WO2003099301A1 - Preparation a inhaler renfermant de la tetrodotoxine, utile contre les dependances et comme analgesique - Google Patents

Preparation a inhaler renfermant de la tetrodotoxine, utile contre les dependances et comme analgesique Download PDF

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Publication number
WO2003099301A1
WO2003099301A1 PCT/CN2003/000370 CN0300370W WO03099301A1 WO 2003099301 A1 WO2003099301 A1 WO 2003099301A1 CN 0300370 W CN0300370 W CN 0300370W WO 03099301 A1 WO03099301 A1 WO 03099301A1
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Prior art keywords
tetrodotoxin
water
preparation
administration
citrate
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PCT/CN2003/000370
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English (en)
Chinese (zh)
Inventor
Xinfu Pan
Zhuguo Liu
Zhiqiang Huang
Song Pan
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Xinfu Pan
Zhuguo Liu
Zhiqiang Huang
Song Pan
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Application filed by Xinfu Pan, Zhuguo Liu, Zhiqiang Huang, Song Pan filed Critical Xinfu Pan
Priority to AU2003231564A priority Critical patent/AU2003231564A1/en
Publication of WO2003099301A1 publication Critical patent/WO2003099301A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • 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]

Definitions

  • the present invention relates to tetrodotoxin and its analogues for use in detoxifying and analgesic respiratory administration.
  • BACKGROUND Tetrodotoxin (TTX) is also known as prion toxin.
  • Fugu poison Depending on the source, there are Fugu poison, Spheroidine, Maculotoxin gobytoxin, and Tarichatoxin.
  • the molecular formula is C diligentH 17 N 3 0 8 and the molecular weight is 319.28. It belongs to perhydroaminoquinazoline compounds.
  • tetrodotoxin is particularly effective as a muscle relaxant for dominant spasms.
  • TTX To study neural excitement and found that TTX has a highly specific effect on the Na + ion channels of the excitatory membrane. As a result, TTX quickly became One of the most important tool medicines in neurophysiology research.
  • muscle cell membranes and nerve nodes are bounded by membranes.
  • Living cell membranes have different permeability to different substances.
  • the ion accumulation inside and outside the membrane is different.
  • the main ion inside the membrane is K +, and the ion outside the membrane is mainly Na +. If the concentration on the outside of the membrane is zero, the inside of the membrane is usually maintained at a negative resting potential of 50-100 nw compared to the outside.
  • the potential difference changes, that is, depolarization occurs. This potential change increases the permeability of Na + to the cell. Na + flows into the nerve cell membrane, the membrane potential changes, and K + flows out.
  • a part of the tetrodotoxin molecule is mainly a guanidyl group, which is close to the Na + channel, so that Na + is blocked, and it is impossible to approach the transmission channel.
  • guanidino moiety in the saxitoxin molecule, so the mechanism of action is similar. See Figure 1 and Figure 2 for details.
  • tetrodotoxin is easily absorbed by the digestive tract.
  • the toxin is absorbed by the stomach and intestines and then transported to the whole body.
  • the poisoning event occurs within half an hour to eight hours. If, after this period, it is generally not caused by ingestion of puffer fish poisoning.
  • TTX is absorbed through the mucous membranes and transported to the whole body through the blood system. After 20 minutes of subcutaneous injection in rats, TTX reached the highest value in the organs such as kidney, heart, intestine, brain, and lung.
  • TTX is called the strongest vomiting agent. Vomiting also occurs in humans, which is the most intuitive symptom of clinical TTX poisoning. And the symptoms are likely to be central. Ogura believes that TTX stimulates the vomiting center of the fourth ventricle and the chemical vomiting area (CTZ) in the peripheral cortex (Okura: Advances in Neurological Research 24 (5), 860 1971).
  • iv TTX 0.5-2 yg / kg in rabbits caused blood pressure drop (average 5-6 mmHg, time 0.5-33 minutes); the same dose of iv TTX in rats also caused blood pressure drop (10-44mmHg, 7.5-61 minutes).
  • TTX has both peripheral and central effects on the heart, but it is mainly central. After TTX poisoning, the blood pressure changes caused by stimulation of the vagus nerve and the sciatic nerve's central efferent site disappeared. Experiments on transected cervical spinal cord in rabbits showed that the toxin mainly affects the vascular motor center. TTX has different effects on autonomous cells.
  • TTX can inhibit the contraction of smooth muscle, but visceral smooth muscle is less sensitive to it, and TTX has a significant relaxation effect on vascular smooth muscle.
