CN100363006C - Drug addiction-stopping formulation and preparation thereof - Google Patents
Drug addiction-stopping formulation and preparation thereof Download PDFInfo
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- CN100363006C CN100363006C CNB200410064338XA CN200410064338A CN100363006C CN 100363006 C CN100363006 C CN 100363006C CN B200410064338X A CNB200410064338X A CN B200410064338XA CN 200410064338 A CN200410064338 A CN 200410064338A CN 100363006 C CN100363006 C CN 100363006C
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Abstract
The present invention provides a drug abstinence preparation and a preparation method thereof, which relates to a medicine preparation with natural organic active ingredients and a preparation method thereof, particularly to a drug abstinence preparation (with a recipe of using accurately quantitive tetrodotoxin monomers as main active ingredients matched with proper auxiliary material carriers and a functional regulator and using tetrodotoxin perylene derivatives as stabilizing agents), a preparation method thereof and an application method thereof. The tetrodotoxin monomers adopted by the present invention has the tetrodotoxin purify of higher than 99%, acid solvent carriers are acetic acid-sodium acetate trihydrate or citric acid-trisodium citrate dihydrate or citric acid-disodium hydrogen phosphate, and the functional regulator is at least one kind of materials in chlorobutanol, benzyl alcohol and lidocaine hydrochloride. The drug abstinence preparation of the present invention is mainly used for blocking dependence withdrawal syndromes of cannabis drugs and opium drugs such as amphetamin chloride, heroin, etc. The present invention provides the clinical drug abstinence preparation with the advantages of rapid effect taking, high stability, high efficiency, high safety, small irritability on muscles, conspicuous effect (on drug dependence paroxysm control and abstinence reaction eliminate), painless drug abstinence (under a consciousness state of patients) and high drug abstinence withdrawal effective rate (which reaches 100%).
Description
Technical field
The present invention relates to a kind of pharmaceutical product that contains natural organic active ingredient, with marine biotoxins nerve centre Na-ion channel blocker as methamphetamine hydrochloride class [amphetamine (amfetamine), methamphetamine (methamphetamine hydrochloride), 3,4 methylene dioxy ylmethyl amfetamine (MDMA, be commonly called as: head-shaking pill, claim XTC again, The Smurfs, Adam, it is dead to like him, One's spirit has freed itself from his body etc.)], opiatess such as heroin (heroin, morphine, codeine, dolantin, dihydroetorphine, Opium, methadone etc.), cannabis [comprises Cannabis resin, cannabis oil, " marijuana " (India claims " Ganja ", and north African claims " Kib " Middle East to claim " Bhang ", and South Africa claims " Dagga ") that processes by big straw and leaf, and " hashiss " that process by the flower and the partial blade at Fructus Cannabis female plant top] method for making and the application of drugs drug addiction-stopping formulation, relate in particular to accurate quantitative Fugu ocellatus toxin monomer (purity＞99%) as main effective ingredient and collaborative suitable adjuvant carrier, function regulator and with derivative of tetradotoxin as drug addiction-stopping formulation of stabilizing agent prescription and its production and application.
Background technology
The used marine biotoxins of the present invention is different from synthetic toxic agent fully, mainly act on voltage-dependent ion channel (as sodium, calcium channel etc.) on the excitable cell films such as nervus centralis, muscle, thereby blocking-up, disturb or destroy diffusion or the transmission that the vital movement process is played " information " of significant role, produce a series of pharmacology and toxicological effect.The research of toxicology and pharmacology aspect discloses, and mainly acts on the central nervous system as the Fugu ocellatus toxin of one of most important marine biotoxins.Excavate the clinical value of Fugu ocellatus toxin, be domestic and international research institution research emphasis in recent years always.The effect major part of Fugu ocellatus toxin depends on neural mediation, and the initial link of influence is the various histiocytic nerves of domination.At the research Fugu ocellatus toxin paralysis of central nervous tissue is done the time spent, it is found that low dose of Fugu ocellatus toxin just can produce retardation to sensory fiber, heavy dose of motor fiber that just has influence on, its main pharmacological is by suppressing the sodium ion inflow of neurocyte, the conduction of block nerves excitement, optionally blocking sodium-ion channel, is a kind of Na-ion channel blocker with high specific, 10
-7～10
-8Just can produce blocking effect under the concentration of M, particularly the blocking effect to the central nervous system is direct and reversible.This is applied to treat the drugs withdrawal syndrome to Fugu ocellatus toxin theoretical foundation is provided.Numerous researchs disclose, methamphetamine hydrochloride class drugs are powerful central stimulant, opium drug directly acts on the central nervous system, the heroin that is called as " king of hard drug " is one of material that addiction is the strongest in the opioid, very easily enter the central nervous system rapidly by blood brain barrier, capture the maincenter receptor fast, make junkie produce tread on air sense of euphoria and can not extricate oneself.The world today, the drug issue of globalization has constituted significant threat to human existence and development, drug rehabilitation method in the world mainly is to rely on alternative medicine at present, the drug addiction treatment method of western developed country first-elected " methadone maintenance therapy ", in treatment opioid addict, play a part certain, but methadone belongs to the agonist of opiate receptor, the same with other opium drugs, long-term and repeatedly use can cause the dependence of human body to methadone, used the patient of methadone detoxification treatment high to the close medicine degree of methadone, someone once investigated the close medicine degree of heroin addict with close medicine scoring method, the discovery heroin addict is kept the score to the close medicine of methadone and is only second to heroin, therefore, no matter methadone is detoxification treatment or is used to keep treatment, in case stop using, drug addiction is shown effect immediately, need to rely on medication all the life, but be a kind of, still have the drawback of drug addiction with mild toxicity " with poison generation poison " therapy for big poison.
Therefore the anti-additive medicament preparation that press for a kind of efficient, no addiction of exploitation, hangs down side effect or have no side effect.The pharmacological action that Fugu ocellatus toxin is out of the ordinary, the mechanism that is central stimulant with opium drugs such as methamphetamine hydrochloride class, heroin is opposite, can promote the recovery of body opioid peptide system and related system function thereof fast, can can bring into play blocking effect by peripheral nervous again by nerve centre, have the withdrawal syndrome of opium drugs such as remarkable antagonism methamphetamine hydrochloride class, heroin due to relying on.
