CN104688766A

CN104688766A - Alginic sodium diester powder-injection pharmaceutical composition for injection and preparation method thereof

Info

Publication number: CN104688766A
Application number: CN201510149259.7A
Authority: CN
Inventors: 徐愈富; 陈文国; 黄楠; 张爽; 赵春雁
Original assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Current assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Priority date: 2015-03-31
Filing date: 2015-03-31
Publication date: 2015-06-10
Anticipated expiration: 2035-03-31
Also published as: CN104688766B

Abstract

The invention relates to an alginic sodium diester powder-injection pharmaceutical composition for injection and a preparation method thereof, in particular to the pharmaceutical composition. The pharmaceutical composition comprises alginic sodium diester, mannitol and an optional acid-base regulator, wherein every 100 parts of alginic sodium diester correspond to 5-25 parts of mannitol in included materials by weight. The alginic sodium diester powder-injection pharmaceutical composition for injection can be used for ischemic heart and cerebrovascular diseases (cerebral thrombosis, cerebral embolism, coronary heart disease and the like) and hyperlipemia and has good pharmaceutical properties.

Description

Polysaccharide sulphate for injection injectable powder pharmaceutical composition and method for making

Technical field

The invention belongs to pharmaceutical preparations technology field, relate to the medicine that one can be used for ischemic cardiac, cerebrovascular (cerebral thrombosis, cerebral embolism, coronary heart disease etc.) and hyperlipemia, particularly relate to a kind of polysaccharide sulphate for injection injectable powder pharmaceutical composition, and their preparation method, this polysaccharide sulphate for injection injectable powder pharmaceutical composition has good pharmaceutical properties.

Background technology

The propylene glycol alginate sodium sulfate that the present invention relates to is a kind of effective ischemic cardiac, cerebrovascular (cerebral thrombosis, cerebral embolism, coronary heart disease etc.) and hyperlipidemia.

The English of propylene glycol alginate sodium sulfate is called Alginic Sodium Diester, and chemistry is by name: alginic acid propyl ester sulfuric ester sodium salt, molecular formula: (C ₁₅h ₁₈cO ₂2NA ₄s ₃) _nn=12-15, molecular weight: 10000-25000 dalton, chemical structural formula is:

The clinical indication of alginate diester sodium injection is: ischemic cardiac, cerebrovascular (cerebral thrombosis, cerebral embolism, coronary heart disease etc.) and hyperlipemia, preparation specification has 0.1g/ bottle usually.Its usage and dosage is: intravenous drip; Adult, by body weight 1 ~ 3mg/kg, is dissolved in 250 ~ 500ml normal saline before use, slowly instil (drip speed and should be not more than 0.75mg/kg hour), once-a-day; Every day, research on maximum utilized quantity can not more than 150mg.

Propylene glycol alginate sodium sulfate is raw material based on Sargassum extract, belongs to heparinoid medicine.This product can reduce blood viscosity, improves microcirculation.In addition, this product can make thrombin inactivation, suppress because tunica intima is impaired, adenosine diphosphate (ADP) and thrombin activation etc. platelet aggregation extremely, there is anticoagulant effect.The content of T-CHOL in blood plasma, triglyceride and low density lipoprotein, LDL (LDL) can also be made to reduce after this product application, high density lipoprotein (HDL) D level raises, and has the effect of blood fat reducing.

Propylene glycol alginate sodium sulfate is acidic polysaccharose class medicine, is raw material based on alginic acid, chemically introduces effective group and is synthesized into.It has strong dispersion and emulsion performance, and be not subject to external factor impact, because it has the feature of anionic polyelectrolyte fibre structure, along chain charge concentration, under the effect of its electric repulsion, the cell surface being rich in negative charge can be made to strengthen mutual repulsive force, therefore the adhesion between energy impedance erythrocyte and between erythrocyte and blood vessel wall, have and improve hemorheological viscoelastic effect.In addition, these product can make thrombin inactivation, its anticoagulation effect is equivalent to 1/3 ~ 1/2 of heparin, platelet can be stoped the adhesion of collagen protein, suppress because tunica intima is impaired, adenosine diphosphate (ADP) thrombin activation, and the platelet aggregation that release reaction etc. is caused, thus there is prostacyclin (PGI2) the sample effects such as antithrombotic, reducing blood viscosity, fine motion vein spasmolytic, erythrocyte and platelet disaggregation.These product also have the effect obviously reducing blood fat, cholesterol in blood plasma, triglyceride, low density lipoprotein, LDL (LDL), very low density lipoprotein (VLDL) (VLDL) etc. can not only be made after application to decline rapidly, simultaneously again can the level of increasing serum high density lipoprotein (HDL), generation and the development of atherosclerotic lesion can be suppressed, this product human peripheral blood pipe has obvious dilating effect, effectively can improve microcirculation, suppress the formation of thrombosis in arteriovenous, not only there is therapeutical effect, have reliable preventive effect simultaneously.In addition, these product also have the several functions such as blood sugar lowering and blood pressure lowering.

The pharmacokinetics of alginate diester sodium injection intravenously administrable in Mice Body meets open three compartment models, intravenous injection 3mg/kg, the first distribution phase blood drug level decrease speed, t _1/2be 1.21 minutes, the second distribution phase t _1/2be 15.6 minutes, illustrate that medicine distributes comparatively fast in vivo, eliminate phase t _1/2be 37.95 hours, apparent volume of distribution V _dfor 3.90L/kg, show that medicine is wider in tissue distribution.Administration is after 30 minutes, and medicine to obtain distribution peaking each organizing, and wherein the highest with liver, kidney, lung, spleen, intestinal take second place, and fat, brain, skeleton content are lower.This product is mainly through urine drains, and after intravenously administrable, excretion in 3 hours reaches excretions in 40%, the 12 hours excretion 80% in 70%, 72 hours of injection volume.Human plasma protein fraction combination rate is 98.1%.

Have in prior art many about propylene glycol alginate sodium sulfate particularly its lyophilization injectable powder technology report.

CN103083261A (201310052570.0, honest) disclose a kind of propylene glycol alginate sodium sulfate lyophilization injectable powder, its formula is: propylene glycol alginate sodium sulfate 80g, compositions (part by weight of three is 3: 5: the 2) 250g of mannitol, glucose and dextran, compositions (the two part by weight is 2: the 3) 15g of arginine and cysteine hydrochloride, disodiumedetate 10g, hydrochloric acid solution (0.1mol/l) regulates pH to 6.5 in right amount, and water for injection adds to 1000ml; Its preparation method is: take the propylene glycol alginate sodium sulfate of recipe quantity, mannitol, glucose, dextran, arginine, cysteine hydrochloride and disodiumedetate respectively, add in water for injection, be fully stirred to dissolve, add active carbon, absorption, decarburization is filtered.Hydrochloric acid solution adjust ph to 6.5.After 0.22 μm of membrane filtration, fill, to cleaning in the cillin bottle of drying and sterilizing, is often propped up dress 3mL, half gland, is opened freeze dryer, be cooled to-40 DEG C, lyophilizing, roll lid, check, packaging.