  • TTX can dilate pupils, causing animals to weaken or disappear from light reflections.
  • TTX can inhibit the secretion of sweat glands caused by nerve stimulation, can inhibit the secretion of gastric acid, reduce free acid and lower the pH value. TTX has a very strong local anesthesia effect.
  • TTX solution A very low concentration of TTX solution is injected around the sciatic nerve of mice, and the half effective concentration ED 5 of the local anesthesia effect of TTX is measured. 0.89 ⁇ g / ml, compared to 3596 times that of procaine. And the duration of the two effects is 73 minutes and 10 minutes (P ⁇ 0.01> (Cai Zhiji et al .: Hebei Fisheries Science and Technology 1983 (1) 1-3). The difference is greater in some organizations.
  • TTX and some classic Local anesthetic drugs can increase the effectiveness of local anesthesia, prolong the time, reduce toxicity, and increase the therapeutic index.
  • the combination of a small amount of TTX and commonly used antiarrhythmic drugs can significantly enhance its efficacy (Zhu Cheng Hua et al. Marine Medicine, 1984 (1) 7).
  • TTX was measured by the rat formaldehyde method to have analgesic activity 2950 times stronger than morphine.
  • the mouse hot plate method TTX was 1600 times that of pethidine and the mouse writhing method was 594 times that of pethidine (see People's Daily, 1986 1, 6, 7th edition "A professor at Sendai Medical College in Japan found that tetrodotoxin has an excellent analgesic effect. According to research, the analgesic effect of tetrodotoxin is about 4000 times that of morphine").
  • Used as an antispasmodic it can be used to relax muscle cramps, stomach cramps and other cramps, especially for tetanus cramps, which is called a special effect.
  • Tetrodotoxin has a unique antihypertensive effect.
  • Administration to cats (iv) at 2 to 3 ⁇ g / kg can cause a sudden decrease in normal arterial pressure by 2/3, and the action time is relatively short. There is still a secondary boosting period thereafter. . Therefore, it can be considered that tetrodotoxin may have some uses in clinical rescue of hypertension.
  • tetrodotoxin has a congestive effect, it is also effective for impotence and lack of sexual desire in women. However, those with bladder and urinary tract diseases should not use it, because the toxin can make the mucosa congested or the strength is depressed (quoted from Pan Xinfu, Huang Zhiqiang, Pharmaceutical Bulletin, 1984 (2)).
  • mice 50 times of the minimum death dose per kilogram of mice (generally 50kg in weight) is used to dissolve 1ml of 0.5% pectic carbonic acid in water as a single injection amount (that is equivalent to 1 / 14th of human death dose). Based on this calculation, each ampule contained 35.7 w g of pure tetrodotoxin.
  • tetrodotoxin injection After the injection of tetrodotoxin injection, some patients may have symptoms such as mouth and tongue sensation, congestion of the head, and headache, but the duration is not long.
  • the present invention is a preparation for the administration of respiratory tracts of aminohydroquinazoline compounds and their derivatives represented by tetrodotoxin in terms of indications such as detoxification and analgesia, mainly including aerosol (Aer OS ol) and spray (Spray ) Or Powder Inhaler (aerosol).
  • indications such as detoxification and analgesia, mainly including aerosol (Aer OS ol) and spray (Spray ) Or Powder Inhaler (aerosol).
  • the preparation for respiratory administration according to the present invention is composed of tetrodotoxin citrate or tetrodotoxin acetate and selected from pharmacologically acceptable agents including diluents, propellants, stabilizers, flavoring agents, skin penetration aids or carriers One, two or more aerosols, sprays or aerosols formulated.
  • the propellants include hydrocarbons and Freon (by Mao Lei, “Medicinal Aerosols", China Medical Science and Technology Press, First Edition, June 1997, P49).
  • the stabilizer includes an antioxidant and vitamin E, mainly to improve the chemical stability of the preparation.
  • the flavoring agents include flavors and other flavoring agents in order to improve the patient's acceptability of the formulation. '
  • the mucocutaneous penetration aids include Azone (Az 0ne), caffeine, vitamins (e.g. nicotinamide) and pharmaceutical excipients include vanillin, benzyl alcohol.
  • the aforementioned adjuvants for preparing the tetrodotoxin respiratory preparations of the present invention are all commonly used in the preparation of sprays, aerosols or aerosols, and they are all commercially available products.
  • the optimal formulations of the tetrodotoxin respiratory preparations of the present invention are as follows:
