CN101347408B - Kukoline intravenous transfusion preparation - Google Patents
Kukoline intravenous transfusion preparation Download PDFInfo
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- CN101347408B CN101347408B CN2008102121024A CN200810212102A CN101347408B CN 101347408 B CN101347408 B CN 101347408B CN 2008102121024 A CN2008102121024 A CN 2008102121024A CN 200810212102 A CN200810212102 A CN 200810212102A CN 101347408 B CN101347408 B CN 101347408B
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Abstract
The invention provides a sinomenine injection special for intravenous administration. The sinomenine injection is an injection which comprises 0.005-0.3wt% of sinomenine and an aqueous solvent for injection, or an injection which comprises sterile injection powder or lyophilized injection powder used for preparation just before injection to cause the sinomenine concentration to be 0.005-0.3wt% in the injection and the aqueous solvent for injection. The sinomenine injection of the invention is used for treating rheumatism, chronic pain and other chronic inflammatory diseases. Compared with other existing injection forms, the sinomenine injection special for intravenous injection has lower drug adverse reaction, and the clinical curative effect is obviously improved.
Description
Technical field
The present invention relates to a kind of intravenous medicine that is used for, particularly relate to a kind of rheumatism of treating and have the intravenous fluid that there is disease in the chronic inflammatory disease pathomechanism with other.
Background technology
Sinomenine (sinomenine) is one of alkaloid that from the stem of menispermaceous plants Sinomenium acutum Sinomenium acutum (Thunb.) R.et Wils. and root, extracts, and is a kind of known medical substance.Modern pharmacology research shows that sinomenine has multiple pharmacological effect.Put it briefly, the main pharmacological of the sinomenine of having known at present is following: effects such as antiinflammatory, immunosuppressant, blood pressure lowering, inhibition maincenter, arrhythmia.
Sinomenine hydrochloride has following pharmacological action:
1. antiinflammatory action: can suppress acute and ooze out and chronic hyperplastic inflammation; Can significantly suppress 5-HT vascular permeability increase effect, suppress the synthetic of prostaglandin and discharge; Act on H2 receptor on the fibroblast film, be suppressed to fibroblast proliferation; Can obviously suppress rat paw edema and formaldehyde property and albumen arthritis due to the carrageenin; Suppress granulation tissue hyperplasia, can obviously quicken disappearing of bacterial arthritis.
2. analgesic activity: electrostimulation, hot plate method, photostimulation method and the various pain reaction of acetic acid twisting method induced mice are all had significant analgesia role.
3. immunoregulation effect: can suppress phagocytic function and inflammation-inhibiting medium IL-1, the IL-6 of macrophage, the generation of TNF; Can suppress the generation of antibody hemolysin, lymphocyte transformation and macrophage synthetic inflammatory mediator PGE2, LTC4 and oxynitride; But antagonism T lymphopoiesis also suppresses its synthetic IL-2; Can suppress synovium of joint propagation and synovial fluid secretion; Can suppress the immunity of organism rejection, prolong the time-to-live after transplanting.
4. histamine release effect: can impel mastocyte and basophilic granulocyte release tissue amine.
5. quick hypotensive effect: hypotensive effect is fast arranged significantly for dog, rat and intravenous rabbit injection sinomenine hydrochloride.
All kinds of preparations of sinomenine are widely used in clinical, and at present the main preparation of listing has: 1. sinomenine hydrochloride enteric coatel tablets, 2. Sinomenine hydrochloride sustained-released, 3. sinomenine hydrochloride injection.Preceding two kinds of dosage forms are ripe, and its clinical efficacy and untoward reaction doctor are familiar, and injection is an intramuscular injectable formulations; Every hydrochloric sinomenine 50mg of medicinal liquid 2ml; Its concentration is 2.5wt%, the each maximum injection dosage of conventional intramuscular injection 50mg (2ml), and every day, maximum injection dosage was 100mg; The advantage that intramuscular injection is more oral to have fast usually, bioavailability is high; But still have the part medicinal liquid to cause serious adverse effects during owing to intramuscular injection, for example the generation of anaphylactic shock, the fast skin allergy of sending out etc. directly into blood.Because there is above-mentioned serious adverse in intramuscular dose, restricted the extensive use of this medicine in clinical treatment, the effective dose that therefore many patients also can't receive treatment with reach in time, convenient, safety and efficacious therapy.Given this, injection went on the market over 15 years, and the clinician has been discovered and developed the multiple new purposes and the administering mode of this medicine in real work: like iontophoresis; Half amount of injection is first used the generation that can reduce untoward reaction; Articular cavity inner injecting and administering; Method (Li Yunlin such as acupoint injection therapy administration and the administration of focus local injection; Rheumatism and osteoarthritis ZHENGQINGFENGTONGNING fixed point interventional therapy; The academic meeting paper compilation of the 6th boundary China combination of Chinese and Western medicine rheumatism, 2006.9), but no matter how administering mode changes; Still have two hang-ups puzzlement clinician and patient, i.e. inconvenience multiple injection every day and the untoward reaction of appearance inevitably.
The adverse effect of sinomenine (ARD) has the multiple form of expression (Cheng Zongqi; Miu Liyan. ZHENGQINGFENGTONGNING untoward reaction and document analysis. the infection pharmacy; 2007; 12 (4): 184-186), but from the modal adverse effect of ratio that takes place comprise that skin allergy and anaphylactic shock, granulocyte alkali are few, gynecologic menstrual prolongation, arrhythmia, otorhinolaryngology allergy, thrombocytopenia purpura, acute hematopoietic disorder (the Xiao Wen magnitude. just fresh breeze causes acute hematopoietic disorder bitterly. adverse effect magazine, 2006; 2 (8) 1:62), stripping off must dermatitis (Shi Shengwen; Ye Songnian. ZHENGQINGFENGTONGNING causes exfoliative dermatitis dead 1 example of failing to respond to any medical treatment. the Strait Pharmaceutical Journal magazine, 1999,11 (1): 61), xerostomia, tired, drowsiness (Hu Yonghong etc. the curative effect and the side effect of ZHENGQINGFENGTONGNING treatment osteoarthritis. Chinese rehabilitation; 2001,6 (16) 2:85-88), etc.
Journey ancestor's fine jade literature review 63 routine sinomenine untoward reaction constituent ratio such as following tables 1
A situation arises and constituent ratio (n) for table 1 journey ancestor fine jade report sinomenine ADR
Can find out that from above data the formation of untoward reaction mainly is allergic rash (74.64%) and anaphylactic shock (11.11%), other untoward reaction proportion is all lower.7 routine anaphylactic shock all occur in after the intramuscular injection.
Though though the anaphylactic shock incidence rate is lower than the common skin anaphylaxis, really belong to very serious adverse effects, the clinician is very careful to the application with this type of untoward reaction medicine, perhaps under unavoidable situation, just uses., how to reduce its incidence rate of adverse reaction and eliminate serious adverse effects (like anaphylactic shock) over 15 years from the injection listing, be the difficult problem during the sinomenine clinical safety is used always.