CN102824357A (201210350009.6, high sharp) disclose a kind of polysaccharide sulphate pharmaceutical compound for injection, it is characterized in that, polysaccharide sulphate for injection pharmaceutical composition described in every 1000, its formula consists of: propylene glycol alginate sodium sulfate 100g, mannitol 860-2150g, water for injection add to 100L-250L; The preparation method of described polysaccharide sulphate pharmaceutical compound for injection comprises the steps: 1) doublely in weighing room check through having weighed propylene glycol alginate sodium sulfate and mannitol raw material according to recipe quantity; 2) in dense preparing tank, add 40 ± 5 DEG C of waters for injection of recipe quantity 70%, add propylene glycol alginate sodium sulfate and the mannitol of recipe quantity, mixing speed 20 revs/min, stirring 10 minutes to dissolving completely, adding to the full amount of water for injection; 3) exist by 4% hydrochloric acid solution or 10% sodium hydroxide solution adjust ph; 4) squeeze in dilute preparing tank with pump, by 5000MW membrane ultrafiltration device filtering pyrogen; 5) pH value, content is measured; 6) after 0.22 and 0.45 μm of filtering with microporous membrane, by specification subpackage; 7) high pressure 121 ± 2 DEG C, sterilizing 20 minutes; 8) visible foreign matters inspection;

CN1481809A (03127651.2, Zhuo Yi) disclose a kind of freeze-dried type polysaccharide sulphate for injection, containing propylene glycol alginate sodium sulfate, excipient (mannitol, mannitol, Dextran 40 etc.), weight proportion wherein containing described each composition in every 1000 bottles is: propylene glycol alginate sodium sulfate 25-200 gram, excipient 200-25 gram.It is believed that this invention adopts advanced frozen drying technique, be made into lyophilized formulations, namely the shortcoming that tablet form product bioavailability is lower is overcome, solve again injection type product because the variable color caused by high temperature sterilize, shortcoming unstable in storage life, make this product more stable in storage life, be more suitable for clinical practice.It is believed that this invention product has reduction blood viscosity, anticoagulation, blood fat reducing, improves the effects such as microcirculation, for the control of ischemic cardiac, cerebrovascular and hyperlipemia, there is stable performance, safe and reliable, the advantages such as Clinical practice is convenient.

CN1524534A (03105281.9, bold and generous) relates to a kind of novel form of propylene glycol alginate sodium sulfate, i.e. powder ampoule agent for injection.It is believed that it is injectable sterile powder, have transport easy to carry, dosage is accurate, the features such as production technology is simple.It is believed that this invention overcomes the deficiency of existing dosage form, such as peroral dosage form not easily absorbs, the shortcoming of liquid drugs injection and injection type instability.It is believed that this invention also relates to the preparation method of this novel form.

But existing propylene glycol alginate sodium sulfate formulation example such as its lyophilized injectable powder still has technical problem to be overcome.Therefore, those skilled in the art still expect there is new method to prepare the polysaccharide sulphate for injection lyophilized injectable powder with Good Pharmacy performance.

Summary of the invention

The object of the invention is to provide a kind of polysaccharide sulphate for injection lyophilized injectable powder with Good Pharmacy performance.The present inventor has been surprisingly found that, the polysaccharide sulphate for injection lyophilized injectable powder with present composition feature can realize above-mentioned purpose valuably.Therefore the present invention is accomplished.

For this reason, first aspect present invention provides a kind of pharmaceutical composition, wherein comprises: propylene glycol alginate sodium sulfate, mannitol and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the material wherein comprised is in the propylene glycol alginate sodium sulfate of every 100 weight portions, and the amount of mannitol is 5 ~ 25 weight portions, such as 5 ~ 20 weight portions, such as 5 ~ 15 weight portions.

The pharmaceutical composition of arbitrary embodiment, wherein also optionally comprises citric acid according to a first aspect of the present invention.The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the material wherein comprised is in the propylene glycol alginate sodium sulfate of every 100 weight portions, and the amount of citric acid is 5 ~ 20 weight portions, such as 5 ~ 15 weight portions, such as 5 ~ 10 weight portions.

The pharmaceutical composition of arbitrary embodiment, wherein comprises according to a first aspect of the present invention

Propylene glycol alginate sodium sulfate 100 weight portion,

Mannitol 5 ~ 25 weight portion,

Citric acid 5 ~ 20 weight portion,

And optional acid-base modifier.

Propylene glycol alginate sodium sulfate 100 weight portion,

Mannitol 5 ~ 20 weight portion,

Citric acid 5 ~ 15 weight portion,

And optional acid-base modifier.

Propylene glycol alginate sodium sulfate 100 weight portion,

Mannitol 5 ~ 15 weight portion,

Citric acid 5 ~ 10 weight portion,

And optional acid-base modifier.

Have been surprisingly found that, when using the mannitol of specified quantitative and citric acid to combine simultaneously, effectively can suppress the growth of injectable powder impurity in long-term preservation process, this is completely beat all.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is dissolved in water and dilutes the solution made containing propylene glycol alginate sodium sulfate 10mg in every 1ml, and the pH value of this solution is 5.0 ~ 7.0, and such as pH value is 5.5 ~ 6.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, its solution before lyophilization, except comprising propylene glycol alginate sodium sulfate, mannitol and optional citric acid and optional acid-base modifier, also comprises water for injection.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, its solution before lyophilization also comprises water for injection except comprising propylene glycol alginate sodium sulfate, mannitol and optional citric acid and optional acid-base modifier, the solid content of described solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it redissolves to substantially identical with solution before lyophilization volume with water for injection, solid content in gained solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein comprise propylene glycol alginate sodium sulfate 100 weight portion, mannitol 5 ~ 25 weight portion (such as 5 ~ 20 weight portions, such as 5 ~ 15 weight portions), citric acid 5 ~ 20 weight portion (such as 5 ~ 15 weight portions, such as 5 ~ 10 weight portions) and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the consumption of acid-base modifier is, make this pharmaceutical composition when being dissolved in water and dilute the solution made containing propylene glycol alginate sodium sulfate 10mg in every 1ml, the pH value of this solution is 5.0 ~ 7.0, and such as pH value is 5.5 ~ 6.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, its the every bottle propylene glycol alginate sodium sulfate weight comprised is 20 ~ 1000mg, the such as every bottle propylene glycol alginate sodium sulfate weight comprised is 50 ~ 500mg, and the such as every bottle propylene glycol alginate sodium sulfate weight comprised is 50 ~ 200mg.

As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 5%, be particularly usually less than 3%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 5.0 ~ 7.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing active component 10mg/ml concentration, the amount of pH value in 5.5 ~ 6.5 scopes of such as this solution.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is prepare by comprising following step substantially:

A () takes the propylene glycol alginate sodium sulfate of recipe quantity and mannitol and optional citric acid, add appropriate water for injection, make dissolving, then add active carbon, stir, filtering decarbonization;

B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensuration active component content, if desired by the scope that acid-base modifier regulates this solution to conform with the regulations to pH;

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing propylene glycol alginate sodium sulfate 10mg/ml, the pH value of gained dilute solution is in 5.0 ~ 7.0 scopes, the pH value of such as this dilute solution is in 5.5 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.0.Although the activity component concentration (about 50mg/ml) of step (b) gained solution measures the normal concentration (being about 5 times) of pH value higher than finished product, but step (b) solution dilution 5 times easily can be measured the pH value of gained diluent by those skilled in the art, needs according to this pH value determining step (b) gained solution the amplitude regulating Acidity of Aikalinity.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein also optionally comprises the acceptable excipient of other pharmacy.Described excipient is such as but not limited to mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, mannitol and combination thereof.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=10 μm in each test sample container is less than 6000, such as be less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as, be less than 250.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=25 μm in each test sample container is less than 600, such as be less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as, be less than 25.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, be less than 6000 containing the particle number of >=10 μm in each test sample container and (be such as less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250), and the particle number of >=25 μm is less than 600 and (is such as less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25).

Further, second aspect present invention provides the method for the pharmaceutical composition described in the arbitrary embodiment of preparation first aspect present invention, and it consists essentially of following steps:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

The method of arbitrary embodiment according to a second aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing propylene glycol alginate sodium sulfate 10mg/ml, the pH value of gained dilute solution is in 5.0 ~ 7.0 scopes, the pH value of such as this dilute solution is in 5.5 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.0.

Method according to a second aspect of the present invention described in arbitrary embodiment, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the described appropriate water for injection of step (a) is about 70 ~ 90% of water for injection recipe quantity.

Method according to a second aspect of the present invention described in arbitrary embodiment, the water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 10-30 times of propylene glycol alginate sodium sulfate weight, such as 15-25 doubly, such as about 20 times.The amount of this water for injection easily controls by solid content described in step (c).

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.05% ~ 0.2%.

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

State on the invention in the step of preparation method, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize the above method step completely according to the open in detail of the present invention's full text.

Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.The invention will be further described below.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

Propylene glycol alginate sodium sulfate (PPS) is the marine polysaccharide class medicine of Chinese Marine University's independent research, and it is raw material based on alginic acid, introduces effective group synthesis gained by chemical method.As first ocean heparinoid drug of Chinese independent research, more than 20 years of clinical practice are dropped at present.Through the retrieval of State Food and Drug Administration 2012 annual data, nearly 300 of domestic approved PPS production approval number, comprises crude drug, tablet and injection, is the maximum kind of Discussion on Chinese Listed marine drug production scale.

Current PPS has been applied to the control of the disease such as ischemic cardiac, cerebrovascular, increasingly deep along with its molecular mechanism and pharmacokinetic, and its clinical indication is further extensive.Thing followed untoward reaction also highlights increasingly.

PPS is heparinoid class material, with negative charge, changing hemorheology, suppressing intrinsic coagulation pathway by reducing blood viscosity etc.; And by suppressing hematoblastic activation and gathering, improve the level of thrombomodulin, Function protein C system, suppresses as thrombosis cofactors such as Endothelin (ET-1), palatelet-selectin (P-selectin), VEGF (VEGF) and platelet activating factor (PAF).Propylene glycol alginate sodium sulfate affects the processes such as lipid absorption, degraded, excretion and reduces blood fat in addition; And then improve microcirculation by the number of ways such as anticoagulant, blood fat reducing.In addition, propylene glycol alginate sodium sulfate, also by promoting neure growth, suppressing its apoptosis, regulating the expression of correlation factor to reach neuroprotective, regulating carbohydate metabolism, the effects such as antiinflammatory.

In clinical practice.Patients with coronary heart disease is divided into treatment group (PSS injection) and matched group (nitroglycerin injection) by Pan Xiaoqun etc. at random.Result: after treatment group treatment, cardiac output, cardiac index and ejection fraction all significantly increase before comparatively treating, and ST section forces down total degree, ST section significantly reduces before forcing down and all comparatively treating total time, and corresponding matched group is without significant change; Symptom scores two groups treatment after all have clear improvement, but treatment group comparatively matched group symptom improve more obvious.Unstable angina pectoris in-patient is divided into conventional therapy group (calcium ion antagonist, B receptor blocking agent, nitrate esters, blood vessel converting enzyme inhibitor, aspirin, statins), Low molecular heparin group (basis of conventional therapy adding with Low molecular heparin) and treatment group (basis of conventional therapy adding with PSS) by Liu Zhengyuan etc. at random, result: treatment group successful is better than conventional therapy group, is better than Low molecular heparin group in tune fat, blood sugar lowering.Show the effect that PSS has blood sugar lowering, adjusts fat, improves vascular endothelial function, microcirculation, prevention coronary spasm can be improved, obviously can improve the ischemic state of cardiac muscle.

Pulmonary heart disease aspect, Luo Chunnian by be diagnosed as patients with cor pulmonale be divided at random matched group (antiinflammatory, eliminate the phlegm, cough-relieving, relieving asthma, heart tonifying, the integrated approach such as diuresis and oxygen uptake) with observation group's (giving PSS to treat on the basis of Comprehensive Treatment).Result: two groups of total effective rate differences have statistical significance, and observation group is without obvious adverse reaction.Illustrate that PSS can be used as pulmonary heart disease adjuvant therapy medicaments.

Transient ischemic attack aspect, application for organizing the Olympic Games wait patients with transient ischemic attack is divided at random treatment group (PSS injection) and matched group (XUESHUANTONG ZHUSHEYE) result treatment group comparatively matched group hemorheology, blood fat etc. change obvious, PSS curative effect is obviously better than XUESHUANTONG therapy.Show that PSS injection has anticoagulation and prostaglandin-like effect, can reduce blood fat, suppress generation and the development of atherosclerotic lesion, expansion peripheral blood vessel, effectively can improve microcirculation, thus increases cerebral blood flow, reduces cerebral vascular resistance.

Cerebral thrombosis aspect, cerebral thrombus patient is divided into treatment group (PSS injection) and matched group (FUFANG DANSHEN ZHUSHEYE) by Yan Jiang etc. at random.Result: treatment group obvious effective rate is apparently higher than matched group.May can reduce that ischemic cerebrovascular blood is glutinous with PSS, blood fat, to improve hemorheological property relevant.