  • the preparation method of the aerosol, spray or aerosol administration preparation of the present invention is a method commonly used in medicine (By Mao Lei, "Medicinal Aerosol", China Medical Science and Technology Press, 1997 6 The first edition of this month, P2-6), is to dissolve tetrodotoxin citrate or tetrodotoxin acetate, penetration aid, etc. in water, adjust the pH if necessary, sterilize by filtration or isotope irradiation, and then Fill into a spray can or aerosol generator under aseptic conditions.
  • the tetrodotoxin citrate or tetrodotoxin acetate according to the present invention includes those commercially available or prepared according to the method of Example 1.
  • the method of administration of the preparation of the present invention includes nasal, oral or tongue administration, preferably nasal administration.
  • the spraying device used for administration is known.
  • Intranasal administration has now become a mode of administration.
  • the absorption rate of the nasal mucosa depends on many variable factors, however, the surface area absorbed by the nasal cavity and the local blood flow in the nasal cavity are the key.
  • the surface area of the nasal cavity is controlled by airflow resistance, which is determined by capillaries, which relax and cause rhinitis or nasal congestion.
  • Vasodilation can also increase blood flow and enhance absorption by increasing drug mobility at the absorption site.
  • tetrodotoxin and its analogs can be successfully absorbed by capillaries through the nasal mucosal route of administration, and its absorption rate is no less than that of subcutaneous, intramuscular or intravenous routes of administration.
  • the dosage of tetrodotoxin of the present invention should be 0.01 to 10 micrograms / spray, more preferably 0.1 to 1 microgram / spray; it can be administered one or more times, and more preferably 1 to 4 times a day.
  • the volume of each shot is 5 to 200 microliters, and more preferably 50 to 100 microliters.
  • the nasal administration solution preparation can be administered as a nasal drop from a nasal drop bottle, or as an aerosol from a compressed bottle, a single unit dose or a metered pump spray.
  • a standard buffer system such as citrate, acetate, lactate, benzoate and other buffer systems can be used to control the pH value, so that the preparation is preferably buffered to pH 3 to 7, and more preferably buffered to pH 4 to 6.
  • standard isotonic substances such as sodium chloride, mannitol, or glucose
  • Powder particle size is an important factor in nasal mucosal absorption. When the powder particles are smaller than 1 micron, it is easy to be inhaled into the lungs; when the powder particles are larger, it is not easy for the nasal mucosa to absorb or exhale.
  • the present invention preferably has a particle size distribution of 0.1 to 100 microns, and more preferably a particle size of 5 to 40 microns.
  • carrier powders such as lactose and glucose are often mixed with drug powders to aid production and dose reproducibility when administered intranasally.
  • the tetrodotoxin respiratory preparation of the present invention can directly administer the drug to the site of action, has fast effects, small toxic and side effects, and is convenient to use. It does not require injections and medicines, and is convenient for family use. At the same time, it can solve some patients' injection of tetrodotoxin injection Later, problems such as abnormalities in the mouth and tongue, and headaches may occur. Therefore, the present invention is a good analgesic and detoxification drug preparation.
  • Dogs were used to evaluate the effectiveness of the preparations for respiratory administration of the present invention: 4 fasted heroin-addicted dogs were lightly anesthetized, and each dog received 1 microgram of the tetrodotoxin preparation in the nostrils. After 5 minutes, 4 dogs withdrew The symptoms disappeared. This is consistent with human clinical withdrawal symptoms. It is generally valid for 4 to 18 hours.
  • Figure 1 is a schematic diagram of the saxitoxin STX structure
  • FIG. 2 is a schematic diagram of Tetrodotoxin TTX. Embodiments of the present invention The features of the present invention will be further explained by specific examples.
  • This example is the preparation of tetrodotoxin API.
  • D152 weakly acidic cation exchange resin (about 60 mesh) is pretreated by conventional methods, it is converted into NH 4 + type with 8% ammonia water, and the water is washed to pH 8.
  • the toxin stock solution is finely filtered once during the exchange, and the column (hl30cm, (0 12cm), flow rate 80-120ml / min, the late stage of exchange was monitored by mouse toxicity tracking. After the exchange, flush the column with water (150 liters) until it is colorless and contains no solids. The 10% acetic acid aqueous solution was used to elute the toxin, and the flow rate was 30-50 ml / min. The mouse toxicity was followed and the fractions were collected step by step.
