AU2007246046A1 - Pharmaceutical composition comprising high concentrate of polydatin - Google Patents
Pharmaceutical composition comprising high concentrate of polydatin Download PDFInfo
- Publication number
- AU2007246046A1 AU2007246046A1 AU2007246046A AU2007246046A AU2007246046A1 AU 2007246046 A1 AU2007246046 A1 AU 2007246046A1 AU 2007246046 A AU2007246046 A AU 2007246046A AU 2007246046 A AU2007246046 A AU 2007246046A AU 2007246046 A1 AU2007246046 A1 AU 2007246046A1
- Authority
- AU
- Australia
- Prior art keywords
- polydatin
- cyclodextrin
- pharmaceutical composition
- aqueous solution
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
VERIFICATION OF TRANSLATION I Yajuan, Liu state that the attached document is a true and complete translation of PCT/CN2007/001233 to the best of my knowledge and belief. ______ _, ~4 November 2008 Liu yajuan A pharmaceutical composition comprising high concentration of polydatin Technical Field of the Invention 5 The present invention relates to a pharmaceutical composition comprising high concentration of polydatin. Particularly, it relates to a pharmaceutical composition comprising polydatin as pharmaceutically active component and meglumine and/or cyclodextrin as solution adjuvant. Background of the Invention 10 Polydatin, known as 3,4',5-trihydroxy-stilbene-3-p-D-glucoside (C 20
H
22 0 8 ), has been reported in some literatures or patents as pharmaceutical component. Pharmacological studies prove that it has the pharmacological activities to improve microcirculation, decrease blood lipid and resist against tumors. The patent No.CN1709269A points out that literatures of pharmacological studies on 15 polydatin show that the medicine is often administered by intravenous injection in in vivo studies. The tested sample solution for these studies is usually prepared with water or normal saline at the concentration of 2 to 5mg/ml. However further introduction about the practicable preparation method of the solution is unavailable in the literatures. According to the literatures, the effective dose in clinical use of polydatin (for adults) should be above 112mg each time. By specification 20 for a I to 20 ml routine injection, the concentration of polydatin injection in clinical use should be above 5.6 mg/ml. Because the solubility of polydatin is limited in pure water or normal saline, it is difficult for polydatin in the routine solutions to reach the concentration described in such literature. At room temperature, the saturated concentrations of polydatin in both water and normal saline are lower than 0.5mg/ml, which is far from the administration concentration of 2 to 25 5mg/ml as mentioned above. There are some common methods to increase solubility of compounds such as to adjust pH values, heat or add surfactants. However, some researches show that such methods are of limited value for preparation of pharmaceutical composition of polydatin with the pharmacodynamic concentration stable for clinical use. For example, the adjustment of pH value may increase the solubility of polydatin, but when it is adjusted with NaOH in preparation of aqueous solution of polydatin at room temperature, the pH value of the aqueous solution should be above 12 in order to make its solubility reach 3mg/ml. Whereas the pH value for injections should be generally in a 5 range of 4.0 to 9.0, it would be difficult to obtain the polydatin solution with pharmacyodynamic concentration. The method of heating is obviously unsuitable for preparation of pharmaceuticals. Furthermore, the polydatin solution for injection with comparatively higher concentration with the methods of the adjustment of pH value and/or addition of surfactant (Tween 80) has the defect in storage due to its difficulty in refrigeration preservation. 10 As described in the patent No.CN1709269A, it is difficult to obtain an ideal program for preparation of polydatin injection with routine pharmaceutical methods such as adjustment of pH value, addition of surfactants of tweens within the range of clinical preparations. The patent No.CN1709269A proposes a high-concentration polydatin solution for injection with ethanol and/or propylene glycol as surfactants and the preparation method 15 thereof. The patent realizes for the first time the preparation of the injection for clinical use, but what it is provided is a high-concentration solution of polydatin for clinical use, that is to say, such high-concentration solution of polydatin should be diluted with injection water or normal saline to some extent before used in injection administration. The reason is that the injection with high concentration of organic solvent is unsuitable for direct injection. 