Sinomenine is as the clear and definite monosomic alkali of structure; The treatment rheumatism (Li Xiaojuan etc. the sinomenine anti-inflammatory and Antirheumatic Mechanism. Traditional Chinese Medicine University Of Guangzhou's journal, 2004,21 (1): 34), nephropathy (Liang Ruiyan etc. the research of sinomenine antiinflammatory action mechanism. Traditional Chinese Medicine University Of Guangzhou's journal; 2007; 24 (2): 141-143) and ophthalmic diseases (Sun Xuguang etc. the application of sinomenine in preparation treatment immunological eye diseases medicine, Chinese patent CN1199623A) in curative effect, generally acknowledged by medical circle; Compare with the synthetic drug of antirheumatic disease during present clinical practice is used; The long-term toxic and side effects of sinomenine is very slight, and curative effect is sure, is a kind of alkaloid with broad prospects for development.Can know that from Chinese literature search the existing at present sinomenine correlational study document that surpasses a piece of writing surplus in the of 800 is published, and it serves to show the attention degree of clinician to this medicine.But in clinical practice, this prodrug complex and unique untoward reaction has become its clinical widely used greatest difficulty of restriction.
The root of sinomenine untoward reaction is where, existing correlational study show (Hu Yonghong etc. the curative effect and the side effect of ZHENGQINGFENGTONGNING treatment osteoarthritis. Chinese rehabilitation, 2001,6 (16) 2:85-88.Fu Shao Yi, etc. Sinomenine pharmacological effects II, toxicity and general pharmacology. Pharmaceutical Journal ,1963,10:673 -676.Wang Naiqin etc. the pharmacological action IV of table rattan alkali, sinomenine blood pressure lowering Study on Mechanism .1965,12 (2): 86-91.Mo Zhixian etc.), histamine release is to cause the principal element of most of untoward reaction with quick blood pressure drops.
Histamine release: sinomenine is to know one of short histamine liberator the strongest in the plant amedica at present.Histamine release be since mast cell degranulation due to, experiment showed, sinomenine can make mastocyte 90% take off granule (Ji Yubin. effective components of Chinese medicinal pharmacology and application (M). Harbin, Heilungkiang science tech publishing house, 1995:427-431.Liu Qiang etc. sinomenine research overview (J). Chinese herbal medicine, 1997,28 (4): 247-249).It is generally acknowledged that the mode of bringing out mast cell degranulation, release histamine mainly contains immunity stimulates (like specific antigen) and non-immunity to stimulate (like CP48/80) two types.Immunity stimulates and is mainly caused by specific antigen, brings out mast cell degranulation through antigen antibody reaction and discharges histamine.It is to trigger histamine release through the mechanism different with immunoreation that the non-immunity of mastocyte stimulates.Sinomenine cause histamine release be belong to the non-immunity stimulation mode (effect of sinomenine histamine release and antihistamine shrink intestinal tube effect research. Pharmacology and Clinics of Chinese Materia Medica, 2006,22 (6): 16-19).Clinical manifestation after the histamine release mainly contains flush, pruritus, erythra welt and tissue edema etc., and these phenomenons just in time with the sinomenine clinical practice in untoward reaction consistent.
Quick blood pressure drops: the pharmacology phenomenon of the quick blood pressure lowering of sinomenine is confirmed through multiple zoopery in the sixties in last century; After giving Canis familiaris L., rat and intravenous rabbit injection sinomenine hydrochloride; All can produce sure hypotensive effect; And antihistamine drug can not influence its antihypertensive effect (Wang Naiqin etc. the pharmacological action IV of table rattan alkali, sinomenine blood pressure lowering Study on Mechanism .1965,12 (2): 86-91).Another research, the quick hypotensive effect that sinomenine is described not are to be caused by histamine release, but an independently pharmacological action.The serious direct result of blood pressure lowering fast shows as anaphylactic shock clinically.
Said like the 3rd, 8 two of patent CN1679574A claims to contain 0.5-99.5WT% sinomenine or pharmaceutically acceptable salt in administration of intravenous mode and the said medicine; This administration concentration in fact can not be used for the actual clinical treatment, and the administration of experiment proof 0.10wt% concentration can cause 50% subjects skin allergy to occur.Like the 0.5-99.5WT% concentration administration by patent CN1679574A requirement, the incidence rate of its skin allergy and the order of severity all are unacceptable concerning doctor and patient, and very easily cause the generation that quick blood pressure drops causes anaphylactic shock.
Use sinomenine to cause the essence of anaphylactic shock mainly to be because sinomenine has this pharmacological mechanism of quick blood pressure drops.It should be noted that all anaphylactic shock all occur in after the local injection administration, oral administration does not have relevant report, proves absolutely that the anaphylactic shock main cause is quick blood pressure lowering, and its concentration and speed that takes place to get in the blood with medicine has clear and definite dependency.Zoopery has confirmed that sinomenine can cause quick blood pressure drops and the report of the clinical anaphylactic shock be on the increase in addition; It is very careful to make when the clinician is expert at administered intramuscular; Generally believe that simultaneously the intravenous injection sinomenine will cause fatal serious adverse reactions such as anaphylactic shock, so sinomenine has been sealed up hill and dale with the gate of venous transfusion mode administration.
Can find out from above research,, hinder application and the drug effect of this medicine in whole body multi-joint, many internal organs, multi-section position disease because this medical instrument has histamine release and these two pharmacological actions that cause various untoward reaction of quick blood pressure drops rapidly.So how effectively controlling rapid release of histamine and quick blood pressure drops and can continuing medication is clinical problem demanding prompt solution.
Summary of the invention
The inventor unexpectedly finds, through a kind of sinomenine intravenous injection of specific low concentration is provided, can controls the rapid release of histamine and blood pressure drops reaction fast effectively, thereby solve a clinical difficult problem that is prone to anaphylactic shock after the medication.Compare with sinomenine intramuscular dose in the past; Injection of the present invention can significantly reduce untoward reaction; Especially can avoid the generation of its serious adverse effects such as anaphylactic shock; Improved its clinical practice safety, promoted its extensive use, overcome the impossible prejudice of sinomenine for a long time simultaneously through the intravenous route administration.
The present invention provides a kind of sinomenine injection that is specifically designed to intravenously administrable; It is to comprise the sinomenine of 0.005-0.3wt% and the injection of injection aqueous solvent, or comprise be used for facing the injection before the preparation so that injection sinomenine concentration is the aseptic injection powder of 0.005-0.3wt% or the injection of lyophilizing injection powder injection and injection aqueous solvent.
In the injection of the present invention, injection aqueous solvent can be the injection solvents commonly used such as water for injection, injection normal saline or D/W of sterilization, and sinomenine is selected from sinomenine or its officinal salt, its acid-addition salts for example, example hydrochloric acid sinomenine.