Cerebral infarction aspect, Patients with Cerebral Infarction is divided into observation group (quiet of PSS) and matched group (quiet of citicoline) by Zhao Hongxia at random.Result: before and after treatment, neurological deficits score compares, observation group improves more obvious, and observation group's curative effect is better than matched group.Consider that PSS can from anticoagulant, antithrombotic, improve Hemorheology, Ca2+ overloading, neuroprotective tissue and suppress atherosclerosis, blood vessel dilating, improve the aspects such as microcirculation therapeutical effect is risen to acute cerebral infarction.And have impact to intrinsic coagulation pathway, and the impact of exogenous coagulation pathway is little, not easily causes bleeding, therefore be thromboembolism preventing medicine safely and effectively.Separately, apply PSS clinically and combine ozagrel treatment efficacy of acute cerebral infarction significantly, can obviously improve ischemic region microcirculation, protection cerebral tissue, alleviates dysfunction.

Oculomotor paralysis migraine aspect, quiet of strong beautiful jade PSS treats oculomotor paralysis type migraine, and after treatment, symptom is comparatively front takes a turn for the better, and laboratory examination, imaging examination show no obvious abnormalities.Visible PSS can be used for the migraine initial cerebral vasospasm phase, makes it lax, improves cerebrovascular function, stop cerebrovascular pathological dilatation, remove the compressing to oculomotorius, alleviates intensity and the time of outbreak, recovers the function of oculomotorius.

Pneumonia aspect, infantile pneumonia infant is divided into observation group (antibiotic, antiviral therapy+PSS) and matched group (antibiotic, antiviral therapy) by Zhang Aizhen at random.Result: observation group comparatively matched group pulmonary rale and x-ray rabat all obviously shortens recovery time.Bronchopneumonia mechanism is the deformability leukocyte reduced and the leukocyte attaching to vascular endothelial cell, capillary vascularization spile in lung, cause Pulmonary microcirculatory disturbance, and PSS has and improves White Blood Cell Deformability, and reduce adhesive force and improve pulmonary microcirculation, thus can reach therapeutic effect.

Tuberculous exadative pleurisy aspect, Yang Qi will to make a definite diagnosis or strong suspicion tuberculous exadative pleurisy case is divided into experimental group ((tuberculosis take out the conventional therapies such as hydrothorax+thoracic cavity drawing liquid after PSS, normal saline intrapleural injection) and matched group (conventional therapy) at random.Result: experimental group is better than matched group in clinical symptoms improvement, iconography etc.This shows that PSS is by its antiinflammatory action, blocks the development of inflammatory exudation, reduces blood viscosity, improves microcirculation, accelerates absorbing again of visceral pleura, reduces fibrin and directly affects the fibrinous deposition of pleura.COPD: have been found that PSS can reduce blood viscosity, improve microcirculation, reduce pulmonary hypertension, reduce microthrombusis, effective relieve chronic obstructive pulmonary disease blood samples of patients hypercoagulability, significant to treatment AECOPD.Also find, PSS has inhibitory action to the blood clot that thrombin and fibrin and platelet are formed, and has synergism with aspirin chlorine, pyrrole Gray use in conjunction, significantly can reduce platelet aggregation rate.

Diabetes and complication aspect thereof: type 2 diabetes mellitus: have been found that PSS blood fat reducing, reduce blood viscosity, improve microcirculation of pancreatic gland, promote insulin secretion, receptor can be improved blood glucose is reduced to the sensitivity of insulin, can be used as assistant hypoglycemic medicine.Diabetictrunk angiopathy: have been found that PSS can avoid the generation of lower limb atherosclerosis, reduces vascular endothelial cell damage, reduces platelet aggregation, and Blood denseness, regulates lipid metabolism.Diabetic foot: have been found that PSS can expand blood vessel, to improve foot microcirculation, blood sugar lowering and blood glutinous, foot blood supply can be increased, improve symptom.Diabetic peripheral neuropathy: have been found that PSS can blood fat reducing effectively, reduce Plasma Viscosity, whole blood viscosity and Fibrinogen, improve hemorheology; Improve sensory nerve and motor nerve conduction velocity, have good result to diabetic peripheral neuropathy.Diabetic nephropathy: have been found that PSS has and obviously reduce blood pressure, blood fat, blood vessel dilating, improve renal function, reduce the function of urine protein.It by protection vascular endothelial cell and the effect of prostacyclin sample, thus improves microcirculation, increases kidney blood supply, improves glomerular filtration rate.

Hyperlipidemia height blood sticks disease aspect: hyperlipidemia: have been found that PSS can reduce serum total cholesterol, triglyceride, low density lipoprotein, LDL and very low density lipoprotein (VLDL); High density lipoprotein increasing, also can reduce the deposition of cholesterol and cholesteryl ester in tremulous pulse, obviously alleviate arteriosclerosis plaque and form suppression atherosclerosis hyperlipidemic pancreatitis: have been found that PSS can improve microcirculation of pancreatic gland, have auxiliary therapeutic action to acute pancreatitis.High blood sticks: have been found that PSS is by reducing blood viscosity, spasmolytic, tune fat, and then improve high blood and stick the microcirculation disturbance caused, reach therapeutic purposes.

Hepatic disease aspect: acute hepatitis B: have been found that PSS can reduce Endothelin release, improves microcirculation disturbance, promote liver function recovery.Cholestatic hepatitis: have been found that PSS and soothing the liver enzyme in anticoagulant, expand blood vessel, blood fat reducing, reduction blood viscosity and platelet aggregation, to improve the function aspects effects such as microcirculation similar, and can reducing enzyme and treating jaundice.Chronic active hepatitis hyperbilirubinemia: have been found that PSS group jaundice eliminating subcutaneous ulcer, comparatively motassium magnessium aspartate group is obvious to fall ALT curative effect, improve microcirculation, and reduce bilirubin level.

The nephrotic syndrome: have been found that, PSS has heparinoid effect, blood viscosity can be reduced, anticoagulation, antithrombotic, expands blood vessel, promote fibrinolytic, anticoagulant, improve microcirculation, blood fat reducing to improve plasma albumin, thus can improve low albumen, hyperlipidemia, high blood sticks, platelet function is hyperfunction symptom.

Gout aspect, have been found that PSS and the equal tool anticoagulant of mannose ester, antiplatelet stick poly-property, blood fat reducing, improves haemoconcentration and improving micro_circulation effect.Xanthelasma palpebrarum aspect, has been found that PSS is heparinoid class material, by blood fat reducing, falls blood viscosity and blood vessel dilating, improving micro_circulation effect to reach therapeutic purposes.Postoperative intestinal is adhered aspect, has been found that PSS can regulate and control the expression of matrix metalloproteinase (MMP)-2 and Timp (TIMP)-2, so promote wound healing complete the formation be adhered with prevention of intestinal.In addition, PSS is also applied to uneasy lower limb syndrome, anaphylactoid purpura, disseminated inravascular coagulation, skin related disease as scleroderma neonatorum etc.