20 Doubtlessly, the preparation of high-concentration polydatin injection is of great practical importance to realize the value of polydation for clinical use. Summary of the Invention The object of the present invention is to provide a pharmaceutical composition comprising 25 high concentration of polydatin. The high concentration of polydatin contained in such pharmaceutical composition can meet the demand of the drug for clinical use. It is particularly for direct injection administration because the composition contains no organic solution adjuvant such as ethanol. In the present invention, the pharmaceutical composition comprising polydatin adopts meglumine and/or cyclodextrin as solution adjuvant. The dosage is in the form of aqueous solution or lyophilized product which is to be prepared as aqueous solution with water or normal saline before use . The concentration of polydatin in the aqueous solution or in the solution prepared with the lyophilized product can reach above 5mg/ml. 5 Said meglumine in the present invention refers to 1-deoxy-1-(methylamino)-D-Glucitol, while said cyclodextrin refers to 03- cyclodextrin or its derivatives, especially P3-cyclodextrin, hydroxypropyl- 03-cyclodextrin, sulfobutylether-3-cyclodextrin and so on. Said solution of high concentration of polydatin refers to the concentration of polydatin is around or above 5mg/ml in the solution. 10 The present invention firstly provides a high-concentration polydatin aqueous solution with meglumine as solution adjuvant. The solution can contain around 5mg/ml to 20mg/ml of polydatin and the content of meglumine can be around 7.5mg/ml to 60mg/ml as solution adjuvant. It is known that pH adjuster may be applied in increasing the water-solubility of polydatin, 15 but it is difficult to use only routine pH adjusters in preparation of high-concentration solution of polydatin within the clinical allowance of pH values (4.0 to 9.0) for injections. Just as described in the patent No. CN 1709269A, the solubility of polydatin is lower than 0.5mg/ml in NaOH aqueous solution with the pH 7 to 10. The inventors discover that meglumine has a rather favourable action to increase the solubility of polydatin. For example, at room temperature the 20 saturated solubility of polydatin can reach 5.69mg/ml in 10mg/ml meglumine aqueous solution with the pH value as about 8.9 and may reach up to 9.68mg/ml in 20mg/ml meglumine aqueous solution with the pH value as about 9.5, while it may reach around 7.2mg/ml in 20mg/ml meglumine aqueous solution prepared with phosphate buffer with the pH value as about 9.0. Obviously, solubilization of meglumine on polydatin is not realized only by adjustment of pH 25 values. The application of pure water and buffer as solvent may maintain the pH value of meglumine aqueous solution around 7.5mg/ml to 9.0mg/ml and when the concentration of meglumine is around 7.5mg/mi to 60mg/ml, aqueous solution of polydatin with the concentration of 5mg/ml to 15mg/ml can be prepared.
Secondly, the present invention provides a high-concentration polydatin aqueous solution with P-cyclodextrin as solution adjuvant. This aqueous solution may contain 5 mg/ml to 15 mg/ml of polydatin and the content of -cyclodextrin may be around 20 mg/ml to 60 mg/ml as solution adjuvant. 5 In P-cyclodextrin solution prepared with pure water, when the concentration of P3-cyclodextrin is around 25mg/ml, the solubility of polydatin may exceed 5mg/ml. In P3-cyclodextrin solution prepared with phosphate buffer with pH value as 9.0, when the concentration of P3-cyclodextrin is around 20mg/ml, the solubility of polydatin can exceed 5mg/ml while the concentration of 3-cyclodextrin is around 60mg/ml, the solubility of polydatin 10 may exceed 20mg/ml. It is known that P3-cyclodextrins may be used to prepare inclusion complex of several chemical compounds. During preparation, the inclusion complex is generally dried to achieve solid substances and may have a certain inclusion rate. In the present invention, 3-cyclodextrin and the like are used as solution adjuvant in preparation of polydatin solution according to the 15 similar fundamental physicochemical principle as that of inclusion complex. However, the polydatin solution obtained in the present invention is clear such that it needs no process of solidification and has nothing to do with inclusion rate. In the present invention, although the solubility of polydatin increases along with the increment of the concentration of P3-cyclodextrins, no obvious linear correlation exists between them, and the reason may be due to the variation of 20 dissolving behavior of the inclusion complex. There is other unexpected results when j3-cyclodextrin is used in the present invention as solution adjuvant in preparation of polydatin solution, e.g. according to literature and the results measured by the inventors, it is proved that the solubility of P3-cyclodextrin in pure water is about 18mg/ml at room temperature. When pure water is used as solvent, the highest solubility of 25 -cyclodextrin could reach up to 60mg/ml in presence of polydatin. That is to say, the solubility of 3-cyclodextrin itself may be obviously tripled at room temperature. The solubility of polydatin is only 2.5 mg/ml in 18mg/ml 3-cyclodextrin aqueous solution, but in the solution prepared with pH buffer comprising 60mg/ml of cyclodextrin, the solubility of polydatin could be around 20mg/ml.