Injection of the present invention also can further comprise isoosmotic adjusting agent, pH regulator agent and pH buffer agent, solubilizing agent, stabilizing agent and/or antioxidant etc.Said isoosmotic adjusting agent is selected from sodium chloride, glucose etc.; PH regulator agent and pH buffer agent are selected from hydrochloric acid, sodium hydroxide, sodium bicarbonate and/or sodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution etc.; Solubilizing agent is selected from meglumine, poloxamer, propylene glycol and/or hydroxypropyl etc.; Stabilizing agent and/or antioxidant are selected from vitamin C, disodiumedetate and/or sodium sulfite etc.
Can further comprise lyophilized powder excipient, sterile powder for injection forming agent in the injectable powder of the present invention or improve the adjuvant that redissolves.The adjuvant that said lyophilized powder excipient, sterile powder for injection forming agent or improvement are redissolved is selected from mannitol, glycine, arginine, glucose, lactose, polyvinylpyrrolidone and/or low molecular dextran etc.
In the injection of the present invention, the content of sinomenine is preferably 0.01-0.20wt%, and more preferably 0.02-0.10wt% especially is preferably 0.03-0.06wt%, most preferably is 0.04-0.05wt%.
The content of the isoosmotic adjusting agent in the injection of the present invention is 0.1-10wt%, the content 0-10wt% of pH regulator agent and buffer agent, the content 0-50wt% of solubilizing agent, the content 0-10wt% of stabilizing agent and/or antioxidant.Preferred 1.2wt% of the consumption of stabilizing agent and/or antioxidant and 4.0wt%.The content of pH regulator agent is 0-8wt% at injection, is 0-5wt% in powder needle injection.
Injection of the present invention preferably comprises the glucose of 0.9wt% sodium chloride or 5～10wt% as isoosmotic adjusting agent, is preferably 0.9wt% sodium chloride.
In the sterilized powder injection of the present invention, the consumption of lyophilized powder excipient accounts for 10～90wt% of freeze-dried powder weight, preferred 60-80wt%; The consumption of aseptic powder forming agent is 0～90wt% of sterilized powder, preferred 60-80wt%.
In most preferred embodiment of the present invention, injection is the solution of 0.9% sodium chloride that comprises the sinomenine of 0.04-0.05wt%.
Particularly; Intravenous injection of the present invention comprises forms such as intravenous drip liquid, injection powder pin and infusion solutions; For example containing the sinomenine of 0.005-0.3wt% and the low capacity or the high-capacity injection of injection aqueous solvent is venous transfusion, or comprise be used to face the injection before the preparation so that injection comprises aseptic powder injection, freeze-dried powder or the intravenous drip liquid of 0.005-0.3wt% sinomenine and the product of injection aqueous solvent.
The method for preparing of injection of the present invention comprises with sinomenine and aqueous injection solvent directly being prepared into injection or being mixed with described injection with preceding use injection aqueous solvent and perhaps processing to face with preceding use and inject aseptic powder and the lyophilized injectable powder form that aqueous solvent is mixed with said injection in facing with the commercially available sinomenine injection that is higher than 0.3wt%.The method for preparing of these preparations adopts the conventional method for preparing of intravenous injection, and these method for preparinies all state clearly in the pharmaceutics textbook.
Preparation of the present invention can directly be prepared into injection through conventional method for preparing, for example is prepared into to comprise sinomenine is dissolved in water for injection etc., preferably uses decolorizing with activated carbon degerming depyrogenation, filters and fine straining sterilization or unsterilised.
Preparation of the present invention also can be processed freeze-dried powder or aseptic powder injection, for example is mixed with concentrated solution and is prepared into lyophilized powder through freeze-drying method; Perhaps be mixed with concentrated solution and be prepared into aseptic powder through decompression or vacuum drying method.Lyophilized powder or aseptic powder are formulated as venous transfusion or intravenous injection liquid with water for injection or 0.9% sodium chloride sodium chloride injection or 5～10% glucose injections facing with preceding.
The method for preparing of intravenous drip liquid of the present invention and infusion solutions comprises: feed intake-dosing-filtration-fill-sterilization etc.; Method for preparing freeze-dried powder comprises: feed intake-dosing-filtration sterilization-fill-lyophilization etc.; The aseptic powder method for preparing comprises: feed intake-dosing-filtration sterilization-vacuum drying-pulverizing-fill etc.
The detailed process that the present invention prepares injection comprises, takes by weighing raw material, adjuvant, injection active carbon, adds an amount of water for injection, is heated to 60～100 ℃, temperature retention time 0～100 minute, embedding behind filtration and the fine straining, sterilization, lamp inspection.The detailed process of preparation lyophilized powder comprises, takes by weighing raw material, adjuvant, injection active carbon, adds an amount of water for injection, is heated to 60～100 ℃, temperature retention time 0～100 minute, embedding after the filtration sterilization, lyophilization, check.The detailed process of preparation aseptic powder comprises, takes by weighing raw material, adjuvant, injection active carbon, adds an amount of water for injection, is heated to 60～100 ℃, temperature retention time 0～100 minute, filtration sterilization final vacuum drying, pulverizing, fill, check.For guaranteeing that content meets the requirements, raw material feeds intake by 100～110%; Before fill, sampling detects midbody solution, comprises pH value, content, clarity; PH value can directly be regulated, and pH value is controlled between 3～10, and allows to fluctuate 2 with interior or above pH value; Can filter repeatedly for the assurance clarity, medicament contg detects also and is controlled between 90～110%; Consider the difference that medicinal liquid is mobile, actual sample-loading amount is confirmed between 100～130% according to measuring the result.
During the injection fill, if necessary, can lead to nitrogen or carbon dioxide etc.
The specific embodiment
Embodiment 1:
Sample method for making: get sinomenine hydrochloride 0.3g, disodiumedetate 0.0005g, sodium sulfite 0.016g, sodium chloride 9g,, be heated to 80 ℃ with an amount of water for injection dissolving;, add an amount of injection active carbon, be incubated 15 minutes, the filtering active carbon; Behind the microporous filter membrane fine straining; On filter, add the injection water to 1000ml, fill is 250ml/ bottle, sterilization, promptly gets.Prepare 200 bottles altogether.Sinomenine concentration is 0.03wt%
Usage: intravenous drip, a 250ml, 1～2 time on the one.
Embodiment 2:
Sample method for making: get sinomenine hydrochloride 0.6g, disodiumedetate 0.0005g, sodium sulfite 0.016g, sodium chloride 9g,, be heated to 80 ℃ with an amount of water for injection dissolving;, add an amount of injection active carbon, be incubated 15 minutes, the filtering active carbon; Behind the microporous filter membrane fine straining; On filter, add the injection water to 1000ml, fill is 250ml/ bottle, sterilization, promptly gets.Prepare 200 bottles altogether.Sinomenine concentration is 0.06wt%.