According to the present invention, term " excipient " also can be described as adjuvant, filler etc." the acceptable excipient of pharmacy " used herein refers to the excipient that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.

The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:

Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.

Moisture in lyophilization injectable powder is general below 8%, preferably lower than 5%, more preferably less than 3%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.

In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.

When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

Term " solid content " refers to solid matter (such as reactive compound of the present invention and whole excipient used, weight/gram) join in solvent (such as water for injection), a solution is obtained after dissolving, the weight of described solid matter such as, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.Such as in the present invention, add appropriate aqueous solution for injection with 100mg reactive compound and other solid content amounting to about 20mg, be mixed with the solution that final volume is 2ml, its solid content is 6%.

In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.

When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.

According to pharmaceutical composition of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), in per unit dosage, the amount (it is all converted in the present invention if not otherwise indicated in propylene glycol alginate sodium sulfate) of reactive compound can such as but not limited to about 50mg, about 100mg, about 150mg, about 200mg.

According to pharmaceutical composition of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.

According to lyophilized injectable powder of the present invention, its with water make in every 1ml containing reactive compound 10mg solution and according under Chinese Pharmacopoeia version in 2010 two annex VI H items method measure, the pH value of this solution is 5.0 ~ 7.0, and such as pH value is 5.5 ~ 6.5.

Lyophilized injectable powder provided by the invention can be preserved at least 24 months at dry place below 25 DEG C, can meet the Storage Requirement of general lyophilization injectable powder.

Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally white or the lyophilizing block of off-white color or its fragment or its powder, odorless, bitter in the mouth, soluble in water.

Detailed description of the invention

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when making to prepare injectable powder, make the pH value of the solution prepared before lyophilization be adjusted to a certain setting or scope, this setting or scope are value or the scopes that lyophilization gained dry powder water for injection is diluted to the pH value that the solution containing active component 10mg/ml measures.The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.Dosing is prepared in various compositions below, if not otherwise indicated, the total dosing amount often criticized is 10000ml, but when listing formula, the amount all containing active component 100mg with every bottle is illustrated, and is dispensed into sealing preservation in vial with every bottle of amount containing active component 100mg.

The method of quality control of injectable powder and standard issue concrete grammar in standard YBH01262004 according to office of State Food and Drug Administration and standard is carried out.The clarity of the character of such as gained injectable powder of the present invention, discriminating, acidity, solution and color, moisture, aseptic, the project such as pyrogen, molecular weight and molecular weight distribution, content uniformity, visible foreign matters, particulate matter, assay.

Some mensuration project in these projects can also measure with reference to relevant official method, and the method for the particulate matter inspection of such as injectable powder is carried out according to " first method (light blockage method) " in Chinese Pharmacopoeia 2010 editions two annex IX C particulate matter inspection techniques.

Extraly, injectable powder prepared by the present invention, can measure their related substance, particularly investigates the situation of change of their related substances after experience simulation Long-term Storage.The literature methods such as Related substances separation method reference Ren Lianjie (Ren Lianjie, etc., the mensuration of propylene glycol alginate sodium sulfate related substance, capital medicine, 2008,16:46), this Related substances separation method can be described as Ren Lianjiefa in the present invention.The present inventor has been found that, various alginate diester sodium injection, comprise commercially available, biliographic data method obtains, and the various method of the present invention is obtained, they all detect according to this Ren Lianjiefa, main constituent retention time is 4.50 ± 0.05min, and present an impurity peaks all more or less (its relative retention time RRT relative to main constituent is 1.92 at about 8.65 ± 0.05min place, this impurity is called RRT1.92 impurity in the present invention), and at RRT1.52, RRT1.79, three impurity at RRT2.65 place all do not detect, and these three impurity have no and increase significantly in powder pin Long-term Storage process.It is consistent that the main constituent retention time that the present invention detects and the retention behavior of these impurity in chromatogram are all recorded with the document.Surprisingly, RRT1.92 impurity can extend and the growth that present in various degree along with injectable powder storage.

study on the stability method:

This method may be used for the stability (such as physical stability and chemical stability) under investigation the present invention various product simulation Long-term Storage condition.Concrete grammar is: placed 5 months at 42 DEG C by obtained lyophilization injectable powder, measure content [42 DEG C of Mays of propylene glycol alginate sodium sulfate in sample, can be described as high temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] when processing the corresponding time relative to this sample at 20 DEG C the content of active component [in 20 DEG C of Mays, can be described as room temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] percent, can referred to as residual content (%), calculating formula is as follows:

Wherein, high temperature average content (mg/ bottle) and room temperature average content (mg/ bottle) are that sample obtains according to the contained content assaying method of pharmacopeia.Above-mentioned residual content (%) more shows more stable close to 100%, lower than 100% instability, more low more unstable.

In addition, check that each sample is in the related substance situations of change of placing 5 months front and back through above-mentioned 42 DEG C, and calculate the increase percent (%) that RRT1.92 impurity after 5 months placed by these powder pins at 42 DEG C, its calculating formula is as follows:

In above formula, RRT1.92 impurity content refers to, shine at injectable powder in the HPLC chromatogram of the Related substances separation that above-mentioned Ren Lianjiefa carries out, RRT1.92 impurity peak area is multiplied by the percent of 100% gained again divided by main constituent peak area.

In addition, check the particulate matter of each sample, add up each sample >=10 μm of particle numbers.For each sample, calculate the percent change of >=10 μm of particle numbers after above-mentioned 42 DEG C of placements 5 months high-temperature process, this parameter is called microgranule percent change, and calculating formula is as follows:

Wherein, after high-temperature treatment after >=10 μm of particle numbers and room temperature are disposed >=10 μm of particle numbers are that sample obtains according to light blockage method assay method mentioned above.Above-mentioned microgranule percent change (%) more shows more stable close to 100%, increase higher than 100% particulate matter, and product is unstable, is worth more high more unstable.

one, compositions preparation example part

preparation example 1, preparation comprise the injectable powder of propylene glycol alginate sodium sulfate

Formula:

propylene glycol alginate sodium sulfate	100mg,
		mannitol	10mg,
citric acid	7.5mg,
		pH adjusting agent	to pH6.0,
water for injection	in right amount, 2ml is added to.

Preparation method:

(1) principal agent and the adjuvant (except pH adjusting agent) of recipe quantity is taken, be placed in stainless steel cask, add the water for injection of recipe quantity about 80%, be stirred to dissolve, the active carbon of 0.1% (w/v) is added again by liquor capacity, stir 30 minutes, filtering decarbonization, mend and inject water to close to prescription full dose.

(2) filtrate sampling, measure pH value, setting is adjusted to (namely if desired by pH adjusting agent, get filtrate to inject in right amount and be diluted with water to containing active component 10mg/ml, the pH value measuring this diluent should reach 6.0, otherwise suitably regulates with pH adjusting agent and acid-base modifier again), then benefit injects water to prescription full dose, measure pH value, pH adjusting agent described above is adjusted to the pH6.0 of regulation again if desired; Measure the content of active component in medicinal liquid.

(3) 0.45um filtering with microporous membrane first used by medicinal liquid, then uses 0.22um filtering with microporous membrane 2 times.

(4) with every bottle of liquid drug 2ml fill, in 7ml cillin bottle, (in following example, when quoting this preparation example method, if not otherwise indicated, liquid drug amount is the medicine liquid volume comprising 100mg reactive compound; If liquid drug volume obviously increases or obviously reduces in other example, the volume of cillin bottle rule of thumb suitably can be adjusted), false add plug.

(5) lyophilization is carried out, to moisture lower than 3% according to freeze-drying curve A described herein; After lyophilizing terminates, carry out hydraulic pressure and jump a queue; Prick aluminium lid, to obtain final product.The sample of preparation example 1 can referred to as Ex1 in the present invention; The sample of other preparation example also can similarly represent.

Supplement preparation example 1: with reference to the method for above preparation example 1, adjust unlike by the amount of mannitol wherein, be respectively 0mg, 1mg, 2mg, 5mg, 11mg, 15mg, 20mg, 25mg, 50mg, the injectable powder numbering obtained is respectively Ex111, Ex112, Ex113, Ex114, Ex115, Ex116, Ex117, Ex118, Ex119 nine powder pins.Supplement preparation example 2: with reference to the method for above preparation example 1, adjust unlike by the amount of citric acid wherein, be respectively 0mg, 1mg, 2.5mg, 5mg, 8mg, 10mg, 15mg, 20mg, 30mg, the injectable powder numbering obtained is respectively Ex121, Ex122, Ex123, Ex124, Ex125, Ex126, Ex127, Ex128, Ex129.Supplement preparation example 3: with reference to the method for above preparation example 1, amount unlike citric acid is 5mg, the amount of mannitol is 0mg, 3mg, 5mg, 10mg, 15mg, 20mg or 30mg, and the injectable powder numbering obtained is respectively Ex131, Ex132, Ex133, Ex134, Ex135, Ex136, Ex137.Supplement preparation example 4: with reference to the method for above preparation example 1, amount unlike citric acid is 10mg, the amount of mannitol is 0mg, 3mg, 5mg, 10mg, 15mg, 20mg or 30mg, and the injectable powder numbering obtained is respectively Ex141, Ex142, Ex143, Ex144, Ex145, Ex146, Ex147.Supplement preparation example 5: with reference to the method for above preparation example 1, amount unlike mannitol is 5mg, the amount of citric acid is 0mg, 3mg, 5mg, 7.5mg, 10mg, 15mg or 30mg, and the injectable powder numbering obtained is respectively Ex151, Ex152, Ex153, Ex154, Ex155, Ex156, Ex157.Supplement preparation example 6: with reference to the method for above preparation example 1, amount unlike mannitol is 15mg, the amount of citric acid is 0mg, 3mg, 5mg, 7.5mg, 10mg, 15mg or 30mg, and the injectable powder numbering obtained is respectively Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, Ex167.Supplement preparation example 7: with reference to the method for above preparation example 1, replace with the sucrose of equivalent, sorbitol, lactose or glucose unlike mannitol, the injectable powder obtained numbering is respectively Ex171, Ex172, Ex173, Ex174; With reference to the method for above preparation example 1, replace with the sodium citrate of equivalent, potassium citrate or tartaric acid unlike citric acid, the injectable powder obtained numbering is respectively Ex175, Ex176, Ex177; With reference to the method for above preparation example 1, the amount unlike mannitol and citric acid is 0mg, and the injectable powder numbering obtained is respectively Ex178.This supplementary preparation example 7 obtains 8 injectable powder samples.Supplement preparation example 8:(1) get mannitol 50g, add appropriate water for injection to dissolve, separately get propylene glycol alginate sodium sulfate 100g, be added in mannitol solution, stir, add 0.03% active carbon, 60 DEG C of adsorption bleaching 15min, charcoal is taken off with 0.45 μm, aperture microporous filter membrane, filtrate surveys pH value to 5.0, benefit adds to the full amount of water for injection 2000mL, stir, semi-finished product are through after the assay was approved, with 0.22 μm of microporous filter membrane fine straining, fill, often prop up 2mL, pressure half plug, lyophilization,-35 DEG C are given and freeze 2h,-20 DEG C of distillation 16h, 30 DEG C of dry 5h, tamponade, roll aluminum lid, obtain powder pin, be numbered Ex181 (wanting Ruili), (2) prescription feeds intake as propylene glycol alginate sodium sulfate 100g, mannitol 50g, and water for injection adds to 2000mL, make 1000 bottles, method for making is carried out with reference to preparation example 1 of the present invention, obtains powder pin, is numbered Ex182, (3) meet injection specification and aseptic propylene glycol alginate sodium sulfate crude drug is directly sealed in cillin bottle, every bottle of 100mg active component, obtains powder pin, is numbered Ex183 (#534A), (3) according to the alginate diester sodium freeze-dried powder injection that following method prepares, be numbered Ex184 (#809A) and get water for injection 1600 milliliters, by concentration, to be 10% hydrochloric acid solution or concentration be that 4% sodium hydroxide solution adjusts pH value to 4.5, add mannitol 50g, be stirred to and dissolve completely, get propylene glycol alginate sodium sulfate 100g, needle-use activated carbon 2 grams, add in above-mentioned solution, be stirred to after dissolving completely, benefit injects water to 2000 milliliters, by concentration, to be 10% hydrochloric acid solution or concentration be that 4% sodium hydroxide solution adjusts pH value to 4.5, uses 0.22 μm of filtering with microporous membrane again: by the bottling of gained fine straining liquid, partly jump a queue, lyophilization 37 hours after de-charcoal with after 0.45 μm of microporous membrane filtration, wherein: cryogenic temperature-40 DEG C, freezing 7 hours, sublimation temperature is sublimate into 30 DEG C by-40 DEG C, 20 hours for the first time, sublimation temperature is by 30-38 DEG C for the second time, 10 hours, the full plug of pressure, gland obtain powder pin afterwards, (4) formula: propylene glycol alginate sodium sulfate 95g, mannitol 270g, cysteine hydrochloride 20g, disodiumedetate 12g, citric acid (0.1mol/l) regulate pH to 5.5 (when actual feeding intake as calculated in right amount, for every 100 parts by weight of activated compositions, the amount of citric acid used is 1.75 weight portions), water for injection adds to 1000ml, method for making: take the propylene glycol alginate sodium sulfate of recipe quantity, mannitol, cysteine hydrochloride and disodiumedetate respectively, adds in water for injection, is fully stirred to dissolve, add active carbon, absorption, and decarburization is filtered, hydrochloric acid solution adjust ph to 5.5, after 0.22 μm of membrane filtration, fill, to cleaning in the cillin bottle of drying and sterilizing, is often propped up dress 3mL, half gland, is opened freeze dryer, be cooled to-40 DEG C, lyophilizing, roll lid, powder pin, be numbered Ex184 (#261A), (5) with reference to formula and the method for making of preparation example 1 of the present invention, and add cysteine hydrochloride 20mg, obtain powder pin and be numbered Ex185.This supplementary preparation example 8 obtains 5 injectable powder samples altogether.