Hydroxypropyl-3-cyclodextrin and sulfobutylether-p3-cyclodextrin posses similar but a little stronger solubilizing action on polydatin than P-cyclodextrin. Due to better water-solubility owned by themselves, they are more suitable to prepare aqueous solution of polydatin with high concentration. Therefore, the present invention provides also a high-concentration polydatin 5 aqueous solution with hydroxypropyl-p3-cyclodextrin or sulfobutylether-p3-cyclodextrin as solution adjuvant. Said solution can contain around 5mg/ml to 60mg/ml of polydatin, while the concentration of hydroxypropyl-3-cyclodextrin or sulfobutylether-p3-cyclodextrin applied in it can be around 25mg/ml to 500mg/ml. At room temperature and with pH value around 6 to 9, the aqueous solution of 10 hydroxypropyl-p-cyclodextrin or sulfobutylether-3-cyclodextrin with the concentration of no less than 25mg/ml can dissolve more than 5mg/ml polydatin. At room temperature and with pH value around 6 to 9, the solubility of polydatin increases along with the increment of the concentration of hydroxypropyl-3-cyclodextrin or sulfobutylether-p-cyclodextrin, but no obvious linear correlation exists between them. In the 15 solution prepared with buffer at pH 9.0, the solubility of polydatin could be up to 60mg/ml when the concentration of hydroxypropyl-p-cyclodextrin or sulfobutylether-p-cyclodextrin is 300 mg/ml. The present invention also discovers a previously unimagined synergistic action of solubilization on polydatin when hydroxypropyl-p-cyclodextrin or sulfobutylether-p3-cyclodextrin 20 is used as solution adjuvant. For example, meglumine at 5mg/ml may increase the solubility of polydatin by 3.17mg/ml and P-cyclodextrin at 15mg/ml may increase the same by 2.72mg/ml, the sum of both being 5.89 mg/ml. However, in the mixed solution of meglumine and P3-cyclodextrin with same concentrations correspondingly, the solubility of polydatin increased by 7.64mg/ml, being 30% higher than the value of the simple summation. Obviously, the solubilization of 25 meglumine and 3-cyclodextrin is stronger than the simple summation of both when they are used alone. Therefore, the present invention provides further a high-concentration aqueous solution of polydatin with meglumine and P-cyclodextrin as solution adjuvant. In said solution, the concentration of polydatin can be around 5mg/ml to 40 mg/ml, while the concentration of -cyclodextrin can be around 10mg/ml to 60mg/ml and that of meglumine can be around 2.5mg/ml to 45mg/ml. Likely, the application of hydroxypropyl-p3-cyclodextrin or sulfobutylether-3-cyclodextrin in combination with meglumine as solution adjuvant may also produce a synergistic action of 5 solubilization on polydatin. Accordingly, the present invention still provides a high-concentration aqueous solution of polydatin with hydroxypropyl-p-cyclodextrin or sulfobutylether-p-cyclodextrin plus meglumine as solution adjuvant. In the said solution, the concentration of polydatin can be around 5mg/ml to 100 mg/ml, while the concentration of hydroxypropyl-3-cyclodextrin or sulfobutylether-3-cyclodextrin can be around 10mg/ml to 10 300mg/ml, comprising meglumine around 2.5mg/ml to 100mg/ml. Said high-concentration polydatin aqueous solution in the present invention can be prepared with pure water, normal saline or buffer at pH 7.0 to 9.0, e.g. aqueous solution of 0.9% sodium chloride, solution of 5% glucose, carbonate buffer, phosphate buffer, Tris buffer and Hepes buffer. 15 Because the solubilization of meglumine is different from that of ordinary pH adjuster, high-concentration polydatin aqueous solution for clinical use, especially for injection administration, can be prepared when its pH value is adjusted back at 6 to 9 with pharmaceutically acceptable pH adjusters after it exceeds 9 during the course of preparation of high-concentration polydatin aqueous solution. 