Embodiment 3:
Sample method for making: get sinomenine hydrochloride 1.0g, glucose 50g,, be heated to 80 ℃ with an amount of water for injection dissolving;, add an amount of injection active carbon, be incubated 20 minutes, the filtering active carbon; Behind the microporous filter membrane fine straining; On filter, add the injection water to 1000ml, fill is 250ml/ bottle, sterilization, promptly gets.Prepare 200 bottles altogether.Sinomenine concentration is 0.1wt%
Usage: intravenous drip, a 250ml, 1～2 time on the one or follow the doctor's advice.
Embodiment 4:
The sample method for making: get sinomenine hydrochloride 10 or 20g, disodiumedetate 0.24g, sodium sulfite 0.08g, dissolve with an amount of water for injection, behind the microporous filter membrane fine straining, add the injection water to 1000ml, embedding is that 10ml/ props up, sterilizes, and promptly gets.Prepare 200 bottles altogether, every contains sinomenine 100 or 200mg.
Usage: intravenous drip, these article 5～10ml adds 5% glucose injection or 0.9% sodium chloride injection, 100～250ml, and quiet, every day 1～2 time or follow the doctor's advice.
Embodiment 5:
Sample method for making: get sinomenine hydrochloride 10 or 20g, disodiumedetate 0.24g,, add an amount of mannitol solution to 1000ml with an amount of water for injection dissolving; After the degerming of supermicro filtration membrane fine straining; Be packed as that 10ml/ props up, lyophilized powder is processed in lyophilization, gland seal promptly gets.Every contains sinomenine 100 or 200mg.
Usage: intravenous drip, face with preceding and dissolve with water for injection, shake up to dissolving, add 5% glucose injection or 0.9% sodium chloride injection, 100～250ml, quiet.One time 1, every day 1～2 time or follow the doctor's advice.
Embodiment 6:
The sample method for making: get sinomenine hydrochloride 50g, disodiumedetate 0.6g, arginine 50g, with the dissolving of an amount of water for injection, after the degerming of supermicro filtration membrane fine straining, drying under reduced pressure and be ground into fine powder under gnotobasis, packing, every 0.1g promptly gets.
Usage: intravenous drip, face with preceding and dissolve with water for injection, shake up to dissolving, add 5% glucose injection or 0.9% sodium chloride injection, 100～250ml, quiet.One time 1～2, every day 1～2 time or follow the doctor's advice.
The sinomenine hydrochloride injection that uses among following examples 7-11,50mg/ props up, available from Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov..
Embodiment 7 (0.01wt% sinomenine)
0.9wt% sodium chloride 100ml
Sinomenine hydrochloride injection 10mg
Embodiment 8 (0.03wt% sinomenine)
0.9wt% sodium chloride 100ml
Sinomenine hydrochloride injection 30mg
Embodiment 9 (0.06wt% sinomenine)
0.9wt% sodium chloride 100ml
Sinomenine hydrochloride injection 60mg
Embodiment 10 (0.1wt% sinomenine)
0.9wt% sodium chloride 100ml
Sinomenine hydrochloride injection 100mg
Embodiment 11 (0.25wt% sinomenine)
0.9wt% sodium chloride 100ml
Sinomenine hydrochloride injection 250mg
Preparation of the present invention can be through intravenous drip or the administration of intravenous injection mode.The common concentration of sinomenine is 0.005-0.3wt% in the intravenous transfusion preparation, is preferably 0.01-0.2wt%, and more preferably 0.02-0.1wt% most preferably is 0.03-0.06wt%, especially preferred 0.04-0.05wt%.Its concentration is generally 0.005-0.2wt% in the injection of intravenous injection, is preferably 0.01-0.1wt%, most preferably is 0.02-0.06wt%.When intravenous drip and intravenous injection, the amount of liquid that gets into human body in the unit interval is different, and that the concentration of sinomenine and adverse effect have is clearly relevant, so both formulation concentrations have difference.The preferred modes of preparation of the present invention is intravenous drip.In addition, transfusion speed is another key link of adverse effect due to the control histamine release, and transfusion speed is generally clinical common administration and drips speed during with adverse effect concentration administration shown in the present.More preferably suitably control injection speed, for example 20-80 drip/minute.
The disease that preparation of the present invention can be used for treating comprises: rheumatisms such as rheumatoid arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, all kinds of articular synovitis, gouty arthritis, scapulohumeral periarthritis, fibromyalgia syndrome, PHN, costal chondritis and all kinds of tenosynovitiss, pain, uveitis, iridocyclitis, nephritis, the nephrotic syndrome etc. after prolapse of lumbar intervertebral disc, cervical spondylosis, postoperative pain and all kinds of wound.Sinomenine intravenous formulations of the present invention is suitable for intravenous drip (venous transfusion) most, especially can be used for treating various rheumatisms and soft tissue chronic inflammatory disease.
Preparation of the present invention preferably can be realized following effect (discussing the effect of preparation of the present invention from all possible aspect) with appropriate concentration intravenously administrable:
1. histamine is slowly discharged greatly to have slowed down the generation of adverse effect.
2. eliminate quick hypotensive effect to avoid the generation of anaphylactic shock.
3. sustainable administration is to reach efficacious therapy dosage or multiple dosing or accurately control dosed administration at times.
4. can avoid repeatedly the administration due to the local injection painful.
5. the patient that can't implement administration to gastrointestinal tract also can treat.
The objective of the invention is to realize through following technical scheme
The drug level of sinomenine intravenous formulations of the present invention is controlled at 0.005-0.3wt%, is preferably 0.01-0.2wt%, and more preferably 0.02-0.1wt% most preferably is 0.03-0.06wt%, especially preferred 0.04-0.05wt%.In above preferable range, the untoward reaction of drug-induced is minimum.In more preferably scope, lower and patient can tolerate in the untoward reaction of medicine; In most preferred range, the untoward reaction of medicine is very slight, and clinical convenience is good.Both all have obvious curative effects.Clinical practice confirms that the adverse reaction rate that is caused with the administration of venous transfusion mode is minimum, in preferable range; Do not cause the case of serious adverse reaction anaphylactic shock; Compare with intramuscular dose, avoided the generation of anaphylactic shock fully, clinical safety is good.Secondary administration, untoward reaction obviously reduce especially.
The present invention has selected to be suitable for intravenous valid density scope, and sinomenine preparation of the present invention can effectively solve a difficult problem that causes all kinds of untoward reaction after other dosage form administration of sinomenine easily.
Major advantage of the present invention comprises that also sinomenine is known, clinical medicinal Main Ingredients and Appearance sinomenine, and its chemical constitution is clear and definite, and clinical practice is extensive and have the clinical practice history of many decades, and treatment effectiveness and drug safety property are good.