Referring to Fig. 1-8, Fugu ocellatus toxin and main derivant thereof are to extract to obtain from globe fish ovary and liver, and except that the clear and definite Fugu ocellatus toxin of molecular structure (Fig. 1), the main derivant of known molecular structure has: (1) 4,9-Anh-TTX 4,9-Anhydrotetrodotoxin; (2) 4,9-dehydration-6-show Fugu ocellatus toxin; (3) 4-table Fugu ocellatus toxin; (4) 6-table Fugu ocellatus toxin; (5) 11-deoxidation Fugu ocellatus toxin; (6) 11-deoxidation-4-shows Fugu ocellatus toxin; (7) 4,9-dehydration-11-deoxidation Fugu ocellatus toxin etc. (Fig. 2～Fig. 8).The pharmacological research of relevant Fugu ocellatus toxin is from early in the twentieth century just, Xiang Naixi (full state medical journal, 1939:639-647) once junkie was implemented clinical drug rehabilitation research with Fugu ocellatus toxin crude product injection, its specific implementation method is: the maximum consumption of Fugu ocellatus toxin crude product injection is 12ml, minimum amount is 3ml, become mixed liquor to do intravenous injection with 20% glucose solution 20ml, obtain certain effect, but it is impure to be limited to the Fugu ocellatus toxin that extracted at that time, the experimental technique means are backward relatively, lacking can accurate quantitative crucial detection technique, and the violent factors such as toxicity of Fugu ocellatus toxin, most subjects occurs having limited its use clinically from the poisoning symptom that Fugu ocellatus toxin brought out.China starts from early 1980s to the medicinal research of Fugu ocellatus toxin, to the nineties, both at home and abroad the chemicals of Fugu ocellatus toxin being learned research and clinical application research constantly makes progress and breaks through, the application tetrodotoxin formulation is quit drug abuse to opiates drug abuse patient report is at home and abroad all arranged, and the patent of wherein having reported or having announced has:
Publication number is that the patent application of WO95/24903 discloses " multi-ring amino perhydro quinazoline derivant such as Fugu ocellatus toxin treatment alkaloidal drug with the bridge formation formula rely on for example opium; morphine; heroin " (open day: 1995.09.21), this invention is dissolved in Fugu ocellatus toxin in the benzoic acid solution of the acetum of pH4～5 or pH4～5, every part of Fugu ocellatus toxin dosage 30～150 μ g/2ml, the control dosage of Fugu ocellatus toxin is 5～300 μ g when muscle or intravenous injection, patent working drug rehabilitation example uses the dosage of Fugu ocellatus toxin to be: each 30～150 μ g of intramuscular injection, high injection amount: intramuscular injection in 3 days 8 times, each 150 μ g, intravenous injection: each 30 μ g or 60 μ g, high injection amount: intravenous injection in 4 days 13 times, each 60 μ g.
The patent No. provides a kind of " being used for drug rehabilitation, analgesic medicament and method for making thereof " (notification number CN1072486C for 96119454.5 patent, day for announcing 2001.10.10), the preparation technology of its Fugu ocellatus toxin adopts " resin-activated carbon chromatography method ", and its technical process divided for five steps: i.e. " stock solution preparation → ion exchange → activated carbon adsorption → crystallization → recrystallization ".It is crude drug that above-mentioned technology gained Fugu ocellatus toxin is adopted in the preparation of injection of being used to quit drug abuse, ease pain, be dissolved in the acetum of pH4～5, through bottle, seal, autoclaving forms.The Fugu ocellatus toxin content of making injection is 0.5～10.0 μ g/1-20ml, or adds 0.0125～1.00% procaine and make compound injection, and medication is by oral or subcutaneous injection, intramuscular injection, intravenous injection.
The patent No. provides " a kind of medicament of giving up drug dependence " (notification number CN1085532C for 98102072.0 patent, day for announcing 2002.05.29), with Fugu ocellatus toxin is that main effective ingredient is made injection or buccal tablet, and the Fugu ocellatus toxin content in the clinical medicament ultimate unit of making (per ampoule or every) is 0.001～0.45 μ g.
Publication number is that the patent application of CN1459286A discloses a kind of " being used for drug rehabilitation, analgesic tetrodotoxin respiratory tract administration preparation " (open day 2003.12.03), be characterized in that with Fugu ocellatus toxin citrate or Fugu ocellatus toxin acetate be crude drug, make aerosol, spray or aerosol preparations according to a conventional method.
Publication number is that the patent application of CN1353990A discloses a kind of " being used for the dependent preparation of analgesia, anesthesia or medicine " (open day 2002.06.19), relate to Fugu ocellatus toxin or saxitoxin as main active, make injection and be applied to analgesia and drug rehabilitation, the Fugu ocellatus toxin proportion is 5～100 μ g/ml in the preparation.
Publication number provides " a kind of drug rehabilitation, analgesic medicament and preparation method thereof of being used for " (open day 2004.03.31) for the patent application of CN1485039A, and this medicament effluent tetrodotoxin, citric acid and distilled water are formed,
More than invention enters clinical application research to the promotion Fugu ocellatus toxin and has played positive effect, but remains at unsolved key technical problem in the accurate metering of its preparation active ingredient and the aspects such as stability of clinical use effective dose.Wherein publication number is that the toxic dose of the disclosed drug rehabilitation dosage of patent of WO95/24903 and Fugu ocellatus toxin is approaching, and the example experimenter presents the poisoning symptom (tongue, mouth, lip are numb fully, and part also comprises the complete numbness of upper and lower extremities) that Fugu ocellatus toxin brings out; The patent No. is in 9611549454.5 the patent, the therapeutic dose of Fugu ocellatus toxin is 0.5～10.0 μ g/1～20ml, intramuscular injection every day of example using dosage or intravenous injection 1 time, each 20 μ g, but the non-pure product of the tetrodotoxin, TTX prime system that extraction process obtained that it is used, but contain the mixture of 2～3 kinds of derivants at least, there are the following problems in clinical use: the dosage of Fugu ocellatus toxin can't accurately be controlled, unsegregated derivant can't be determined content or proportion in preparation, this will cause the uncertain of Fugu ocellatus toxin content in the preparation, not only influence therapeutic effect, and drug safety can't ensure; In the patent No. was 98102072.0 patent, the Fugu ocellatus toxin therapeutic dose was 0.001～0.45 μ g, and required dose-effect still remains further checking in this dosage and the practical application.Publication number is in the patent application of CN1353990A, has the uncertain factor of the derivate complex and the preparation stability thereof of uncertain amount in its preparation equally.What should draw attention especially is: the toxicity of Fugu ocellatus toxin is extremely strong, and its toxicity than Cyanogran. is eager to excel 1250 times, according to Fugu ocellatus toxin LD
50Result of the test calculate, to the adult of 50kg body weight as long as injection 400 μ g can cause its death.Make a general survey of the above-mentioned patent of domestic and international report, the main contents of its invention embody a concentrated reflection of that clinical using method, using dosage are formed, are used for to Fugu ocellatus toxin as the preparation of active ingredient and as preparation method of the Fugu ocellatus toxin of crude drug or the like.But the accurate metering that how to guarantee Fugu ocellatus toxin main body effective ingredient guaranteeing the safety of the clinical use of Fugu ocellatus toxin, and is wherein all commented or solved as the aspects such as stability of Fugu ocellatus toxin in the preservation process of effective ingredient after forming preparation.
The present application people provides a kind of process for large-scale preparing tetrodotoxin high-purity monomer in Chinese patent 02121463.8 (day for announcing is 2004.07.21).
Summary of the invention
The object of the present invention is to provide a kind of drug addiction-stopping formulation with quantitative Fugu ocellatus toxin and at least a quantitative derivative of tetradotoxin monomer prescription and preparation method thereof, be mainly used in opiates and cannabis dependency withdrawal syndrome such as blocking-up methamphetamine hydrochloride class, heroin.
Another object of the present invention is to provide with the Fugu ocellatus toxin monomer is that main effective ingredient and at least a derivative of tetradotoxin monomer are the application of stabilizing agent as drug addiction-stopping formulation.