20 Apparently besides the active component of polydatin and the solution adjuvants mentioned above, the high-concentration polydatin aqueous solution contains also other pharmaceutically acceptable adjuvant such as antioxidants, osmotic regulators, pH adjusters and so on, among which said pH adjusters refer to the pharmaceutically acceptable hydroxides such as base metals and alkaline earth metals, the pharmaceutically acceptable inorganic alkali such as natronite and 25 sodium phosphate, the pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid and phosphonic acid, the pharmaceutically acceptable organic alkali such as basic amino acid, and the pharmaceutically acceptable organic acids such as citric acid and fumaric acid. In addition, the said high-concentration polydatin aqueous solution may also comprise other active components that might be used in combination with polydatin.
As a pharmacological preparation that suits to be administered in liquid, the high-concentration polydatin aqueous solution of the present invention can apparently be in form of oral liquid as well as the liquid preparation for injection or local administration. The high-concentration polydatin aqueous solution of the present invention can be applied by 5 optimization as the injections for parenteral administration such as intravenous injection, intramuscular injection or subcutaneous injection. The present invention provides further a method to prepare the high-concentration polydatin aqueous solution.Said method comprises: preparing a mixed aqueous solution of high-concentration polydatin of the present invention with stoichiometric polydatin, meglumine 10 and/or P3-cyclodextrin by using pure water, normal saline or water buffer as solvents. It can also comprise the step of adding any other pharmaceutical adjuvants such as antioxidant. Said solution may be filled into containers especially for injections such as ampoules after it is treated with the well-known arts in the fields such as sterilization and/or pyrogen-freedom, which may be for example micropore ultrafiltration or sterilization by thermocompression. 15 The high-concentration polydatin aqueous solution provided in the present invention in meeting the demand of clinical application may contain no organic solvent, thus such solution can be used further to prepare the lyophilized product, e.g. the lyophilized powder for injection. Therefore, the present invention provides further a lyophilized preparation that can be re-prepared into the high-concentration polydatin aqueous solution with injection water or normal saline 20 before use. Obviously, the lyophilized product such as lyophilized powder for injection provided in the present invention can be achieved from the polydatin aqueous solution at the concentration of around 5mg/ml to 100mg/ml with meglumine and/or P-cyclodextrin as solution adjuvant after it is treated with cryodesiccation, before which pharmaceutically acceptable fillers, antifreezing 25 agents, osmotic regulators and pH adjusters can be added optionally into the polydatin solution. It could be easily understood that during the course of preparing the lyophilized product of polydatin in the present invention, the amount of the solvent used in the solution prior to cryodesiccation can be properly higher than the aforesaid amount of solvent needed for praparing said high-concentration polydatin aqueous solution. In other words, the concentration of polydatin in the aqueous solution prepared before cryodesiccation can be lower than that of the polydatin aqueous solution prepared with its lyophilized product before use. Generally, in the aqueous solution prepared with the lyophilized product of the present invention, the concentration of polydatin may be around 5mg/ml to 100mg/ml. Apparently, the aqueous solution prepared with 5 the lyophilized product of present invention can be diluted at any ratio according to necessity. The lyophilized polydatin product of present invention can be the pharmacological preparation obtained by cryodesiccation of the aqueous solution of polydatin at the concentration of 5mg/ml to 15mg/ml with meglumine as solution adjuvant. Because the concentration of meglumine in said polydatin aqueous solution might be around 7.5mg/ml to 60mg/ml, the ratio of 10 polydatin and meglumine in the lyophilized product may be around 1:1.5 to 1:12. In the