  • the front fraction is weakly toxic, used for the next soaking and extraction, and the final toxic fraction is very high in acetic acid. It is used to prepare the acetic acid eluent when the next column is punched.
  • the middle highly toxic fraction (3.5 liters, with a toxic concentration of about 1420 mg / l). .
  • This white solid was mixed with 3.59 g of picric acid, dissolved by boiling with 50 ml of water, and filtered while hot. The filtrate was left to cool and precipitate yellow needle-like crystals. After recrystallization from hot water three times, picric acid salt (6.9 g) was obtained. It was dissolved in hot water, ammonia water was added dropwise, and after cooling, the obtained solid was dissolved in acetic acid, converted into ammonia water, washed with water, ethanol, etc. to obtain crude TTX (2.9 g) with a yield of about 51%.
  • the LD 5 Q of this sample is 10.0 ⁇ g / kg (mouse, ip)
  • the white powdery crystals obtained above were dissolved with 0.2 mol of acetic acid-sodium acetate in a 37/63 ratio buffer, and were prepared by HPLC on a C 18 reverse phase column using an RI detector.
  • the mobile phase was an acetic acid aqueous solution at pH 4 with a flow rate of At 1 ml / min, fractions with a combined retention time of 11-12 minutes were collected. Concentrated under reduced pressure to a small volume, adjusted to pH 8.5 with ammonia, and allowed to cool.
  • the solid obtained by filtration was washed with high-purity water and high-grade pure ethanol, and dried under vacuum to obtain pure toxin.
  • This toxin is dissolved with a buffer of 0.1 mol citrate-citrate 44.5 / 55.5 as a stabilizer, and the ratio of toxin to stabilizer is 1: 5. It should be freeze-dried within 24 hours. After passing the inspection, it should be packaged and stored as the drug substance.
  • This example confirms the chemical structure of the tetrodotoxin used to prepare the tetrodotoxin drug substance of the present invention. Appearance: White crystalline powder.
  • Solubility Easily soluble in acid water, insoluble in water, methanol, ethanol and other solvents.
  • test results only contain C, H, N, 0
  • Instrument calibration The instrument calibration was performed according to the infrared spectrometry method of the appendix of the two parts of the Chinese Pharmacopoeia 1995. Polystyrene film was used for calibration and verification.
  • Sample preparation method KBr compression method.
  • UV-VIS Ultraviolet absorption spectrum
  • ⁇ 156.23 is a guanidino carbon signal
  • ⁇ 74.81 (d) is a C-4 signal
  • 4- ⁇ is at the e bond
  • 5 40.36 (d) is a C-4a signal
  • ⁇ 73.49 (d) is a C-5 signal
  • ⁇ 71.12 (s) is a C-6 signal with 6-OH in the a bond (6-C-TTX C-6 signal at ⁇ 72.8ppm);
  • 5 79.31 (d) is the C-7 signal; 5 70.53 (d) is the C-9 signal; ⁇ 110.49 (s) is the hemicondensed carbon C-10 signal, which is C-0 with C-5 and C-7.
  • the bonds form a cage structure.
  • the chemical shift of hydroxymethyl of C-11 is
  • ⁇ 156.23 is a guanidino carbon signal
  • ⁇ 74.81 (d) is a C-4 signal
  • 4- ⁇ is at the e bond
  • ⁇ 40.36 (d) is a C-4a signal
  • ⁇ 73.49 (d) is the C-5 signal
  • ⁇ 71.12 (s) is the C-6 signal with 6-OH in the a bond
  • (6--6-TTX C-6 signal is ⁇ 72.8ppm)
  • 5 79.31 (d) It is a C-7 signal
  • ⁇ 70.53 (d) is a C-9 signal
  • ⁇ 110.49 (s) is a hemicondensed carbon C-10 signal, which forms a cage structure with C-5 and C-7 by CO bonds.
  • C-11 has a methylol chemical shift of ⁇ 65.18 (t). The results of carbon spectrum analysis are consistent with those reported by TTX in the literature.
  • the molecular ion peak m / z 319 (M +) provided by mass spectrometry is consistent with the results of elemental analysis. Mass spectrometry and the fragment peaks (see figure) are consistent with the tetrodotoxin structure.
  • the IR, MS, 'HNMR, and 13 C NMR spectra of the samples were further compared with the signals of the structure of the literature values, which were completely consistent. The chemical structure of the sample was proved to be tetrodotoxin.
  • the tetrodotoxin citrate and the tetrodotoxin acetate were prepared by the method of Example 1 as the raw drug of tetrodotoxin. 1 mg was dissolved in high-purity water so that its concentration was 5 micrograms per milliliter.
  • a 1 mg tetrodotoxin API was prepared by the method of Example 1 and a 5% weight / volume aqueous glycerol solution was added to 100 ml of water for injection.
  • tetrodotoxin API 200 mg was prepared by the method of Example 1, 1.5 grams of caffeine, water was added to 20,000 milliliters, and the mixture was stirred until dissolved. After filtering through a sterile funnel, 40,000 single-dose nasal spray devices were filled.

Abstract

la présente invention concerne une préparation à inhaler contenant de la tétrodotoxine qui permet de combattre les dépendances et la douleur. Cette préparation, dont la matière première est constituée par de du citrate de tétrodotoxine ou de l'acétate de tétrodotoxine, est fabriquée de manière classique et se présente sous forme d'aérosol, de vaporisation ou de nébulisation. Administrée par inhalation, la préparation selon l'invention est sure, efficace, d'emploi pratique, et ne crée pas de dépendance. Cette préparation à inhaler à base de détrodotoxine est efficace à 97 % comme anti-douleur chez des malades atteints de cancer et jusqu'à 100 % contre les toxicomanies ; elle constitue donc un remarquable médicament pour son action contre les dépendances et la douleur.
PCT/CN2003/000370 2002-05-23 2003-05-20 Preparation a inhaler renfermant de la tetrodotoxine, utile contre les dependances et comme analgesique WO2003099301A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003231564A AU2003231564A1 (en) 2002-05-23 2003-05-20 Formulation containing tetrodotoxin for abstinence and analgecize which is administered through respiratory tract

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CNB02117928XA CN100360133C (zh) 2002-05-23 2002-05-23 用于戒毒、镇痛的河豚毒素呼吸道给药制剂
CN02117928.X 2002-05-23

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123088A1 (fr) * 2004-06-22 2005-12-29 Wex Pharmaceuticals Inc. Formulations solides de tétrodotoxine administrables par voie orale
EP2397143A1 (fr) * 2008-09-17 2011-12-21 Xiamen Zhaoyang Biological Engineering Co., Ltd. Préparation de tétrodotoxine lyophilisée en poudre et son procédé de préparation
US8124608B2 (en) 2003-07-14 2012-02-28 Wex Medical Limited Stable pharmaceutical composition of freeze-dried tetrodotoxin powder

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100367966C (zh) * 2004-09-28 2008-02-13 黄致强 河鲀毒素油相制剂的制备方法
CN107349206A (zh) * 2017-07-11 2017-11-17 东新皓特（北京）生化科技有限公司 河豚毒素在制备治疗***不良症状及复吸的药物组合物中的应用

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CN1145225A (zh) * 1996-09-24 1997-03-19 王维国 用于戒毒、镇痛的药剂及其制法
CN1227102A (zh) * 1998-06-09 1999-09-01 河北省水产研究所 一种戒除药物依赖性的药剂
CN1343491A (zh) * 2000-09-18 2002-04-10 威克斯医疗仪器有限公司 局部麻醉与镇痛的新方法

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CN1051706C (zh) * 1994-03-17 2000-04-26 南宁枫叶药业有限公司 氨基氢化喹唑啉类化合物及其衍生物戒降药物依赖性的新用途

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1145225A (zh) * 1996-09-24 1997-03-19 王维国 用于戒毒、镇痛的药剂及其制法
CN1227102A (zh) * 1998-06-09 1999-09-01 河北省水产研究所 一种戒除药物依赖性的药剂
CN1343491A (zh) * 2000-09-18 2002-04-10 威克斯医疗仪器有限公司 局部麻醉与镇痛的新方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124608B2 (en) 2003-07-14 2012-02-28 Wex Medical Limited Stable pharmaceutical composition of freeze-dried tetrodotoxin powder
US8222258B2 (en) 2003-07-14 2012-07-17 Wex Medical Limited Stable pharmaceutical composition of freeze-dried tetrodoxin powder
US8530481B2 (en) 2003-07-14 2013-09-10 Wex Medical Limited Stable pharmaceutical composition of freeze-dried tetrodotoxin powder
WO2005123088A1 (fr) * 2004-06-22 2005-12-29 Wex Pharmaceuticals Inc. Formulations solides de tétrodotoxine administrables par voie orale
EP2397143A1 (fr) * 2008-09-17 2011-12-21 Xiamen Zhaoyang Biological Engineering Co., Ltd. Préparation de tétrodotoxine lyophilisée en poudre et son procédé de préparation
EP2397143A4 (fr) * 2008-09-17 2013-07-31 Xiamen Zhaoyang Biolog Engineering Co Ltd Préparation de tétrodotoxine lyophilisée en poudre et son procédé de préparation

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CN1459286A (zh) 2003-12-03
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