Experimental example 1: the clinical observation of sinomenine untoward reaction
Every kind of medicine is after acting on human body; Except the pharmacological action of bringing into play its therapeutic purposes, regular meeting causes some corresponding untoward reaction, and the generation of untoward reaction is except the characteristics of medicine self; Also closely related with administering mode, dosage, dosage form and injection speed; Therefore study the untoward reaction of medicine, its essential purpose is minimum to reach incidence rate of adverse reaction with the reasonable administration of which type of dosage form in effective dosage ranges, and this is only one of final demand of rational use of drug.Through the various untoward reaction that the sinomenine clinical practice is shown, its untoward reaction form and incidence rate that is showed of the sinomenine of different dosage form has evident difference.This paper inquires into the clinical manifestation of sinomenine different modes of administration adverse effect through this group clinical data and causes the possible cause of these differences.The existing summary as follows:
1. experiment material
1.1 Sinomenine hydrochloride sustained-released, the 60mg/ sheet, available from Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov., trade name ZHENGQINGFENGTONGNING slow releasing tablet.
1.2 the sinomenine hydrochloride injection, 50mg/ props up, available from Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov., and trade name ZHENGQINGFENGTONGNING injection.
1.3 the sinomenine hydrochloride venous transfusion is formulated before facing usefulness by the sinomenine hydrochloride injection.Conventional compound method is that 0.9wt% sodium chloride 250ml adds sinomenine hydrochloride injection 100mg.
2. clinical data
2.1 the outpatient service and the inpatient of 3315 routine complete datas of sinomenine different dosage form treatment are adopted in case source and grouping, cumulated volume group, are divided into 3 groups by administering mode:
2.1.1 oral sustained release sheet group 964 examples, every day, dosage was 240mg, and is oral at twice;
2.1.2 local injection administration group 1957 examples (comprising articular cavity, acupuncture point administration and nerve block), be administered twice every day, each 50mg, every patient's first administration 25mg;
2.1.3 venous transfusion administration 234 examples (only in inpatient, implementing), each 100mg, every day 1 time.
2.2 case is included standard in
2.2.1 rheumatism mainly comprises rheumatoid arthritis, ankylosing spondylitis, osteoarthritis etc.
2.2.2 chronic pain disease
2.3 case exclusion standard
2.3.1 history of drug abuse is arranged, morphine class medicine addict.
2.3.2 just using anti-resistance drug amine person at present.
2.3.3 because of systemic lesion life-time service glucocorticoid medicine person.
2.3.4 be associated with serious diseases such as cardiovascular, liver, kidney, hemopoietic system or stupor, psychotic.
2.3.5 asthma medical history person is arranged.
2.3.6 anemia of pregnant woman and patient below 14 years old.
2.3.7, can't not judge curative effect person and untoward reaction person by the prescribed dose medication.
2.4 the selection of administering mode
2.4.1 oral group, meet the patient that case is included the multiple pathological changes of whole body of standard in.
2.4.2 the local injection group meets case and includes standard in, and the patient of clear and definite pain spot or arthritis or a certain neural inflammation is arranged.
2.4.3 the venous transfusion group meets the inpatient that case is included standard in.
2.5 follow up a case by regular visits to: all cases are followed up a case by regular visits to all above 1 month.
2.6 untoward reaction evaluation criteria
2.6.1 skin allergy, comprise pruritus, erubescence, welt.Pruritus is a foundation with patient main suit, and erubescence, welt and maculopapule are observed with the doctor and be as the criterion.
Pruritus: only limit to injection or transfusion needle and thrust in the 5cm of the portion scope, tickle by contralateral hand or scope surpasses above scope, be recorded as untoward reaction like need to normal.
Flushing: only limit to inject or transfusion needle thrusts slight rubescent in the 5cm of the portion scope this type of is rubescent for normal, after lowering transfusion drip speed, can disappear rapidly, above 5cm, then be recorded as untoward reaction like the flushing scope.
Welt: area is greater than 2cm
2Welt be recorded as untoward reaction because after some skin sensitivity person runs into environmental stimuli, be prone to form little welt.
2.6.2 anaphylactic shock, dizziness, headache, rapid breathing, heart rate quickening, mind variation promptly appear in the patient after medication, and blood pressure is lower than 90/60mmHg.
2.6.3 hypertension, the normotensive hypertension occurs to 140/100mmHg or hyperpietic's hypertension 20mmHg.
2.6.4 xerostomia, tired, drowsiness, headache, dim eyesight, stomachache, menostaxis, otorhinolaryngology are irritated, are foundation with patient main suit, vomiting is with the objective foundation that occurs as.
2.6.5 granulocytopenia, thrombocytopenic purpura and acute blood dysfunction are as the criterion with the Clinical Laboratory foundation.
2.6.6 arrhythmia is a foundation with the electrocardiogram.
2.7 efficacy assessment standard: the general curative effect evaluation when following up a case by regular visits to is as the criterion.
Produce effects: patient's pain disappears, and joint movement function obviously improves, and swelling disappears.
Effectively: patient's pain is partly improved, and joint movement function partly improves, and tumor disappears.
Invalid: patient's pain is improved not obvious, and joint movement function does not have obvious improvement, and swelling is eliminated not remarkable.
The result:
The various untoward reaction that the outpatient service of cumulated volume group 3315 routine complete datas and inpatient are taken place with three kinds of different modes administrations, its distribution is constructed as follows table 2.
A situation arises for three kinds of main adverse effectes of administering mode of table 2 sinomenine
Annotate: 1. administering mode untoward reaction example number statistics is as the criterion with the first administration mode, and multiple untoward reaction counts corresponding group respectively, need add in the therapeutic process with other administering mode person no longer to repeat statistics.
2. ' other ' comprises that xerostomia, stomachache, granulocytopenia, thrombocytopenic purpura, memory hematopoietic disorder, gynecologic menstrual prolong and otorhinolaryngology is irritated in the table.
Shown in the table 2, oral group of the incidence rate of skin allergy is near with the local injection winding, and local injection and intravenous drip have approximate part on administering mode, and both relatively have more clinical meaning.
The skin allergy distribution situation relatively after two kinds of different modes of administration first administration of table 3
Annotate: 1. skin allergy is made up of welt, pruritus and three kinds of clinical manifestations of erubescence.
2. the non-patient's number that only refers to of routine number refers to above three kinds of situation generation number separately, and three kinds of situation can have stack mutually.
Skin allergy due to the venous transfusion group obviously lowers than local injection group, and two groups have significant difference, and except that total difference, welt, pruritus, erubescence all have significant difference for three groups.
Skin allergy generation distribution situation ratio after the administration of two kinds of administering mode secondaries of table 4
Annotate: the secondary administration is meant administration next day after the first administration, therebetween can not the next day.
See that from The statistical testing results the skin allergy due to after the administration of two kinds of administering mode secondaries does not have significant difference, and three groups of welts, pruritus, erubescence there are no significant difference.
Two kinds of administering modes of table 5 totally compare first with before and after the secondary administration skin allergy
| Local injection administration (1957) | Venous transfusion (234) | Add up to (2191) | |
| Administration for the first time | 357 | 27 | 384 |
| Administration for the second time | 82 | 7 | 89 |
| Add up to | 439 | 34 | 473 |
| Chi-square value | 194.029 | 12.686 | 206.248 |
| The P value | <0.00 | <0.00 | <0.00 |
Coming ratio first with before and after the secondary medication, the skin allergy due to two kinds of administering modes all has significant difference, and the untoward reaction of prompting sinomenine mainly occurs in after the first administration.