present invention, this ratio is further optimized as 1:1.5 to 1:3. The lyophilized polydatin product of present invention can also be the pharmacological preparation obtained by cryodesiccation of the aqueous solution of polydatin at the concentration of 5mg/ml to 15mg/ml with P-cyclodextrin as solution adjuvant. Because the concentration of 15 P-cyclodextrin in said polydatin aqueous solution might be around 20mg/ml to 60mg/ml, the ratio of polydatin and P-cyclodextrin in the lyophilized product can be around 1:3 to 1:12. In the present invention, this ratio is further optimized as 1:3 - 1:8. The lyophilized polydatin product of present invention can also be the pharmacological preparation obtained by cryodesiccation of the aqueous solution of polydatin at the concentration 20 of 5mg/ml to 15mg/ml with hydroxypropyl-3-cyclodextrin or sulfobutylether-3-cyclodextrin as solution adjuvant. Because the concentration of P-cyclodextrin in said polydatin aqueous solution might be around 20mg/ml to 300mg/ml, the ratio of polydatin and 3-cyclodextrin in the lyophilized product may be around 1:4 to 1:60. In the present invention, this ratio is further optimized as 1:4 to 1:8. 25 The lyophilized polydatin product of present invention can also be the pharmacological preparation obtained by cryodesiccation of the aqueous solution of polydatin at the concentration of 5mg/ml to 15mg/ml with combination of 3-cyclodextrin and meglumine as solution adjuvant. Because the concentration of P3-cyclodextrin in said polydatin aqueous solution might be around 20mg/ml to 300mg/ml and the concentration of meglumine is 2.5mg/ml to 45mg/ml, the ratio of polydatin and meglumine and 3-cyclodextrin in the lyophilized product can be around 1: 0.5:1.5 to 1: 9:12. In the present invention, this ratio is further optimized as 1: 0.5: 4 to 1: 2: 8. The lyophilized polydatin product of present invention can also be the pharmacological preparation obtained by cryodesiccation of the aqueous solution of polydatin at the concentration 5 of 5mg/ml to 15mg/ml with hydroxypropyl-3-cyclodextrin or sulfobutylether- 3-cyclodextrin plus meglumine as solution adjuvant. Because the concentration of P3-cyclodextrin in the said polydatin aqueous solution might be around 10mg/ml to 300mg/ml and the concentration of meglumine is 2.5mg/ml to 45mg/ml, the ratio of polydatin and meglumine and P3-cyclodextrin in the lyophilized product can be around 1:0.5:2 to 1:20:60. In the present invention, this ratio is 10 further optimized as 1:0.5:4 to 1:2:8. The present invention provides further a method to prepare the above-mentioned lyophilized powder for injection. Said method comprises: preparing a mixed aqueous solution of the high-concentration polydatin of the present invention with stoichiometric polydatin, meglumine and/or P-cyclodextrin by using pure water, normal saline or water buffer solution as solvents. It 15 also can comprise the step of adding other pharmaceutically acceptable fillers or other adjuvants. After being removed of pyrogen by ultrafiltration, said solution may be filled into ampoules and the products may be finalized after cryodesiccation, namely the lyophilized mixture of polydatin. Addition of proper fillers is helpful for cryodesiccation finalization of the lyophilized polydatin product of the present invention. By optimization, the filling agents used in the present invention 20 include mannitol, NaCl etc. The lyophilized polydatin product of present invention can be in form of germ-free powder for direct packing, and can also be the lyophilized powder for injection from direct cryodesiccation finalization, the latter being optimized as better. The lyophilized polydatin product of present invention can be administrated parenterally by intravenous injection, 25 intravenous drop infusion, intramuscular injection, subcutaneous injection and local adminstration. The "high-concentration" lyophilized polydatin product referred in the present invention means after the lyophilized product is prepared into aqueous solution with pure water or normal saline, the concentration of polydatin in said solution should be