Another object of the present invention is to propose to be used for the control of the safety using amount scope of opiates such as methamphetamine hydrochloride class, heroin and the main effective ingredient of cannabis drug addiction-stopping formulation, be the clinical drug addiction-stopping formulation that a kind of stable, efficient, safety, no addiction is provided and has no side effect of quitting drug abuse.
The objective of the invention is to realize by the following technical solutions: adopt Fugu ocellatus toxin monomer and main symbiosis derivant thereof, but extract in their effluent filefish ovaries and the liver, adopt the optimization integrated technology of multiple membrane separation technique such as microfiltration, ultrafiltration, nanofiltration and reverse osmosis and high performance liquid preparative chromatography technology to extract and obtain.
The component of the said drug addiction-stopping formulation of the present invention is Fugu ocellatus toxin, acid solvent carrier, function regulator and stabilizing agent, and said Fugu ocellatus toxin is the Fugu ocellatus toxin monomer of purity＞99%; Said acid solvent carrier is acetic acid-acetate, or citric acid-citrate, or citric acid-phosphate; Said function regulator is at least one in chlorobutanol, benzyl alcohol, the lidocaine hydrochloride; Said stabilizing agent is at least one with Fugu ocellatus toxin symbiosis derivant.
Disclose the essential concentration that Fugu ocellatus toxin is blocked sodium-ion channel based on the correlational study result, the pharmaceutical dosage that mainly contains the effective constituent Fugu ocellatus toxin is selected 0.8～16 μ g/ each clinical applying unit or ml for use.In other each component of preparation, the content of acetic acid-sodium acetate is the acetic acid of 0.25～15mg/ml and the sodium acetate of 0.40～25mg/ml; The content of citric acid-sodium citrate is the citric acid of 0.01-0.65mg/ml and the sodium citrate of 0.015-0.90mg/ml; The content of citric acid-sodium hydrogen phosphate is the citric acid of 0.1～3.0mg/ml and the sodium hydrogen phosphate of 0.3～6.0mg/ml.The content of function regulator chlorobutanol is 0.1～5.0mg/ml, and benzyl alcohol is 0.5～20mg/ml, and lidocaine hydrochloride is 0.5～20mg/ml.Be selected from 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin with the symbiotic derivant of Fugu ocellatus toxin; 4,9-dehydration-6-shows Fugu ocellatus toxin; 4,9-dehydration-11-deoxidation Fugu ocellatus toxin; 4-shows Fugu ocellatus toxin; 6-shows Fugu ocellatus toxin; 11-deoxidation Fugu ocellatus toxin; 11-deoxidation-4-shows Fugu ocellatus toxin.The content of derivative of tetradotoxin is 0.1～50 μ g/ml.
The preparation method of the said drug addiction-stopping formulation of the present invention is:
1, by each components contents, earlier the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier, control pH is 3～6;
2, dissolve in function regulator and stabilizing agent again, place after filtering;
3, fill obtains formulation products after the filtration sterilization.
Said filtration in step 2, can be respectively through the filter membrane vacuum filtration of 0.4 μ m and 0.22 μ m, and placed at room temperature 12～24 hours.In step 3, said filtration can be through 0.05～0.20 μ m charged microporous membrane (Chargemodified microporous membrane) or submicron order filtering with microporous membrane.Said preparation can adopt injection, tablet, and pill or capsule etc. especially adopt injection, for intramuscular injection or intravenous injection; Be 2～10 days its 1 course of treatment, and use is every reusing more than 8 hours, and the highest per 24 hours use amount is the Fugu ocellatus toxin of 2 * 16 μ g or 3 * 12 μ g.Usually, the drug abuse patient uses 1 course of treatment and urges addiction test negative after naloxone excites, behind the quick detoxification and addiction-removing of drug abuse patient, can oral naloxone or naltrexone or nalmefene implement the anti-rehabilitation of reverting to take drugs, preferably adopt nalmefene, the anti-rehabilitation efficacy of reverting to take drugs is remarkable.
Up to now, be used for the treatment of the existing reports of opium drug withdrawal syndrome such as heroin about Fugu ocellatus toxin, but still do not have the report that is applied to the drug rehabilitation of methamphetamine hydrochloride class drugs.Said here drug abuse patient withdrawal syndrome results from the excessive continuous action of health to dependent drug, and its symptom comprises: osteodynia, myalgia, shed tears, yawn, shiver, goose pimples, platycoria, diarrhoea, vomiting, skin pruritus, the whole body are shaken, manic, anxiety, dispirited, insomnia or the like.Preparation provided by the invention is used for detoxification and addiction-removing, clinical use through thousands of routine volunteer addicts shows, determined curative effect, onset is rapid, no pain drug rehabilitation under clear-headed state, no addiction and toxic and side effects, patient through preparation healing of the present invention, detection of urine morphine and naloxone excite urges the addiction test all negative, and the detoxification and addiction-removing effective percentage reaches 100%, and curative effect is better than existing anti-additive medicament.
Purity is unimodal greater than its spectrogram of Fugu ocellatus toxin monomer of 99%, no matter with fluoroscopic examination reversed-phase high-performance liquid chromatography or ultraviolet detection high performance liquid chromatography, or capillary electrophoresis analysis when detecting Fugu ocellatus toxin all be unimodal spectrogram (seeing Fig. 9～11), the C of its elementary analysis, H, N and theoretical value coincide (seeing Table 1).After adding a kind of and the symbiotic derivant of Fugu ocellatus toxin, its HPLC spectrogram is the bimodal spectrogram of 2 components (Figure 12) of Fugu ocellatus toxin and symbiosis derivant.
Table 1 Fugu ocellatus toxin monomer C, H, N elementary analysis and theoretical value comparative result
| Element | Measured value (%) | Theoretical value (%) |
| C | 41.04 | 41.34 |
| H | 5.26 | 5.32 |
| N | 13.22 | 13.16 |
Another feature of the present invention is that selected function regulator can reduce the stimulation sensitivity of injection to human body, alleviates the human body pain on injection.