Three kinds of different modes of administration skin allergies of table 6 time of occurrence distributes
Annotate: the time division is the clinical experience gained, is primarily aimed at the local injection administering mode.React violent person, having injected promptly has pruritus or welt to occur, and mostly in 40 minutes, occurs, and surpasses 40 minutes persons of appearance, and clinical manifestation is also very slight, so 40 minutes be an empirical value, also becomes in our clinical position start time of capable local injection once more.
Three kinds of different modes of administration skin allergies of table 7 resolution time distributes relatively
Three kinds of administering mode curative effects of table 8 sinomenine relatively
Can know that from last table the obvious effective rate of venous transfusion group and total effective rate are apparently higher than other two groups.
3. result
Can find out from table 2, give with three kinds of different modes of administration of sinomenine to amount to 3315 routine patient Shi Zhihou that it is inferior in the various adverse effectes due to the sinomenine, to occur untoward reaction 597 examples altogether; Total incidence rate is 23.02%; But adverse reaction rate has notable difference between three groups of each groups, and wherein oral group is 24.73%, and local injection administration group is 23.05%; And the venous transfusion group is merely 17.09%, explains through the adverse reaction rate of intravenously administrable approach minimum.
Can find that after all untoward reaction are analyzed skin allergy is the main body of untoward reaction, total incidence rate is 18.01%.Except that the skin anaphylaxis, tired and drowsiness untoward reaction rate surpasses 1%, and all the other several individual event adverse reaction rates all are lower than 1%, do not have 1 routine death.Have 9 routine patients anaphylactic shock to occur, this 9 example all occurs in local injection administration group, and incidence rate is 0.46%, and constituent ratio is 2%, is lower than 11.11% constituent ratio of Cheng Zongqi report.The untoward reaction that should draw attention in addition has, granulocytopenia 3 examples, and thrombocytopenic purpura 1 example, acute hematopoietic disorder 1 example, hypertension 6 example and arrhythmia 2 examples, above case all recover normal after drug withdrawal.Three cases occurred in patients with vomiting Dan nerve block (one case), and carotid 2,3 dorsal branch block (2 cases) after the description of the injection site, and therefore the Department and the vagus nerve section and dry close, as it is stimulated, pole easily lead to vomiting.Other untoward reaction comprises menostaxis, otorhinolaryngology allergy, xerostomia, drowsiness, headache, dim eyesight, stomachache, considers all relevantly with histamine release, after drug withdrawal, all alleviates, and does not leave over long-term untoward reaction.
The incidence rate that skin allergy is three groups is had nothing in common with each other, and wherein oral group is 18.95%, and local injection administration group is 18.24%, and the venous transfusion group is merely 11.54%.Skin allergy mainly is made up of welt, pruritus and three kinds of clinical manifestation forms of erubescence, and whether these three kinds of performances occur simultaneously, vary with each individual, and can be showed by the form of the arbitrary combination of its 1-3 kind.These the three kinds shared ratios of performance have evident difference, and from listed its formation of data of table 3, the incidence rate of pruritus is the highest, and welt and erubescence are secondly.Can find out that from table 3-5 the skin allergy due to local injection, two kinds of administering mode first administration of venous transfusion has significant difference, and welt, pruritus, erubescence all there is significant difference for three groups.But the skin allergy of two kinds of administering mode secondary administration indications does not have significant difference.Explain that the skin allergy human body due to the sinomenine can tolerate rapidly.Can find out that from table 6 three kinds of skin adverse reaction major parts of local injection group and venous transfusion group occurred in 40 minutes.Can find out that from table 7 three kinds of skin adverse reaction major parts of local injection group and venous transfusion group were at 4 hours inner dissipations, and the dissipation of venous transfusion group welt is faster, these two groups have notable difference.
Though skin allergy is the main body of all untoward reaction of sinomenine, its generation is after drug withdrawal or decrement all can obtain to alleviate or dissipate, and it is residual not have long-term skin lesion.But the skin allergy of promptly sending out is scarcely used the special handling spontaneous remission, and violent person can resist with promethazine.
Anaphylactic shock: be sinomenine serious adverse effects the most; 9 examples take place in this group altogether; This 9 example all occurs in local injection administration group; It is starkly lower than the ratio of pertinent literature report, analyzes possible cause and perhaps is engaged in local injection treatment relevant (nurse does not participate in the local injection administration of any project) with this group patient treatment by full-time doctor.After anaphylactic shock took place, our treatment measure was: oxygen therapy, transfusion, intramuscular injection promethazine 25mg, and only 1 routine patient uses epinephrine, and all the other all obtain to alleviate after above processing.The injection site distributes as follows among the 9 routine patients: mandibular joint is injected 2 examples, and last cervical part of esophagus is injected 6 examples, injection of hip joint 1 example.
Comprehensive literature and the analysis of this group; The generation of anaphylactic shock and injection site vascularity are closely related; More than these positions blood fortune abundant, push away very easily to puncture blood vessel in the medicine process or to cause direct injection blood vessel in injection, because of short duration high concentration medicinal liquid is gone into blood because of syringe needle slightly moves; Cause quick blood pressure drops and histamine and discharge in a large number, thereby cause the generation of anaphylactic shock.The possible cause that medicine is strayed into blood vessel has three: one, and repeated localised puncture has punctured the many places blood vessel, and after medicinal liquid pushed, local pressure was high and order about medicinal liquid and go into blood through the blood vessel that punctures; The 2nd, after puncture, syringe needle has connected blood vessel, but needle point is at the blood vessel opposite side; Pumpback this moment depletion of blood is when injection, because that I guess slight activity of operator's hand; Needle point might be retracted into blood vessel or thrust another blood vessel, and be in high pressure conditions owing to the syringe inner liquid medicine this moment when injecting, and the blood in the blood vessel can't instead flow in the syringe; The operator takes at this moment and does not touch blood vessel at all and medicinal liquid is partly or entirely injected, thereby causes medicine to be strayed into blood vessel; The 3rd; Pain causes muscle contraction and makes needle point produce displacement; Needle point move with injection the time stress of suffering to pain relation is also arranged; The pain of acupuncture adds that medicinal liquid pain due to the extrusion tissue in tissue all can make people's muscle produce contraction or spasm when pushing away medicine, causes medicinal liquid to be strayed into blood vessel thereby change needle point in in-house position.
Analyze and bibliographical information in conjunction with above, when why anaphylactic shock only occurred in innings drug administration by injection treatment due to the sinomenine, to be strayed into blood vessel closely related with the medicinal liquid of high concentration, and related experiment also proves through the intravenous injection administration can cause sure blood pressure drops.It is intramuscular injection that the description of present commercially available sinomenine hydrochloride injection (ZHENGQINGFENGTONGNING injection) is clearly pointed out the usage of said preparation; The 2nd of its [untoward reaction] item: in the injection process; The patient is if brothers occur or lip is numb, uncomfortable in chest, chest pain etc.; Possibly be to be strayed into blood vessel to cause due to the quick blood pressure lowering drug withdrawal immediately, anti symptom treatment in case of necessity; Article 3: anaphylactic shock appears in accidental report individual patient.This explanation forbids that it is that manufacturer prevents that anaphylactic shock from the requisite measure taked taking place that this medicine is gone into blood fast, and key of problem is that the sinomenine medicine goes into this vital link of concentration of blood and be not much accounted of always.
All can produce sure quick blood pressure drops although people and animal go into this administering mode of blood to the quick vein of sinomenine, people and animal are diverse to the toleration of quick this untoward reaction of blood pressure drops of sinomenine.The research of Liu Qiang shows; Give dog and monkey intravenous injection sinomenine 5-13.5mg/kg; Occur reactions such as blood pressure drops, heart rate quickening and dyspnea immediately, and, all be strayed into blood vessel even suppose each maximum injection dosage 50mg sinomenine by everyone average 60 kilograms of calculating; The maximum dosage that causes the people to produce the intravenous injection of quick blood pressure drops can not surpass 1mg/kg yet; In our experience, the drug dose that the local injection administration causes anaphylactic shock to take place all surpasses 50mg or 1mg/kg, carries out intravenous injection and will produce sure quick blood pressure drops so zooperal data are used for clinical practice; Therefore can think that the animal and human has different tolerations to sinomenine.
Comprehensive all documents and this group data, the oral hydrochloride sinomenine does not all have the case of anaphylactic shock, explains that oral this medicine can not cause anaphylactic shock; And after all anaphylactic shock cases all occur in local injection; Review the intravenously administrable group, do not have 1 routine anaphylactic shock, explain that the concentration intravenous drip administration with suitable can't cause the generation of anaphylactic shock; Thereby broken the taboo that this medicine is forbidden intravenously administrable.Intravenous injection of the present invention is compared with the intramuscular dose of present clinical use, has eliminated serious anaphylactic shock side effect, has alleviated other side effect such as skin allergy, has safe and rapid-action advantage.
Can know that from three groups of curative effect comparisons the obvious effective rate of venous transfusion group and total effective rate are apparently higher than other two groups.
4. conclusion
Can draw following 3 conclusions (only keep the content relevant, explain that mainly the advantage of preparation of the present invention and feasibility get final product) from above documents and materials and the clinical practice of this group with preparation of the present invention
(1) administration of sinomenine local injection has the possibility that causes anaphylactic shock, and the Kukoline intravenous transfusion mode administration of suitable concentration then can not.
During (2) with local injection and the administration of venous transfusion mode, sinomenine occurrence of adverse reaction time and resolution time all are significantly shorter than oral way.When the secondary administration, preparation administration of the present invention obviously reduces than the untoward reaction due to the oral administration.
(3) compare for two groups with venous transfusion and local injection, the skin adverse reaction incidence rate that the former caused is starkly lower than the latter, and the dissipation of welt is also fast than the local injection administering mode.
Experimental example 2: the feasibility study of venous transfusion administering mode
In infusion process; The process that medicine gets into blood of human body is progressive process; Because sinomenine is extremely strong short histamine liberator; Untoward reaction due to it at first is skin allergy rather than anaphylactic shock, and therefore, the generation of research skin allergy and the relation of administration concentration in fact are the matters of utmost importance of administering mode feasibility study.
The safety of Kukoline intravenous transfusion administering mode is confirmed in this organizes 234 routine patients' clinical practice, but feasibility study remains to reaching a conclusion on the basis of variable concentrations experimenter tolerance studies.
1. experiment material
The institute medicament: 1, sinomenine hydrochloride injection, 50mg/ props up, available from Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov..2,0.9wt% sodium chloride
Above medicine is mixed with the preparation of variable concentrations by following prescription
Prescription 1: (0.02wt% sinomenine)
0.9wt% sodium chloride 250ml
Sinomenine hydrochloride injection 50mg
Prescription 2: (0.06wt% sinomenine)
0.9wt% sodium chloride 250ml
Sinomenine hydrochloride injection 150mg
Prescription 3: (0.1wt% sinomenine)
0.9wt% sodium chloride 250ml
Sinomenine hydrochloride injection 250mg
2. clinical data
Collect 43 volunteers with rheumatism, male 16 examples, women 27 examples, the age is limited to more than 18 years old the adult, does not have other systemic lesion, does not use antirheumatic medicine and anti-inflammatory analgesic class medicine person in nearest 1 month.
2.1 experiment is divided into groups
The volunteer is divided into 4 groups at random
1,11 of experimental group;
2,12 of experimental grouies;
3,12 of experimental grouies;
Matched group, 8.
2.2 experimental technique
1,11 of experimental group uses concentration to be 0.02wt%;
2,12 of experimental grouies use concentration to be 0.06wt%;
3,12 of experimental grouies use concentration to be 0.10wt%;
Matched group, 8, the normal saline of defeated isodose.
Every group of transfusion speed is decided to be 60 droplets/minute, when untoward reaction occurring, can lower transfusion drip speed gradually to accomplish the transfusion overall process.
3. untoward reaction criterion
Pruritus: only limit to transfusion needle and thrust in the 5cm of the portion scope, tickle by contralateral hand or scope surpasses above scope, be recorded as untoward reaction like need to normal.
Flushing: transfusion needle thrusts slight rubescent in the 5cm of the portion scope, and this type of is rubescent for normal, after lowering transfusion drip speed, can disappear rapidly, above 5cm, then is recorded as untoward reaction like the flushing scope.
Welt: area is greater than 2cm
2Welt be recorded as untoward reaction because after some skin sensitivity person runs into environmental stimuli, be prone to form little welt.
4. experimental result and discussion
Table 9:43 example volunteer's variable concentrations sinomenine venous transfusion administration first skin allergy distributes
Annotate: 60 droplets/minute of quiet speed
Transfusion first; The 0.06wt% group has 2 patients skin allergy to occur, and the 0.10wt% group has 7 patients skin allergy to occur
Table 10:43 example volunteer variable concentrations sinomenine secondary venous transfusion administration skin allergy distributes
See from statistical result, 43 routine volunteer's first administration skin allergies, 20 examples time, secondary administration skin allergy 10 examples, twice administration to skin allergy have significant difference (chi-square value=7.656, P=0.000).
See that from statistical result twice administration skin allergy has significant difference (chi-square value=7.656, P < 0.01).
Table 11: untoward reaction relatively between the variable concentrations group
Skin allergy has significant difference due to two groups of first administration of 0.06wt% and 0.10wt% concentration.