Preparation example 2, preparation comprise the injectable powder of propylene glycol alginate sodium sulfate

Formula:

propylene glycol alginate sodium sulfate	100mg,
		mannitol	15mg,
citric acid	5mg,
		pH adjusting agent	to pH6.5,
water for injection	in right amount, 4ml is added to.

Method for making: prepared by the method with reference to above preparation example 1, but carry out lyophilization according to freeze-drying curve B described herein, and gained injectable powder is designated as Ex2.

preparation example 3, preparation comprise the injectable powder of propylene glycol alginate sodium sulfate

Formula:

propylene glycol alginate sodium sulfate	100mg,
		mannitol	5mg,
citric acid	10mg,
		pH adjusting agent	to pH5.5,
water for injection	in right amount, 1.15ml is added to.

Method for making: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex3.

preparation example 4, preparation comprise the injectable powder of propylene glycol alginate sodium sulfate

Formula:

propylene glycol alginate sodium sulfate	100mg,
		mannitol	10mg,
citric acid	8mg,
		lactose	50mg,
pH adjusting agent	to Ph6.0,
		water for injection	in right amount, 2ml is added to.

Method for making: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex4.

preparation example 5, preparation comprise the injectable powder of propylene glycol alginate sodium sulfate

Formula:

propylene glycol alginate sodium sulfate	100mg,
		mannitol	10mg,
citric acid	7mg,
		dextran	25mg,
pH adjusting agent	to pH6.0,
		water for injection	in right amount, 2ml is added to.

Method for making: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex5.

test example part

test example 1: study on the stability

According to study on the stability method above, the powder pin sample investigating each preparation example and reference examples gained in above compositions preparation example part places the chemical stability after 5 months at 42 DEG C, specifically measures their residual content (%).

Result: whole preparation example 1 to preparation examples 5, and each powder pin sample that whole supplementary preparation examples 1 obtains to supplementary preparation example 8, their active component residual content (%) is all in 96.8 ~ 99.2% scopes, show them and all have good chemical stability, the residual content of such as Ex1, Ex2, Ex3 is respectively 98.5%, 98.8%, 99.2%.

test example 2: study on the stability

According to study on the stability method above, the powder pin sample investigating each preparation example and reference examples gained in above compositions preparation example part places the chemical stability after 5 months at 42 DEG C, and the RRT1.92 impurity specifically measuring them increases percent (%).

Result: the RRT1.92 impurity of five injectable powder that whole preparation example 1 to preparation examples 5 is obtained increases percent (%) all in 21% ~ 38% scope, the RRT1.92 impurity of these 18 injectable powder of Ex114, Ex115, Ex116, Ex124, Ex125, Ex126, Ex133, Ex134, Ex135, Ex143, Ex144, Ex145, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165 increases percent (%) all in 19% ~ 41% scope, shows these injectable powder and has extremely low impurity growth rate; The RRT1.92 impurity of these powder pins of Ex111, Ex112, Ex113, Ex131, Ex132, Ex141, Ex142 increases percent (%) all in 145% ~ 238% scope, and mannitol consumption lower RRT1.92 impurity increase percent is larger; The RRT1.92 impurity of these powder pins of Ex121, Ex122, Ex123, Ex151, Ex152, Ex161, Ex162 increases percent (%) all in 126% ~ 194% scope, and citric acid consumption lower RRT1.92 impurity increase percent is larger; Supplement 8 injectable powder samples of preparation example 7 and 5 injectable powder samples of supplementary preparation example 8, their RRT1.92 impurity increases percent (%) all in 137% ~ 226% scope, there are no regularity; The RRT1.92 impurity of these injectable powder samples of Ex117, Ex118, Ex119, Ex127, Ex128, Ex129, Ex136, Ex137, Ex146, Ex147, Ex156, Ex157, Ex166, Ex167 increases percent (%) all in 43% ~ 68% scope.Above result is visible, only has the injectable powder obtained under at least 5 weight portion mannitol for every 100 parts by weight of activated compositions and at least 5 weight portion citric acid exist, and its RRT1.92 impurity growth rate in simulation Long-term Storage process is only extremely low.

test example 3: study on the stability

According to study on the stability method above, the powder pin sample investigating each preparation example and reference examples gained in above compositions preparation example part places the physical stability after 5 months at 42 DEG C, specifically measures their microgranule percent change.

Result: preparation example 1 to the preparation example 5 that (1) is whole, and each powder pin sample that whole supplementary preparation examples 1 obtains to supplementary preparation example 8,0 month time, >=10 μm of particle numbers all in 3 ~ 19 scopes, such as Ex1, Ex2, Ex3 tri-samples >=10 μm of particle numbers are respectively 4,6,3, (2) for five injectable powder that whole preparation example 1 to preparation examples 5 is obtained, Ex111, Ex112, Ex113, Ex114, Ex115, Ex116, Ex121, Ex122, Ex123, Ex124, Ex125, Ex126, Ex131, Ex132, Ex133, Ex134, Ex135, Ex141, Ex142, Ex143, Ex144, Ex145, Ex151, Ex152, Ex153, Ex154, Ex155, Ex161, Ex162, Ex163, Ex164, Ex165, compared with these injectable powder process with 20 DEG C after experience 42 DEG C of process in 5 months for 5 months, microgranule percent change (%) is all in 54% ~ 89% scope, (3) for Ex117, Ex118, Ex119, Ex127, Ex128, Ex129, Ex136, Ex137, Ex146, Ex147, Ex156, Ex157, Ex166, Ex167, compared with these injectable powder process with 20 DEG C after experience 42 DEG C of process in 5 months for 5 months, microgranule percent change (%) is all in 284% ~ 441% scope.

test example 4: medicine character is investigated

The concrete grammar in standard YBH01262004 is issued according to office of State Food and Drug Administration, measure Ex1, Ex2, Ex3, Ex4, Ex5, Ex114, Ex115, Ex116, Ex124, Ex125, Ex126, Ex133, Ex134, Ex135, Ex143, Ex144, Ex145, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165 these there is the sample of present composition feature: character, differentiate, acidity, the clarity of solution and color, moisture, aseptic, pyrogen, molecular weight and molecular weight distribution, content uniformity, visible foreign matters, particulate matter, the projects such as assay.These of these samples of result detect/and mensuration project is all in the scope that above-mentioned standard specifies, the acidity of such as Ex1 is 6.04, the clarity of solution is qualified, weight average molecular weight should be 13500 ~ 16800,10% macromolecule fraction weight average molecular weight is less than 26000, and 10% micromolecule part weight average molecular weight is greater than 7800, moisture 2.2%, content 99.5%.

The above-mentioned sample that these have present composition feature is experienced 42 DEG C of process in 5 months, concrete grammar in standard YBH01262004 and standard is issued again according to office of State Food and Drug Administration, measure theirs: character, differentiate, acidity, the clarity of solution and color, moisture, aseptic, pyrogen, molecular weight and molecular weight distribution, content uniformity, visible foreign matters, particulate matter, the projects such as assay, result shows these projects still all in the scope that above-mentioned standard specifies, such as Ex1 is 6.02 in the acidity after 42 DEG C of process in 5 months, the clarity of solution is qualified, weight average molecular weight should be 13600 ~ 16800, 10% macromolecule fraction weight average molecular weight is less than 26200, 10% micromolecule part weight average molecular weight is greater than 7800, moisture 2.1%, content 99.4%.

safety testing example: safety testing investigation is carried out to present composition powder pin

Gained sample Ex1, Ex2, Ex3 of the present invention and control sample (commercially available product, polysaccharide sulphate for injection, H20040149, high-tech China of Beijing University is safe to produce), according to existing drug registration laws and regulations requirement, carry out vascular stimulation test, hemolytic experiment, anaphylaxis experiment, result shows the regulation that these samples all meet vascular stimulation test, hemolytic experiment, anaphylaxis experiment.The display present composition has good safety.

Claims

1. a pharmaceutical composition, wherein comprises: propylene glycol alginate sodium sulfate, mannitol and optional acid-base modifier.

2. pharmaceutical composition according to claim 1, is characterized in that:

The material wherein comprised is in the propylene glycol alginate sodium sulfate of every 100 weight portions, and the amount of mannitol is 5 ~ 25 weight portions, such as 5 ~ 20 weight portions, such as 5 ~ 15 weight portions;

Wherein also optionally comprise citric acid;

The material wherein comprised is in the propylene glycol alginate sodium sulfate of every 100 weight portions, and the amount of citric acid is 5 ~ 20 weight portions, such as 5 ~ 15 weight portions, such as 5 ~ 10 weight portions;

Wherein comprise: propylene glycol alginate sodium sulfate 100 weight portion, mannitol 5 ~ 25 weight portion, citric acid 5 ~ 20 weight portion, and optional acid-base modifier;

Wherein comprise: propylene glycol alginate sodium sulfate 100 weight portion, mannitol 5 ~ 20 weight portion, citric acid 5 ~ 15 weight portion, and optional acid-base modifier; And/or

Wherein comprise: propylene glycol alginate sodium sulfate 100 weight portion, mannitol 5 ~ 15 weight portion, citric acid 5 ~ 10 weight portion, and optional acid-base modifier.

3. pharmaceutical composition according to claim 1, is characterized in that:

It is dissolved in water and dilutes the solution made containing propylene glycol alginate sodium sulfate 10mg in every 1ml, and the pH value of this solution is 5.0 ~ 7.0, and such as pH value is 5.5 ~ 6.5;

It is lyophilization injectable powder;

Its solution before lyophilization, except comprising propylene glycol alginate sodium sulfate, mannitol and optional citric acid and optional acid-base modifier, also comprises water for injection;

Its solution before lyophilization also comprises water for injection except comprising propylene glycol alginate sodium sulfate, mannitol and optional citric acid and optional acid-base modifier, the solid content of described solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%;

It redissolves to substantially identical with solution before lyophilization volume with water for injection, and the solid content in gained solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%;

Wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution;

Wherein comprise propylene glycol alginate sodium sulfate 100 weight portion, mannitol 5 ~ 25 weight portion (such as 5 ~ 20 weight portions, such as 5 ~ 15 weight portions), citric acid 5 ~ 20 weight portion (such as 5 ~ 15 weight portions, such as 5 ~ 10 weight portions) and optional acid-base modifier;

Wherein the consumption of acid-base modifier is, make this pharmaceutical composition when being dissolved in water and dilute the solution made containing propylene glycol alginate sodium sulfate 10mg in every 1ml, the pH value of this solution is 5.0 ~ 7.0, and such as pH value is 5.5 ~ 6.5; And/or

It is lyophilization injectable powder, and its every bottle propylene glycol alginate sodium sulfate weight comprised is 20 ~ 1000mg, and the such as every bottle propylene glycol alginate sodium sulfate weight comprised is 50 ~ 500mg, and the such as every bottle propylene glycol alginate sodium sulfate weight comprised is 50 ~ 200mg.

4. pharmaceutical composition according to claim 1, it is prepare by comprising following step substantially:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

5. pharmaceutical composition according to claim 4, is characterized in that:

The scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing propylene glycol alginate sodium sulfate 10mg/ml, the pH value of gained dilute solution is in 5.0 ~ 7.0 scopes, the pH value of such as this dilute solution is in 5.5 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.0;

The wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%;

Wherein also optionally comprise the acceptable excipient of other pharmacy; And/or

Described excipient is such as but not limited to mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, mannitol and combination thereof.

6. pharmaceutical composition according to claim 4, is characterized in that:

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=10 μm in each test sample container is less than 6000, such as be less than 3000, such as be less than 1500, such as be less than 1000, such as, be less than 500, such as, be less than 250;

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=25 μm in each test sample container is less than 600, such as be less than 300, such as be less than 150, such as be less than 100, such as, be less than 50, such as, be less than 25; And/or

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, be less than 6000 containing the particle number of >=10 μm in each test sample container and (be such as less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250), and the particle number of >=25 μm is less than 600 and (is such as less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25).

7. prepare the method for the pharmaceutical composition described in any one of claim 1-6 case, it consists essentially of following steps:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

8. method according to claim 7, is characterized in that:

Wherein the described appropriate water for injection of step (a) is about 70 ~ 90% of water for injection recipe quantity;

Wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.05% ~ 0.2%;

The water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 10-30 times of propylene glycol alginate sodium sulfate weight, and such as 15-25 doubly, such as about 20 times;

Wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.

9. method according to claim 7, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 3 ~ 10%.

10. method according to claim 7, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.