The another inventor of being characterised in that of the present invention passes through long-term a large amount of selectivity test and find the balance and stability relation that Fugu ocellatus toxin symbiosis derivant main with it exists in formulation soln.In the further investigation process of Application and Development tetrodotoxin formulation, we find: natural Fugu ocellatus toxin and derivant symbiosis, certain equilibrium relation is arranged, and have following characteristics: 1, structure is close, separates very difficult.The detection response signal strength difference of the Fugu ocellatus toxin of Gamma Magnitude and its symbiosis derivant can reach several times, unsegregated symbiosis derivant very easily with the stack of the detection signal of Fugu ocellatus toxin, make the remarkable deviation of detection by quantitative result.2, Fugu ocellatus toxin symbiosis derivant main with it can transform and reach certain balance under certain condition mutually in aqueous solution.The Fugu ocellatus toxin aqueous solution is in long storage process, and composition will constantly change, and be difficult to meet medicinal standard.Though Fugu ocellatus toxin is very close with its derivant structure, but toxicity, drug effect difference are very big, Fugu ocellatus toxin biological the uncertain of ratio that gain interest together will cause clinical required safe and effective using dosage uncertain, cause the instability and the medicinal unsafe lethal factor of Fugu ocellatus toxin of safe and effective dosage then.To become and have a strong impact on and restrict the technology barrier that Fugu ocellatus toxin uses at clinical expansion.Figure 13 and Figure 14 are respectively Fugu ocellatus toxin monomer formulation stock solution and said preparation stock solution is preserved the HPLC spectrogram of in one-month period, 2 under normal temperature condition.Figure 15 and Figure 16 are respectively the HPLC spectrogram that does not add main symbiosis derivative formulations stock solution and preserve in one-month period, 2 under normal temperature condition.Disclose from the collection of illustrative plates comparative result of Figure 13～16: after adding a kind of Fugu ocellatus toxin main symbiosis spreading out dirt thing the preparation, in the preservation process of 2 year surplus time, the equilibrium system of Fugu ocellatus toxin and its derivant is kept stable substantially.The physiology toxicity of derivative of tetradotoxin is hanged down 1 more than the order of magnitude than Fugu ocellatus toxin at least, the derivant that adds known Sq in preparation also further ensures the high specific feature of Gamma Magnitude biotoxin pharmaceutical formulation as stabilizing agent in the main active component Fugu ocellatus toxin of stabilization formulations.
In sum, the present invention compares with existing document both domestic and external, be characterized in: (1) is that effective ingredient is mixed with drug addiction-stopping formulation with the Fugu ocellatus toxin monomer (purity is more than 99%) of accurate metering, obtains safety, effective, the clear and definite mainly using dosage scope of effective ingredient.(2) allocate in the drug addiction-stopping formulation with at least a derivative of tetradotoxin monomer, form a kind of stabilising system, guarantee the stability of clinical practice preparation stored process, guarantee the safety and the effectiveness of preparation.
Description of drawings
Fig. 1 is the molecular structure of " Fugu ocellatus toxin ".
Fig. 2 is the molecular structure of " 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin ".
Fig. 3 is the molecular structure of " 4,9-dehydration-6-shows Fugu ocellatus toxin ".
Fig. 4 is the molecular structure of " 4-shows Fugu ocellatus toxin ".
Fig. 5 is the molecular structure of " 6-shows Fugu ocellatus toxin ".
Fig. 6 is the molecular structure of " 11-deoxidation Fugu ocellatus toxin ".
Fig. 7 is the molecular structure of " 11-deoxidation-4-shows Fugu ocellatus toxin ".
Fig. 8 is the molecular structure of " 4,9-dehydration-11-deoxidation Fugu ocellatus toxin ".
Fig. 9 is a Fugu ocellatus toxin monomer capillary electrophoresis analysis collection of illustrative plates.
Figure 10 is a Fugu ocellatus toxin monomer ultraviolet detection HPLC collection of illustrative plates.
Figure 11 detects the HPLC collection of illustrative plates for the Fugu ocellatus toxin monomer fluorescence.
Figure 12 adds a kind of analysis collection of illustrative plates of symbiosis derivant for the Fugu ocellatus toxin monomer.
Figure 13 is that Fugu ocellatus toxin monomer formulation stock solution is analyzed collection of illustrative plates.
Figure 14 is that Figure 13 preparation stock solution is preserved 2 years post analysis collection of illustrative plates.
Figure 15 analyzes collection of illustrative plates for the preparation stock solution that the Fugu ocellatus toxin monomer adds a kind of derivatives monomer.
Figure 16 is that Figure 15 preparation stock solution is preserved 2 years post analysis collection of illustrative plates.
In Fig. 9～16, abscissa is time (min), and vertical coordinate is an absorption value.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
Component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier acetic acid-sodium acetate, function regulator chlorobutanol and stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 5 μ g/ml for use.The content of acetic acid-sodium acetate is the acetic acid of 8.4mg/ml and the sodium acetate of 1.0mg/ml.The content of function regulator chlorobutanol is selected 5mg/ml for use; Lidocaine hydrochloride content is 0.5mg/ml.Derivative of tetradotoxin is selected 4,9 dehydration-6-table Fugu ocellatus toxin for use, and content is 10 μ g/ml.It is unimodal spectrogram with spectrogram that the fluoroscopic examination reversed-phase high-performance liquid chromatography detects to said purity greater than 99% Fugu ocellatus toxin monomer, the C of its elementary analysis, H, N and theoretical value coincide (table 1).After adding 4,9 dehydration-6-table Fugu ocellatus toxin, its spectrogram is bimodal spectrogram.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier acetic acid-sodium acetate solution, dissolve in function regulator chlorobutanol and stabilizing agent 4,9-dehydration-6-shows Fugu ocellatus toxin, and this moment, the pH value of preparation medicinal liquid was 3.6.Through 0.4 μ m membrane filtration, to place at room temperature 15 hours after 0.10 μ m filtering with microporous membrane degerming, the fill ampule sealing is prepared into injection.
Fugu ocellatus toxin monomer and derivatives monomer thereof can be by a kind of process for large-scale preparing tetrodotoxin high-purity monomer preparations that provides in the Chinese patent 02121463.8 (day for announcing is 2004.07.21).
Component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier acetic acid-sodium acetate, function regulator chlorobutanol and benzyl alcohol, stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 16 μ g/ml for use.The content of acetic acid-sodium acetate is the acetic acid of 10.3mg/ml and the sodium acetate of 18.0mg/ml.The content of function regulator chlorobutanol is selected 0.5mg/ml for use, and benzyl alcohol is 4.0mg/ml.Derivative of tetradotoxin selects 4 for use, and 9-Anh-TTX 4,9-Anhydrotetrodotoxin, content are 4 μ g/ml.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier acetic acid-sodium acetate solution, dissolve in function regulator chlorobutanol and benzyl alcohol and stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin, this moment, the pH value of preparation medicinal liquid was 4.5.Through 0.22 μ m membrane filtration, to place at room temperature 15 hours after 0.05 μ m filtering with microporous membrane, the fill ampule sealing is made injection.
Similar to Example 1, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier citric acid-liquor sodii citratis, function regulator benzyl alcohol, stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 10 μ g/ml for use.The content of citric acid-sodium citrate is the citric acid of 0.24mg/ml and the sodium citrate of 0.30mg/ml.The function regulator benzyl alcohol is 10mg/ml; Lidocaine hydrochloride is 5.0mg/ml.Derivative of tetradotoxin selects 4 for use, and 9-dehydration-6-shows Fugu ocellatus toxin, and content is 6.0 μ g/ml.During preparation the Fugu ocellatus toxin monomer directly dissolved in acid solvent carrier citric acid-sodium citrate solution, regulating pH value is 4.3, dissolve in function regulator benzyl alcohol and stabilizing agent 4,9-dehydration-6-shows Fugu ocellatus toxin, through 0.20 μ m membrane filtration, placed at room temperature 24 hours after 0.20 μ m filtering with microporous membrane, the fill ampule sealing is made injection.
Similar to Example 2, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier acetic acid-sodium acetate, function regulator lidocaine hydrochloride, stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin and 4,9-Anh-TTX 4,9-Anhydrotetrodotoxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 14 μ g/ml for use.The content of acetic acid-sodium acetate is the acetic acid of 2.4mg/ml and the sodium acetate of 10.8mg/ml.The content of function regulator benzyl alcohol is 0.5mg/ml; The content of lidocaine hydrochloride is selected 10mg/ml for use, and derivative of tetradotoxin selects 4 for use, and 9-dehydration-6-shows Fugu ocellatus toxin 0.1 μ g/ml and 4,9-Anh-TTX 4,9-Anhydrotetrodotoxin 2 μ g/ml.During preparation the Fugu ocellatus toxin monomer directly dissolved in acid solvent carrier acetic acid-sodium acetate solution, dissolve in function regulator lidocaine hydrochloride and stabilizing agent 4,9 dehydration-6-show Fugu ocellatus toxin and 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin, this moment, the pH value of preparation medicinal liquid was 6.0, through 0.40 μ m membrane filtration, placed at room temperature 12 hours after 0.05 μ m filtering with microporous membrane, the fill ampule sealing is made injection.
Component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier citric acid-sodium hydrogen phosphate, function regulator lidocaine hydrochloride and benzyl alcohol, stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 12 μ g/ml for use.The content of citric acid-sodium hydrogen phosphate is the citric acid of 2.58mg/ml and the disodium phosphate soln of 5.52mg/ml.Function regulator lidocaine hydrochloride 5mg/ml and benzyl alcohol 5mg/ml.Derivative of tetradotoxin selects 4 for use, 9-Anh-TTX 4,9-Anhydrotetrodotoxin 5.0 μ g/ml.During preparation the Fugu ocellatus toxin monomer directly dissolved in acid solvent carrier, dissolve in function regulator bupivacaine hydrochloride and benzyl alcohol and stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin, this moment, the pH value of preparation medicinal liquid was 4.3, through 0.22 μ m membrane filtration, placed at room temperature 18 hours after 0.10 μ m charged microporous membrane filters, the fill ampule sealing is made injection.
Similar to Example 5, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier citric acid-sodium citrate, function regulator lidocaine hydrochloride, stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 4 μ g/ml for use.The content of citric acid-sodium citrate is the citric acid of 0.63mg/ml and the sodium citrate of 0.87mg/ml.Function regulator lidocaine hydrochloride 5.0mg/ml.Derivative of tetradotoxin selects 4 for use, 9-dehydration-6-table Fugu ocellatus toxin 15 μ g/ml.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier citric acid-sodium citrate solution, regulating pH value is 4.0; Dissolve in function regulator lidocaine hydrochloride and stabilizing agent 4,9-dehydration-6-shows Fugu ocellatus toxin, through 0.22 μ m membrane filtration, places at room temperature 15 hours after 0.10 μ m filtering with microporous membrane, and the fill ampule sealing makes injection.
Similar to Example 2, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier citric acid-sodium hydrogen phosphate, function regulator chlorobutanol and lidocaine hydrochloride, stabilizing agent 11-deoxidation Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 8 μ g/ml for use.The content of citric acid-sodium hydrogen phosphate is the citric acid of 0.13mg/ml and the sodium hydrogen phosphate of 0.30mg/ml.The content of function regulator chlorobutanol is selected 2mg/ml for use, and the content of lidocaine hydrochloride is 2.0mg/ml.Derivative of tetradotoxin is selected 11-deoxidation Fugu ocellatus toxin for use, and content is 20 μ g/ml.During preparation the Fugu ocellatus toxin monomer directly dissolved in acid solvent carrier acetic acid-sodium acetate solution; Dissolve in function regulator chlorobutanol and lidocaine hydrochloride and stabilizing agent 11-deoxidation Fugu ocellatus toxin, this moment, the pH value of preparation medicinal liquid was 4.2, through 0.22 μ m membrane filtration, placed at room temperature 18 hours after 0.20 μ m filtering with microporous membrane degerming, the fill ampule sealing is made injection.
Similar to Example 2, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier acetic acid-sodium acetate, function regulator lidocaine hydrochloride and benzyl alcohol, stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 16 μ g/ml for use.The content of acetic acid-sodium acetate is the acetic acid of 3.1mg/ml and the sodium acetate of 5.4mg/ml.The content of function regulator lidocaine hydrochloride is selected 10mg/ml for use, and the content of benzyl alcohol is selected 2.0mg/ml for use.Derivative of tetradotoxin selects 4 for use, and 9-dehydration-6-shows Fugu ocellatus toxin, and content is 2.0 μ g/ml.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier acetic acid-sodium acetate solution, this moment, the pH value of preparation medicinal liquid was 4.5; Dissolve in function regulator lidocaine hydrochloride and benzyl alcohol and stabilizing agent 4,9-dehydration-6-shows Fugu ocellatus toxin, through 0.4 μ m membrane filtration, places at room temperature 15 hours after 0.10 μ m filtering with microporous membrane, and the fill ampule sealing is made injection.
Component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier citric acid-sodium citrate, function regulator lidocaine hydrochloride and benzyl alcohol, stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 1 μ g/ml for use.The content of citric acid-sodium citrate is the citric acid of 0.012mg/ml and the sodium citrate of 0.016mg/ml.The content of function regulator lidocaine hydrochloride is selected 20mg/ml for use, and the content of benzyl alcohol is 20mg/ml.Derivative of tetradotoxin selects 4 for use, and 9-Anh-TTX 4,9-Anhydrotetrodotoxin, content are 50 μ g/ml.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier citric acid-sodium citrate solution, regulating pH is 4.5; Dissolve in function regulator benzyl alcohol, lidocaine hydrochloride and stabilizing agent 4, the 9-Anh-TTX 4,9-Anhydrotetrodotoxin through 0.22 μ m membrane filtration, was placed 15 hours at room temperature after 0.10 μ m filtering with microporous membrane, and the fill ampule sealing is made injection.
Similar to Example 8, component of the present invention is the Fugu ocellatus toxin monomer of purity＞99%, acid solvent carrier acetic acid-sodium acetate, function regulator lidocaine hydrochloride and chlorobutanol, stabilizing agent 4, and 9-dehydration-6-shows Fugu ocellatus toxin.
In the each component of drug addiction-stopping formulation, the content of Fugu ocellatus toxin is selected 2.0 μ g/ml for use.The content of acetic acid-sodium acetate is the acetic acid of 0.26mg/ml and the sodium acetate of 0.45mg/ml.The content of function regulator lidocaine hydrochloride is selected 15mg/ml for use, and the content of chlorobutanol is selected 0.1mg/ml for use.Derivative of tetradotoxin selects 4 for use, and 9-dehydration-6-shows Fugu ocellatus toxin, and content is 30 μ g/ml.During preparation the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier acetic acid-sodium acetate solution, this moment, the pH of medicinal liquid was 4.5; Dissolve in function regulator lidocaine hydrochloride, chlorobutanol and stabilizing agent 4,9-dehydration-6-shows Fugu ocellatus toxin, through 0.4 μ m membrane filtration, places at room temperature 18 hours after 0.05 μ m filtering with microporous membrane, and the fill ampule sealing is made injection.
Similar to Example 1, its difference is that the content of acetic acid-sodium acetate is the acetic acid of 14.3mg/ml and the sodium acetate of 24.75mg/ml.Derivative of tetradotoxin selects 4 for use, and 9-dehydration-11-deoxidation Fugu ocellatus toxin, content are 6 μ g/ml.The pH value of preparation medicinal liquid is 4.5.
Similar to Example 5, its difference is that the content of citric acid-sodium hydrogen phosphate is the citric acid of 1.29mg/ml and the disodium phosphate soln of 2.76mg/ml.Derivative of tetradotoxin is selected 4-table Fugu ocellatus toxin 13.0 μ g/ml for use.The pH value of preparation medicinal liquid is 4.3.
Similar to Example 5, its difference is that the content of citric acid-sodium hydrogen phosphate is the citric acid of 1.8mg/ml and the disodium phosphate soln of 3.86mg/ml.Derivative of tetradotoxin is selected 6-table Fugu ocellatus toxin 7.0 μ g/ml and 11-deoxidation-4-table Fugu ocellatus toxin 8.0 μ g/ml for use.The pH value of preparation medicinal liquid is 4.3.
Below provide the use representative instance of this preparation:
Representative instance 1:
ROM * * (Manila, Philippines), the man, 32 years old, 10 years drug abuse time, average every day consumption 1.5g, drug species is mainly methamphetamine hydrochloride (amphetamines).Follow simultaneously with MDMA, K powder, occupation mode is intramuscular injection or intravenous injection, the back behavior change of taking drugs, fidgety, depressed, selfish, lie, cynical, after body injects methamphetamine hydrochloride, the self-induction excitement, whole body is dynamic, is in a cheerful frame of mind, and feels with " speeding across the sky ".Voluntary accepting drug addiction treatment on May 7 in 2003 was stopped using methamphetamine hydrochloride after 15 hours, and fatigue and weak appears in the patient, and is fidgety unusually, insecure, and unimaginable thing takes place prophesy, and occurs autotomy, suicide idea sometimes.Give 1 in intramuscular injection preparation of the present invention (containing Fugu ocellatus toxin 12 μ g), the patient enters in the sleep after 30 minutes, but that exhales can wake up, and patient's self-induction does not have special discomfort, 1 in the preparation of the present invention of intramuscular injection every day after this, on May 8 to 9, patient's readme mood was fidgety, the sensation fatigue and weak, May 10, the patient gets up voluntarily, there is hunger sensation beginning, emotion was clearly better, but still tired meaning is pure, to May 11, the patient occurred from drowsiness and fidgety go to happy, with processes such as the people exchange in a minute, to May 12, begin to be the sleep of rule and the state of getting up, hunger sensation is obvious, eat 5 from every day beginning on the 11st, tired sense, the aching and limp sense of body disappears, and condition is tending towards normally withdrawal symptom after this not occurring, therapeutic process 5 days, 5 of shared injections (5 * 12 μ g).
Representative instance 2:
AXSLKAT (Philippine nationality), man, 60 years old, 16 years drug abuse time, in the recent period average consumption per day is up to 4 grams, and drug species is mainly methamphetamine hydrochloride (amphetamines), occupation mode is oral, intramuscular injection or intravenous injection, and the patient uses 4～5 times with hypertension (BP:190/110mmHg) every day.Voluntary accepting drug addiction treatment on March 8 in 2003, stop using methamphetamine hydrochloride after 5 hours, and obvious withdrawal symptom appears in the patient, shows as tangible misery, worry, tinnitus, diarrhoea, myasthenia of limbs clinically, the hallucination of taking the order of drugs ice is once more ordered about in appearance seemingly someone, and lip is independently vibration.Give 1 in preparation of the present invention (containing Fugu ocellatus toxin 16 μ g) intramuscular injection, measuring blood pressure is 165/105mmHg after 15 minutes, withdrawal symptom is controlled, patient's self-induction before is clearly better, and showing as idol has tinnitus, and hallucination fades away, significantly painful and worry begins to be eased, March 9, the patient occurred drowsinessly aspect the mental status, significantly fidgety and anxiety occurred, gave this preparation 1 intramuscular injection once more, patient on the 10th improvement of suffering from diarrhoea, self-induction drug rehabilitation self-confidence strengthens, and the mental status takes a turn for the better and language increases tinnitus and auditory hallucination transference cure, be emotionally stable, after this 11 days, continued 1 preparation of the present invention of intramuscular injection every day on the 12nd, the patient was through treatment in 5 days, and the mental status is clearly better, appetite heightens, 5 of average every days, also self-induction was obviously hungry, implemented preparation withdrawal of the present invention and did not have special untoward reaction, and self-induction is owing to take due to the methamphetamine hydrochloride that the tinnitus in year is eased surplus in the of ten simultaneously, lip is independently vibration disappearance not, fidgety and the autotomy of no anxiety, patient's self-induction this time drug rehabilitation are very successful, discontinue medication.Therapeutic process totally 5 days, totally 5 of intramuscular injection injections (5 * 16 μ g).
Representative instance 3:
The village *, the man, 34 years old, 13 years drug abuse time, average consumption per day is 1 gram, and drug species is a heroin, uses the drugs mode to be intramuscular injection or intravenous injection, the patient went into narcotic house on June 12nd, 2002, inactive drugs, obvious withdrawal symptom appears in 21:00 on the same day, the 23:00 sx, be the painful posture of tired song, give 1 in preparation of the present invention (containing Fugu ocellatus toxin 12 μ g) intramuscular injection immediately, withdrawal symptom is obviously controlled after 1 hour, and is quiet sleeping after 2.5 hours, there is not any misery, withdrawal symptom appears again in the patient after 10 hours, obviously alleviates 9:30 on June 13rd, 2,002 1 in intramuscular injection preparation of the present invention once more but the withdrawal symptom degree is more preceding, injection back patient feels well no significant discomfort.Withdrawal symptom and companion's diarrhoea appear in patient once more after about 13 hours at interval, 23:00 gave preparation of the present invention 1 intramuscular injection once more on 13rd, the patient feels good, one night calmness, impose 1 injection of preparation of the present invention every day later on, on June 15th, 2002, the patient is conscious to be clearly better, diarrhoea thoroughly disappears, and begins row normally just.To on June 16th, 2002 no withdrawal symptom occur, excite through naloxone and urge the addiction test negative.Therapeutic process totally 5 days, 6 of shared injections.
Representative instance 4:
Shao * *, the man, 25 years old, 8 years drug abuse time, in the recent period average daily drugs amount 1.5 grams, drug species is mainly heroin, and methamphetamine hydrochloride and K powder (chlore-ammonia ketone) are common to be used, and occupation mode is oral, boiling hot suction, intramuscular injection or intravenous injection.Voluntary accepting drug addiction treatment on June 18 in 2004.Stop using drugs after 10 hours, obvious withdrawal symptom appears in the patient, show as watery nasal discharge clinically, shed tears, sneeze, diarrhoea, whole body is aching and limp, bone pain etc., give 1 in preparation of the present invention (containing Fugu ocellatus toxin 12 μ g) intramuscular injection, observed 30 minutes after the intramuscular injection, the patient does not have special discomfort, withdrawal symptom began to alleviate after intramuscular injection in 20 minutes, and withdrawal symptom appears heavily again in the patient after 10 hours at interval, but its degree before weakens, continue 1 in this preparation of injection, withdrawal symptom was eased after intramuscular injection in 15 minutes, and 1 preparation of the present invention of intramuscular injection every day after this is clearly better through 5 days treatment patient self-inductions, defecation is normal, the diet desire strengthens, and withdrawal symptom disappears, and excites through Allylnoroxymorphone and urges addiction to verify as feminine gender, the totally 5 days course of treatment, use 6 of injections (6 * 12 μ g).
Representative instance 5:
Pipe *, the man, 26 years old, 4 years drug abuse time, average consumption per day 0.5g, drug species is a heroin, with the drugs mode is intravenous injection, the patient went into narcotic house's drugs of stopping using on June 7th, 2002, and obvious withdrawal symptom appears in 24:00 on the same day, patient's sign: watery nasal discharge, shed tears, gape, perspiration, bone flesh pain, shiver, suffer from abdominal pain, suffer from diarrhoea, feel sick, vomit, cover with gooseflesh etc.June 8,0:10 gave 1 in preparation of the present invention (containing Fugu ocellatus toxin 6 μ g) intramuscular injection, withdrawal symptom obviously alleviates after 30 minutes, and the patient does not have any misery, feels good, 24:00 is 1 preparation of the present invention of intramuscular injection once more, June 9, the 21:30 intramuscular injection was 1, withdrawal symptom do not occur after 1 of the intramuscular injection on June 10, and the patient does not have other discomforts, appetite is recovered, begin row normally just, therapeutic process 3 days is with 4 of injections.
Representative instance 6:
Slowly *, the woman, 28 years old, 9 years drug abuse time, daily drugs amount 1.5g, drug species is a heroin, uses the drugs mode to be intravenous injection, follows triazolam drug dependence (each 3).Patient 22:00 on June 14th, 2002 goes into narcotic house, go into institute with yawn, sneeze, perspire, watery nasal discharge, shed tears, cover with gooseflesh, skeleton pain, diarrhoea, vomiting, stomachache, be the painful posture of tired song, 1 in the preparation of the present invention of intramuscular injection immediately (containing Fugu ocellatus toxin 10 μ g), withdrawal symptom is controlled after 30 minutes, patient's no pain, June 15,23:00 gave 1 preparation intramuscular injection of the present invention once more, the patient does not have other discomforts, after this June 16～18 1 this preparation of each intramuscular injection respectively, diarrhoea disappears after the 4th day, and June 19, intramuscular injection was 1, withdrawal symptom after this do not occur, therapeutic process 6 days, 6 of shared injections.Detect and naloxone excites that to urge addiction to test all negative through the urine morphine.
Representative instance 7:
Tom * *, the man, 36 years old, 12 years drug abuse time, drug species was mainly Fructus Cannabis.About 20 grams of average every day of Fructus Cannabis consumption in this year, occupation mode can cause fantasy sense of euphoria and happiness for to suck with medicated cigarette behind the drugs that smoke cannabis, and simultaneously with extraneous separation, the impression of time is taken place unusually.No appetite, the infringement of note note power impacts the central nervous system, causes mental symptom and cheese tincture states such as auditory hallucination, photis, and the unusual symptom of a series of psychology occurs, forms the addiction dependence.On June 10th, 2003, the drug addiction treatment of patient's voluntary accepting is stopped using and is smoked cannabis drugs after 20 hours, and HA appears in the patient, put down when stretching both hands and independently do not tremble, performance is perspired clinically, and withdrawal symptoms such as myalgia give 1 in intramuscular injection preparation of the present invention (containing Fugu ocellatus toxin 16 μ g) immediately, injection back patient main suit does not have special discomfort, after 25 minutes, withdrawal symptom is obviously alleviated, and 1 hour laggard goes into the sleep state, after this bestow 1 of intramuscular injection every day, through treatment in 4 days, withdrawal symptom disappeared, and patient's appetite is good, be emotionally stable, myalgia and the flat transference cure that trembles when stretching both hands, the totally 4 days course of treatment, 4 of shared injections (4 * 16 μ g).
Representative instance 8:
Woods * *, the man, 40 years old, 10 years drug abuse time, average drugs consumption per day 1.6 grams, drug species is that heroin and methamphetamine hydrochloride use jointly, occupation mode is snuffing, with medicated cigarette suction, intramuscular injection or intravenous injection.On December 18th, 2003, the voluntary accepting drug addiction treatment, with constitutional asthma, dyspnea was stopped using drugs after 6 hours before the treatment, the patient because of the drugs of stopping using open control watery nasal discharge occurs, shed tears, whole body ache, extreme are craved for etc. obviously gives up sign.Give 1 in preparation of the present invention (containing Fugu ocellatus toxin 16 μ g) intramuscular injection, compare no change before observing patient's blood pressure and injection after 10 minutes, patient's self-induction systemic pain is alleviated after 30 minutes, and the dyspnea symptom alleviates before than this preparation of intramuscular injection.Continued 1 preparation of the present invention of intramuscular injection on 19th, through 2 days treatment, cardinal symptoms such as patient's whole body ache, dyspnea, agitation were obviously improved, continued 1 this preparation of intramuscular injection on the 3rd day, main withdrawal symptom disappears substantially, and asthma originally continues symptom and also greatly improved, and appetite strengthens.Continued 1 this preparation of intramuscular injection on the 4th day, through treatment in 4 days, patient's withdrawal symptom disappeared substantially, listened the two lung asthma sounds of rash also to disappear substantially.Still depositing idol has the cold and symptom such as not good enough of falling asleep of fear, gives 1 preparation for treating of the present invention the 5th, 6 day every day, and withdrawal symptom thoroughly disappears, and patient's self-induction is given up success.Bestow naloxone and excite and urge addiction, check is negative, therapeutic process 6 days, 6 of shared injections (3 * 16 μ g+3 * 12 μ g), oral naltrexone is anti-reverts to take drugs, by the patient voluntarily, family members cooperate enforcement, and are respond well.
Representative instance 9:
Yellow * *, man, 46 years old, 10 years drug abuse time.A nearly week, average daily drugs amount gram every days 2.0 divided 7～8 injections, and intravenous injection was 1 time in about 3 hours, each 0.25 gram, and drug species is mainly heroin, and the highest consumption per day reaches 3～4 grams.On November 3rd, 2003 connect drug addiction treatment voluntarily, and the two upper limb of the visible skin of having a medical check-up, lower limb present the calm speckle of " white point-like " heroin color poison, and as seen the visible vertical bar shape of two upper limb old pin trace, two lower limb are bar shaped point-like injection pin hole.Stop using drugs after 10 hours, patient's dizziness, feel cold, feel sick, gape, shed tears, bone flesh pain is obvious withdrawal symptoms such as angor shape, 1 in the preparation of the present invention of intramuscular injection immediately (containing Fugu ocellatus toxin 12 μ g), injection back patient feels good, after 30 minutes, the patient goes to sleep peacefully, and about 10 hours at interval, the above-mentioned withdrawal symptom of patient occurred once more, obviously alleviate but its degree is more preceding, common intramuscular injection in the 1st day 2 times, 10 hours at interval, common intramuscular injection in the 2nd day 3 times, each 8 hours at interval, injected dose is 1, after each intramuscular injection 20 minutes, observed the patient, and do not tell special discomfort in 40 minutes.Intramuscular injection was 2 times in the 3rd day, each 1 preparation of the present invention, and through treatment in 4 days, the patient is conscious to be clearly better, and the even fear of shivering of main suit is cold, and all the other do not have uncomfortable, and appetite is good, sleeps.To on November 7th, 2003, withdrawal symptom disappeared, and urged the addiction test negative through naloxone, therapeutic process totally 5 days, 9 in intramuscular injection preparation of the present invention (9 * 12 μ g).
Representative instance 10:
Old * *, the man, 40 years old, 12 years drug abuse time, average daily drugs amount 3 grams over nearly 8 months, drug species is a heroin, adopts intravenous injection or intramuscular injection.On November 16th, 2003 the voluntary accepting withdrawal and treatment, have a medical check-up two lower limb, two upper limb and palm refers to, all visible many places ulcer surface between toe, about 2 * 3 centimetres of sizes of area, the visible purulent secretion in wound surface surface, both hands, foot, the visible skin of lower limb are taupe, edema, not having of pressure caved in, scleroma is injected in two upper limb triangular muscles and the big flesh of arm place as seen, and two upper limb, lower limb, distribution place of both hands dorsal vein are covered with old strip pin trace and non-old and are the strip injection pin hole that distributes, and that touches simultaneously has a scleroma.Since the improper repeatedly injection of drug abuse, part vein superficial vein major injury, and with inflammation, be severe drug abuse patient.Stop using drugs after 8 hours, the patient begins to occur vomiting, diarrhoea, feels sick, yawn, shed tears, goose pimples, bone myalgia, be on tenterhooks, mental state is very abominable, agitation etc. is obviously given up the shape shape, the patient vomitted more than 10 times in the 1st day, suffered from diarrhoea 8 times, was watery stool.1 in intramuscular injection preparation of the present invention (containing Fugu ocellatus toxin 16 μ g), withdrawal symptom begins to alleviate after 20 minutes, enters sleep state about 30 minutes, and inject 2 later 3 day every day, each 1 preparation of the present invention of intramuscular injection, 8～12 hours at interval.In view of the infection conditions of patient's vein blood vessel surface suppuration wound surface, take Cefamezin 1.5 grams or cephazolin I number 1.0 grams simultaneously simultaneously.The 2nd day, the patient reappeared withdrawal symptom, obviously weakened but its degree is more preceding.Patient's self-induction was clearly better in the 4th day, transference cures such as vomiting, diarrhoea, lower limbs edema, and hunger sensation is obvious, appetite is good, begins row normally just, and each intramuscular injection was 1 time in the 5th～6 day, 1 of each dosage, after treatment in 6 days, excite through naloxone and to urge addiction to verify as feminine gender, withdrawal symptom disappears, patient's emotion is good, the blood vessel surface wound surface that originally was suppurative infection also is clearly better, and the totally 6 days course of treatment is with 9 of injections.
Claims (10)
1. a drug addiction-stopping formulation is characterized in that its component is Fugu ocellatus toxin, acid solvent carrier, function regulator and stabilizing agent, and described Fugu ocellatus toxin is the Fugu ocellatus toxin monomer of purity＞99%; Described acid solvent carrier is acetic acid-sodium acetate, or citric acid-sodium citrate, or citric acid-sodium hydrogen phosphate; Described function regulator is at least one in chlorobutanol, benzyl alcohol, the lidocaine hydrochloride; Described stabilizing agent is a derivative of tetradotoxin 4,9-Anh-TTX 4,9-Anhydrotetrodotoxin and 4, at least one in the 9-dehydration-6-table Fugu ocellatus toxin.
2. a kind of drug addiction-stopping formulation as claimed in claim 1 is characterized in that the monomeric content of Fugu ocellatus toxin selects 0.8～16 μ g/ml for use.
3. a kind of drug addiction-stopping formulation as claimed in claim 1, the content that it is characterized in that acetic acid-acetate are the acetic acid of 0.25～15mg/ml and the sodium acetate of 0.4～25mg/ml; The content of citric acid-sodium citrate is the citric acid of 0.01-0.65mg/ml and the sodium citrate of 0.015-0.90mg/ml; The content of citric acid-sodium hydrogen phosphate is the citric acid of 0.1～3.0mg/ml and the sodium hydrogen phosphate of 0.3～6.0mg/ml.
4. a kind of drug addiction-stopping formulation as claimed in claim 1 is characterized in that the content of function regulator chlorobutanol is selected 0.1～5.0mg/ml for use, and benzyl alcohol is selected 0.5～20mg/ml for use, and lidocaine hydrochloride is selected 0.5～20mg/ml for use.
5. a kind of drug addiction-stopping formulation as claimed in claim 1, the content that it is characterized in that derivative of tetradotoxin are 0.1～50 μ g/ml.
6. a kind of drug addiction-stopping formulation as claimed in claim 1 is characterized in that described preparation adopts injection, tablet, pill or capsule.
7. a kind of drug addiction-stopping formulation as claimed in claim 6 is characterized in that described injection is for supplying intramuscular injection injection or intravenous injection injection.
8. the preparation method of a kind of drug addiction-stopping formulation as claimed in claim 1 is characterized in that the steps include:
1), the Fugu ocellatus toxin monomer is directly dissolved in acid solvent carrier, regulating pH value is 3～6;
2), dissolve in function regulator and stabilizing agent, placement after filtering;
3), filtration sterilization, fill.
9. the preparation method of a kind of drug addiction-stopping formulation as claimed in claim 8 is characterized in that in step 2, respectively through the microporous filter membrane vacuum filtration of 0.4 μ m and 0.22 μ m, and places at room temperature 12～24 hours.
10. the preparation method of a kind of drug addiction-stopping formulation as claimed in claim 8 is characterized in that in step 3, and described being filtered into through 0.05 μ m～0.20 μ m submicron order microporous filter membrane or charged microporous membrane filtered.
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| CN105030782A (en) * | 2015-08-07 | 2015-11-11 | 国家海洋局第三海洋研究所 | Tetrodotoxin compound preparation with anti-arrhythmic effect and preparation method thereof |
| CN107349206A (en) * | 2017-07-11 | 2017-11-17 | 东新皓特（北京）生化科技有限公司 | Application of the tetraodotoxin in treatment novel drug ill symptomses and the pharmaceutical composition relapsed are prepared |
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| 替曲朵辛注射液稳定性的初步考察. 康宇红.中国现代应用药学杂志，第20卷第6期. 2003 * |
| 河豚毒素及其注射剂中有关物质的分离与测定. 陈唯真等.药物分析杂志，第20卷第6期. 2000 * |
| 河豚的化学成分研究（II）. 王小逸等.中国海洋药物，第（总第70期）卷第2期. 1999 * |
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