more than 5mg/ml. The pharmaceutical composition comprising high concentration of polydatin provided in the present invention can be used for preparation of therapeutic medicine for diseases concerning microcirculation disturbance. The pharmaceutical composition of the present invention has obvious actions to expand and deoppilate capillaries, reduce blood viscosity and suppress adhesion of blood cells. Therefore it may be used for treatment and prevention of shock and other 5 diseases that are related to microcirculation disturbance such as myocardial ischemia, cerebral ischemia and circulatory disorders of extremities. The patent No.CN 1709269A provided a pharmaceutical agent that provides effective therapeutic dose of polydatin through intravenous drop infusion. Due to the comparatively higher concentration of organic solvent in the agent, it can not be administrated by direct injection. 10 Therefore, there is so far no pharmaceutical medicine of polydatin that is of practical value for clinical application by direct injection. The present invention provides a high-concentration polydatin aqueous solution that contains no organic solvent and can be further prepared into the lyophilized product. Because it contains no organic solvent, the aqueous solution and its lyophilized product can be used for direct injection. 15 Apparently, though the high-concentration polydatin aqueous solution of contains no organic solvent, it doesn't mean no organic solvent could be used. For example, under the condition of no influence over the specific administrative ways and finalization of preparation, the aqueous solution may also have small amount of ethanol or propylene glycol in it. The present invention provides for the first time a practical preparation of polydatin that can 20 be administrated by direct injection in clinical application. This may provide not only a more convenient route for clinical application of polydatin, but also a condition to expand the scope for further clinical use of the drug. In comparison with the level of existing technology, the pharmaceutical composition of the present invention possesses substantial progress. For example, polydatin can be used for the treatment of some critical diseases such as 25 traumatic shock due to its obvious action to improve microcirculation. The administration of direct injection is doubtlessly of great importance in rescuing such cases. Animal experiments and tests of stability of the solution prove that the pharmaceutical composition of polydatin provided in the present invention is safe and effective with good stability, thus it has certainly a great prospection in clinical use.
For better understanding of the nature of the present invention, some examples with comparatively good results are described hereinafter in detail but without limitation to the present invention in combination with drawings. 5 Brief description of drawings Fig 1: Influence of polydatin injection over mean arterial pressure of hemorrhagic shock in dogs; Fig 2: Influence of polydatin injection over coronary blood flow of hemorrhagic shock in dogs. 10 Examples of the invention Materials adopted in the following examples include: Polydatin, with purity of 99.63% and batch number of 20050819, is provided by the technical center of Shenzhen Neptunus Pharmaceutical Co., Ltd. 15 Meglumine, pharmaceutical adjuvant, provided by Shanghai Fuzhei Chemical Co., Ltd; P-cyclodextrin, pharmaceutical adjuvant, provided by Yongguang P3-cyclodextrin Co., Ltd; hydroxypropyl-3-cyclodextrin, adjuvant of first type, provided by Xi'an Deli Biochemical Industrial Co., Ltd; sulfobutylether-p3-cyclodextrin, pharmaceutical adjuvant, provided by Shanghai Fuzhei Chemical Co., Ltd; fluorine F12, provided by Zhejiang Fluorescence Chemical 20 Industrial Co., Ltd; Injection Water, from Neptunus Industrial City; 0.9% sodium chloride solution, prepared with injection water; Na 2
HPO
4 -NaH 2
PO
4 buffer, prepared with injection water. Other test materials used in the present invention are all bought from market if not specified. Preparation of Polydatin injection 25 [Example 1] 1. