiffenstein RJ et al., Annu. Rev. Pharmacol. Toxicol., Vol. 32 , pp.109-134 (1992)), its physiological function was not paid attention. However, relatively high levels of endogenous H ₂ S have been measured in rat, human and bovine brains (Goodwin LR et al., J. Anal. Toxicol., Vol. 13, pp. 105-109 (1989); Warenycia MW et al., Neurotoxicology, vol. 10, pp. 191-200 (1989); Savage JC and Gould DH, J. Chromatogr., Vol. 526, pp. 540-545 (1990)), H ₂ S is physiological function It has been suggested that

Endogenous hydrogen sulfide (H ₂ S) can be formed from cysteine by pyridoxal-5′-phosphate dependent enzymes including cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) (Stipanuk MH and Beck PW, Biochem. J., vol. 206, pp. 267-277 (1982); Griffith OW, Methods in enzymology, vol. 143, pp. 366-376 (1987); Erickson PF et al., Biochem. J., vol. 269, pp. 335-340 (1990); Swaroop M et al., J. Biol. Chem., vol. 267, pp. 11455-11461 (1992)). Both CBS and CSE have been studied for their activity in the liver and kidney (Stipanuk MH and Beck PW, Biochem. J., vol. 206, pp. 267-277 (1982); Erickson PF et al., Biochem. J., vol. 269, pp. 335-340 (1990); Swaroop M et al., J. Biol. Chem., Vol. 267, pp. 11455-11461 (1992)).

Also, CBS is expressed in the brain, CBS inhibitor hydroxylamine and aminooxy acetate suppresses the formation of _{H 2} S is a CBS activator S- adenosyl -L- methionine (SAM) is _{H 2} S production Strengthen. Physiological concentrations of H ₂ S specifically enhance the activity of the NMDA receptor and alter the induction of long-term potentiation (LTP) in the hippocampus (Abe K and Kimura H, J. Neurosci., Vol. 16, pp. 1066 -1071 (1996)). The cAMP-mediated pathway may be involved in the modulation of NMDA receptors by H ₂ S (Kimura H, Biochem. Biophys. Res. Commun., vol. 267, pp. 129-133 (2000)). H ₂ S can also regulate the release of corticotropin releasing hormone from the hypothalamus (Russo CD et al., J. Neuroendocrinol., Vol. 12, pp. 225-233 (2000)). Based on these observations, it was proposed that CBS can generate H ₂ S in the brain and that H ₂ S can function as a neuromodulator (Abe K and Kimura H, J. Neurosci., Vol. 16, pp. 1066-1071 (1996)).

  Furthermore, in recent years, attention has been focused on the relationship with two other gases endogenously produced by enzymes localized in the brain, nitric oxide (NO) and carbon monoxide (CO).

However, although H ₂ S has attracted attention in the liver and kidney from the toxicological aspect and in the brain from the physiological aspect, there has been no report focusing on the relief and disappearance of pain due to H ₂ S.
J. Neurosci., Vol. 16 (3), pp. 1066-1071 (1996) Biochem. Biophys. Res. Commun., Vol. 237 (3), pp. 527-531 (1997) J. Biol. Chem., Vol. 274 (18), pp. 12675-12684 (1999) J. Neurosci., Vol. 22 (9), pp. 3386-3391 (2002) FASEB J., vol. 19, pp. 623-625 (2005)

  The present invention has been made in view of the above prior art, and an object of the present invention is to provide a safe and effective analgesic composition. In addition, the development of therapeutic drugs for intractable pain, which has been difficult to treat with the known mechanism of action so far, and the drug resistance observed with narcotic analgesics, gastrointestinal disorders such as drug dependence or antipyretic analgesics, etc. In order to solve the problem of side effects, it is to provide the above composition having a novel mechanism of action.

The present inventors have conducted research to develop a preferable drug as an analgesic composition, and as a result of diligent research to find a new mechanism of action, the production of hydrogen sulfide (H ₂ S) in vivo is inhibited. For the first time, the present inventors have found that a component that suppresses or lowers has an analgesic action, thereby completing the present invention.
That is, the present invention

(1) An analgesic composition comprising, as an active ingredient, a component that inhibits, suppresses or reduces the production of hydrogen sulfide in vivo,
(2) The analgesic composition according to (1), wherein the component is a cystathionine γ-lyase (CSE) inhibitor,
(3) The analgesic composition according to (2), wherein the cystathionine γ-lyase (CSE) inhibitor is selected from the group consisting of DL-propargylglycine (PAG) and β-cyanoalanine (BCA), and (4) ) The composition according to any one of the above (1) to (3) is provided as a DDS preparation.

  The present invention provides a preventive and therapeutic agent having a novel mechanism of action and an excellent analgesic action, and a method for using the same.

“A component that inhibits, suppresses or reduces the production of hydrogen sulfide in vivo” exists in nature, having the ability to inhibit, suppress or reduce the production of hydrogen sulfide (H ₂ S) in vivo, or This refers to any artificially synthesized substance, and includes, for example, synthetic compounds, peptides, proteins, other compounds, and the like. More specifically, examples of the component include cystathionine γ-lyase (CSE) inhibitors such as DL-propargylglycine (PAG) and β-cyanoalanine (BCA).

  Thus, since the component that inhibits, suppresses, or reduces the production of hydrogen sulfide in vivo increases the pain threshold and has an analgesic action, it inhibits, suppresses, or reduces the production of hydrogen sulfide in the living body of the present invention. The composition containing an ingredient has an analgesic action against various types of pain and is useful.

  When used as a prophylactic or therapeutic agent, the composition of the present invention can be used as it is or after being subjected to various treatments such as diluting in water, and can be used by being blended with pharmaceuticals, quasi drugs, etc. it can.

  The component that inhibits, suppresses, or reduces the production of hydrogen sulfide in vivo contained in the composition of the present invention may be contained in the preparation as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts with bases such as inorganic bases and organic bases, and acid addition salts such as inorganic acids, organic acids, basic or acidic amino acids, and the like. Examples of the inorganic base include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum and ammonium. Examples of the organic base include primary amines such as ethanolamine, secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, trimethylamine, triethylamine, pyridine, picoline, triethanolamine and the like. And tertiary amines. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of organic acids include formic acid, acetic acid, lactic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfone. Examples thereof include acid and p-toluenesulfonic acid. Examples of basic amino acids include arginine, lysine, ornithine and the like. Examples of acidic amino acids include aspartic acid and glutamic acid.

  As the administration method of the composition of the present invention, in addition to oral administration and intravenous administration, transmucosal administration, transdermal administration, intramuscular administration, subcutaneous administration, intrarectal administration and the like can be appropriately selected, and depending on the administration method Can be used as various preparations.

  Hereinafter, each formulation is described, but the dosage form used in the present invention is not limited to these, and can be used as various formulations usually used in the pharmaceutical formulation field.

  When used as an analgesic composition, the oral dose of a component that inhibits, suppresses or reduces the production of hydrogen sulfide in vivo is preferably in the range of 1 mg / kg to 100 mg / kg, more preferably 10 mg / kg. ~ 60 mg / kg. In the case of systemic administration, especially in intravenous administration, there are variations depending on age, sex, body type, etc., but the effective blood concentration is in the range of 30 μg / mL to 900 μg / mL, more preferably 100 μg / mL to 600 μg / mL Should be administered.

  The dosage forms for oral administration include powders, granules, capsules, pills, tablets, elixirs, suspensions, emulsions and syrups, which can be selected as appropriate. Moreover, modifications such as sustained release, stabilization, easy disintegration, poor disintegration, enteric solubility, easy absorption, etc. can be applied to these preparations. In addition, dosage forms for local oral administration include chewing agents, sublingual agents, buccal agents, lozenges, ointments, patch agents, liquid agents, and the like, which can be selected as appropriate. Moreover, modifications such as sustained release, stabilization, easy disintegration, poor disintegration, enteric solubility, easy absorption, etc. can be applied to these preparations.

  For each of the above dosage forms, a known drug delivery system (DDS) technique can be employed. As used herein, DDS preparations include sustained release preparations, topical preparations (troches, buccal tablets, sublingual tablets, etc.), drug release control preparations, enteric and gastric preparations, etc., administration route, bioavailability In addition, it refers to a preparation in an optimal preparation form in consideration of side effects and the like.

  The components of DDS basically consist of drugs, drug release modules, coatings and treatment programs. For each component, a drug with a short half-life, in which the blood concentration decreases rapidly when release is stopped, is preferred. It is preferable to have a sheath that does not react with the biological tissue at the administration site, and it is preferable to have a treatment program that maintains the best drug concentration for a set period of time. The drug release module basically comprises a drug reservoir, a release control, an energy source and a release hole or release surface. It is not necessary to have all these basic components, and the best mode can be selected by adding or deleting as appropriate.

  Materials that can be used for DDS include polymers, cyclodextrin derivatives, lecithin and the like. Insoluble polymers (silicone, ethylene / vinyl acetate copolymer, ethylene / vinyl alcohol copolymer, ethyl cellulose, cellulose acetate, etc.), water-soluble polymers and hydroxyl gel-forming polymers (polyacrylamide, polyhydroxyethyl) Methacrylate cross-linked product, polyacrylic cross-linked product, polyvinyl alcohol, polyethylene oxide, water-soluble cellulose derivative, cross-linked poloxamer, chitin, chitosan, etc.), slow-dissolving polymer (ethyl cellulose, methyl vinyl ether / maleic anhydride copolymer partial ester, etc.) ), Gastric polymer (hydroxypropylmethylcellulose, hydroxypropylcellulose, carmellose sodium, macrogol, polyvinylpyrrolidone, dimethylaminoethyl methacrylate, acrylic acid Acid methyl copolymers), enteric polymers (hydroxypropylmethylcellulose phthalate, phthalcellulose acetate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, acrylic polymers, etc.), biodegradable polymers (thermally coagulated or crosslinked albumin, Cross-linked gelatin, collagen, fibrin, polycyanoacrylate, polyglycolic acid, polylactic acid, polyβhydroxyacetic acid, polycaprolactone, etc.) and can be appropriately selected depending on the dosage form.

  In particular, partial esters of silicone, ethylene / vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, methyl vinyl ether / maleic anhydride male copolymer can be used for drug release control, and cellulose acetate is used as an osmotic pump material. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and methylcellulose can be used as membrane materials for sustained-release preparations, and polyacrylic crosslinked products can be used as oral mucosa or ocular mucosa adhesives.

  In addition, depending on the dosage form (known dosage forms such as orally administered drugs, injections, suppositories, etc.) in the formulation, solvents, excipients, coating agents, bases, binders, lubricants, disintegration Additives such as agents, solubilizers, suspending agents, thickeners, emulsifiers, stabilizers, buffering agents, tonicity agents, soothing agents, preservatives, flavoring agents, fragrances, coloring agents, etc. Can be manufactured.

Each of these additives is exemplified with specific examples, but is not particularly limited thereto.
Solvent: Purified water, water for injection, physiological saline, peanut oil, ethanol, glycerin,
Excipients: Starch, lactose, glucose, sucrose, crystalline cellulose, calcium sulfate, calcium carbonate, talc, titanium oxide, trehalose, xylitol,
Coating agents: sucrose, gelatin, cellulose acetate phthalate and the polymers described above,
Base: Vaseline, vegetable oil, macrogol, oil-in-water emulsion base, water-in-oil emulsion base,
Binders: starch and derivatives thereof, cellulose and derivatives thereof, natural polymer compounds such as gelatin, sodium alginate, tragacanth and gum arabic, synthetic polymer compounds such as polyvinylpyrrolidone, dextrin, hydroxypropyl starch,
Lubricant: stearic acid and its salts, talc, waxes, wheat starch, macrogol, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol,
Disintegrants: starch and derivatives thereof, agar, gelatin powder, sodium bicarbonate, cellulose and derivatives thereof, carmellose calcium, hydroxypropyl starch, carboxymethylcellulose and salts thereof and cross-linked products thereof, low-substituted hydroxypropylcellulose,
Solubilizer: cyclodextrin, ethanol, propylene glycol, polyethylene glycol,
Suspending agent: gum arabic, tragacanth, sodium alginate, aluminum monostearate, citric acid, various surfactants,
Thickener: Carmellose sodium, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, tragacanth, gum arabic, sodium alginate,
Emulsifier: gum arabic, cholesterol, tragacanth, methylcellulose, various surfactants, lecithin,
Stabilizer: sodium bisulfite, ascorbic acid, tocopherol, chelating agent, inert gas, reducing substance,
Buffer: sodium hydrogen phosphate, sodium acetate, boric acid,
Tonicity agents: sodium chloride, glucose,
Soothing agents: Procaine hydrochloride, lidocaine, benzyl alcohol,
Preservatives: benzoic acid and its salts, paraoxybenzoic acid esters, chlorobutanol, reverse soap, benzyl alcohol, phenol, thimerosal,
Flavoring agents: sucrose, saccharin, licorice extract, sorbitol, xylitol, glycerin,
Air freshener: Spruce tincture, rose oil,
Colorant: Water-soluble food color, lake color.

  As described above, by making a pharmaceutical product into a DDS formulation such as a deregulated formulation, an enteric formulation or a controlled drug release formulation, effects such as sustaining the effective blood concentration of the drug and improving bioavailability can be expected.

  In the preparation, components that are used in normal compositions can be used as additives other than those described above, and the amount of these components to be added should be a normal amount within a range that does not interfere with the effects of the present invention. it can.

  Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

The Randall-Selitto method for measuring an analgesic effect in an effective rat hindlimbs H _{2 S} to rat mechanical hyperalgesia measured pain threshold after NaHS injection and examined the effect.
1) Experimental method
i) Experimental animals 6-9 week old male Wistar rats (Japan SLC, Inc., Japan) were used. Rats were subjected to the experiment after 1 week of preliminary breeding in an environment of room temperature 23 ± 2 ° C., humidity 50 ± 5%, and light / dark cycle of 12 hours (light period: 0700 to 1900). During the preliminary breeding period, solid feed (CRF-1, oriental yeast) and water were ingested freely.
ii) Drugs used and administration schedule Sodium hydrogen sulfide (NaHS), which physically generates hydrogen sulfide, was used. The NaHS was dissolved in physiological saline and administered into the rat right hind paw. Saline was administered in the same manner as a control group. 5,5′-Dithio-bis- (2-nitrobenzoic acid) (DTNB) was dissolved in 1% DMSO and administered alone or in combination with NaHS into the right hind limb of the rat. L-cysteine HClH ₂ O and D-cysteine HClH ₂ O were dissolved in physiological saline and administered into the rat right hind paw.
iii) Measurement of mechanical nociceptive threshold The mechanical nociceptive threshold was measured by the Randall-Selitto method. That is, using a pressure-stimulated analgesic effect measuring device (MK-300, Muromachi Kikai Co., Japan), mechanical pressure is applied to the right hind limb of a rat at 30 g / sec, using a postcard response or cry as an index. The acceptance threshold was measured. In order to prevent damage to the hind limbs, the pressure stimulus applied was limited to 500 g. The obtained results were expressed as values calculated by the following mathematical formula with the mechanical nociceptive threshold before drug administration as 100%.
Mechanical nociceptive threshold (% baseline) = obtained threshold (g) / threshold before drug administration (g) × 100
2) Experimental results It was found that NaHS administration (1 nmol / footpad) showed a maximum threshold decrease about 15 to 20 minutes after administration, and that NaHS caused hyperalgesia. This effect was dose dependent (Figure 1). This hyperalgesia of NaHS was suppressed by DTNB, which is an oxidizing agent (FIG. 2). From this, it is considered that the action of NaHS is via H ₂ S. Further, L-cysteine, which is a substrate for cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) and generates hydrogen sulfide via these enzymes, also induces hyperalgesia in a dose-dependent manner, similar to NaHS. However, hyperalgesia was not observed with the optical isomer D-cysteine (FIG. 3). Thus, naturally occurring L-cysteine becomes a substrate for pyridoxal-5′-phosphate-dependent enzyme, and hyperalgesia is induced by producing hydrogen sulfide from the L-cysteine in the rat footpad. Became clear.

Effects of various inhibitors on L-cysteine induced hyperalgesia in rats Effect of cystathionine γ-lyase (CSE) inhibitor and cystathionine β-synthase (CBS) inhibitor on L-cysteine hyperalgesia was investigated. .
1) Experimental method
i) Drug Used and Administration Schedule L-cysteine HClH ₂ O was dissolved in physiological saline and administered into the rat right hind paw. DL-propargylglycine (PAG) and β-cyanoalanine (BCA) were dissolved in physiological saline and administered intraperitoneally 60 minutes before L-cysteine administration. Aminooxyacetic acid (AOAA) was dissolved in physiological saline and administered intraperitoneally 90 minutes before L-cysteine administration.
2) Experimental results Experimental results are shown in Figs. In the following experiment, instead of NaHS administration, L-cysteine that produces H ₂ S by pyridoxal-5′-phosphate-dependent enzyme was locally administered to rat footpads. The CSE inhibitors PAG and BCA improved rat hyperalgesia induced by L-cysteine (FIGS. 4 and 5). On the other hand, COA inhibitor AOAA did not improve the mechanical hyperalgesia induced by L-cysteine in rats (FIG. 6). Therefore, the hyperalgesia induced by L-cysteine was reduced by the CSE inhibitor, whereas it was not reduced by the CBS inhibitor. Therefore, the analgesic action was not central but peripheral. It was suggested.

Effect of CSE inhibitor on LPS-induced hyperalgesia in rats The effect of CSE inhibitor PAG was examined using a lipopolysaccharide (LPS) pain model.
1) Experimental method The effect on hyperalgesia was measured by the method described in Example 1 except that the following pain model was used.
i) Preparation of a lipopolysaccharide (LPS) pain model A pain model was prepared by administering LPS dissolved in physiological saline into the sole of the rat hind limb at a dose of 1 μg / 0.1 mL. PAG (3.75, 11.25 and 37.5 mg / kg) was administered intraperitoneally 30 minutes before LPS plantar administration.
2) Experimental results Compared to saline administration, the CSE inhibitor PAG improved LPS-induced hyperalgesia. The maximum improvement effect was observed in the PAG 11.25 mg / kg administration group (FIG. 7). In general, LPS-induced hyperalgesia is caused by various inflammatory mediators. From this experiment, LPS-induced hyperalgesia was improved by the CSE inhibitor PAG, suggesting that hydrogen sulfide is involved in pain during inflammation.

Tablets Tablets were prepared by a conventional method according to the following formulation.
Crystalline cellulose 50mg
DTNB 50mg
Low substituted hydroxypropylcellulose 50mg
Hydroxypropyl methylcellulose 10mg
Magnesium stearate 5mg
Lactose appropriate amount

Total 1000mg

Tablets Tablets were prepared by a conventional method according to the following formulation.
Crystalline cellulose 50mg
PAG 50mg
Low substituted hydroxypropylcellulose 50mg
Hydroxypropyl methylcellulose 10mg
Magnesium stearate 5mg
Lactose appropriate amount

Total 1000mg

Capsule A capsule was prepared by a conventional method according to the following formulation.
DTNB 50mg
Low substituted hydroxypropylcellulose 50mg
Cross-linked sodium carboxymethylcellulose 5mg
Magnesium stearate 5mg
Lactose appropriate amount

Total 500mg

Capsule A capsule was prepared by a conventional method according to the following formulation.
PAG 50mg
Low substituted hydroxypropylcellulose 50mg
Cross-linked sodium carboxymethylcellulose 5mg
Magnesium stearate 5mg
Lactose appropriate amount

Total 500mg

Injection An injection was prepared by a conventional method according to the following formulation.
Glucose 10mg
DTNB 50mg
Purified water for injection

Total 100mL

Injection An injection was prepared by a conventional method according to the following formulation.
Glucose 10mg
PAG 50mg
Purified water for injection

Total 100mL

Any of the preparations obtained in Examples 4 to 9 can be used as the analgesic composition of the present invention.

FIG. 1 shows the effect of NaHS on rat mechanical hyperalgesia. FIG. 2 shows the effect of the oxidant DTNB on rat mechanical hyperalgesia induced by NaHS. FIG. 3 shows the effect of L- and D-cysteine on rat mechanical hyperalgesia. FIG. 4 shows the effect of the CSE inhibitor DL-propargylglycine on rat mechanical hyperalgesia induced by L-cysteine. FIG. 5 shows the effect of the CSE inhibitor β-cyanoalanine on rat mechanical hyperalgesia induced by L-cysteine. FIG. 6 shows the effect of the CBS inhibitor aminooxyacetic acid on rat mechanical hyperalgesia induced by L-cysteine. FIG. 7 shows the effect of propargylglycine on LPS-induced hyperalgesia in rats.

Claims (4)

An analgesic composition comprising, as an active ingredient, a component that inhibits, suppresses or reduces production of hydrogen sulfide in vivo. The analgesic composition according to claim 1, wherein the component is a cystathionine γ-lyase (CSE) inhibitor. The analgesic composition according to claim 2, wherein the cystathionine γ-lyase (CSE) inhibitor is selected from the group consisting of DL-propargylglycine (PAG) and β-cyanoalanine (BCA). The composition according to any one of claims 1 to 3, which is formulated as a DDS preparation.

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