43 routine experimental group subjectss have all accomplished the transfusion overall process.Three groups with the administration of variable concentrations venous transfusion mode, and 1 routine anaphylactic shock does not take place, and the untoward reaction that it showed is skin allergy.With the administration of 0.02wt% concentration, untoward reaction takes place in none example; With the administration of 0.06wt% concentration, have 16.67% skin adverse reaction to occur; And with the administration of 0.10wt% concentration, the incidence rate of skin adverse reaction is then up to 50%.The statistical testing results shows that the skin allergy that 0.06wt% concentration group and 0.10wt% concentration group cause has significant difference.To volunteer's row secondary intravenously administrable the time, incidence rate of adverse reaction has descended half the.Incidence rate of adverse reaction increasing and increase with liquor strength is described; But during the secondary administration; Untoward reaction but has tangible minimizing, and two groups of skin allergies that cause did not have significant difference when statistical test was presented at the secondary administration, and human body produced tolerance to medicine when the secondary administration was described.In therapeutic process, when this type of untoward reaction of skin allergy occurring, thereby infusion process is accomplished through the degree that the adjustment injection speed can alleviate reaction.So, select suitable drug level administration to realize the important breakthrough of sinomenine route of administration with intravenous route.Clinical practice confirms, implements conventional intravenous drip entering human body according to 1-5mg/kg dosage and then can tolerate fully, and do not have tangible untoward reaction generation.
From the angle of materia medica, have the dosage and the administering mode of clinical applicability, must satisfy following three conditions:
1. dosage must be an efficacious therapy dosage, and under effective prerequisite, dosage is low more good more.
2. in effective dosage ranges, administering mode at first will meet the clinical administration usual manner, and is simpler, convenient good more, and administration number of times is few more good more.
3. in all administering modes, untoward reaction is few more good more.
From the result of above two researchs, sinomenine intravenous drip administering mode is accomplished and is met above three requirements, and clinical practice proves that also Kukoline intravenous transfusion is fully feasible.
5. conclusion:
Can draw four concluding experimental results of relevant sinomenine intravenously administrable from documents and materials and this group clinical summary:
(1) in the dosage range of effective and safe, can eliminate this serious adverse reaction of anaphylactic shock due to the sinomenine fully with suitable concentration row vein transfusion.
(2) the administration concentration scope that venous transfusion administering mode skin allergy untoward reaction occurrence rate is minimum is 0.02-0.1wt%; Drip speed with routine; Reaching the standard grade during first administration of this concentration range; Pruritus or welt appear in 50% patient, and when the secondary administration, pruritus or welt can appear in 25% patient.The incidence rate that skin allergy is described increases and obviously reduces with administration number of times.
(3) when infusing, when routine is dripped speed, do not have 1 example and anaphylactic shock occurs, explain at this drug level to possess clinical safety with the sinomenine medicinal liquid row vein of 0.02-0.1wt% concentration.
(4) sinomenine is fully feasible at human body route of administration medium-sized vein infusion model.
Claims (14)
1. Kukoline intravenous transfusion preparation; It is to comprise the sinomenine of 0.01-0.2wt% and the injection of injection aqueous solvent, or comprise be used for facing the injection before the preparation so that injection sinomenine concentration is the aseptic injection powder of 0.01-0.2wt% or the injection of lyophilizing injection powder injection and injection aqueous solution.
2. infusion preparation according to claim 1, injection aqueous solvent wherein are water for injection, injection normal saline or the D/Ws of sterilization.
3. infusion preparation according to claim 1 and 2, sinomenine wherein are selected from sinomenine or its officinal salt.
4. infusion preparation according to claim 3, sinomenine officinal salt wherein is a sinomenine hydrochloride.
5. infusion preparation according to claim 1 and 2 also can further comprise isoosmotic adjusting agent, pH regulator agent and pH buffer agent, solubilizing agent, stabilizing agent and/or antioxidant.
6. infusion preparation according to claim 1 and 2 wherein further comprises lyophilized powder excipient, sterile powder for injection forming agent or improves the adjuvant that redissolves in the injectable powder.
7. infusion preparation according to claim 5, wherein isoosmotic adjusting agent is selected from sodium chloride, glucose; PH regulator agent and pH buffer agent are selected from hydrochloric acid, sodium hydroxide, sodium bicarbonate and/or sodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution; Solubilizing agent is selected from meglumine, poloxamer, propylene glycol and/or hydroxypropyl; Stabilizing agent and/or antioxidant are selected from vitamin C, disodiumedetate and/or sodium sulfite.
8. infusion preparation according to claim 6, wherein the adjuvant of lyophilized powder excipient, sterile powder for injection forming agent or improvement redissolution is selected from mannitol, glycine, arginine, glucose, lactose, polyvinylpyrrolidone and/or low molecular dextran.
9. infusion preparation according to claim 1 and 2, wherein the content of sinomenine is 0.02-0.10wt%.
10. infusion preparation according to claim 1 and 2, wherein the content of sinomenine is 0.03-0.06wt%.
11. infusion preparation according to claim 5, wherein the content of isoosmotic adjusting agent is 0.1-10wt%, the content 0-10wt% of pH regulator agent and buffer agent, the content 0-50wt% of solubilizing agent, the content 0-10wt% of stabilizing agent and/or antioxidant.
12. infusion preparation according to claim 11, wherein isoosmotic adjusting agent is 0.9wt% sodium chloride or is the glucose of 5～10wt%.
13. according to claim 6 or 8 described infusion preparations, the consumption of lyophilized powder excipient accounts for 10～90wt% of freeze-dried powder weight, the consumption of aseptic powder forming agent is 0～90wt% of sterilized powder.
14. method for preparing according to each described injection among the claim 1-13; Comprise with sinomenine and aqueous injection solvent and directly be prepared into infusion preparation; Perhaps be mixed with described infusion preparation in facing, perhaps use injection aqueous solvent aseptic powder or lyophilized injectable powder dissolving preparation with preceding use injection aqueous solvent with the commercially available sinomenine injection that is higher than 0.3wt%.
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| CN102626382B (en) * | 2012-03-30 | 2013-04-03 | 湖南正清制药集团股份有限公司 | Method for preparing sinomenine hydrochloride infusion solution and freeze-dried powder injection |
| CN102813924B (en) | 2012-05-17 | 2014-06-18 | 高同强 | Drug combination product for analgesia based on sinomenine |
| CN108653287B (en) * | 2018-05-03 | 2020-06-05 | 北京市心肺血管疾病研究所 | Application of sinomenine in preventing and treating thoracic aortic dissection/aortic aneurysm |
| CN110251469B (en) * | 2019-07-31 | 2021-11-09 | 南京康舟医药科技有限公司 | Terlipressin acetate preparation and preparation method thereof |
| CN111773221B (en) * | 2020-07-21 | 2021-08-03 | 李蕴麟 | Application of sinomenine and derivatives or pharmaceutically acceptable salts thereof in preparing medicine for treating breast diseases |
| CN115645409A (en) * | 2022-08-09 | 2023-01-31 | 广东跨元航天医学工程技术有限公司 | Application of sinomenine in medicine for treating coronavirus and influenza virus |
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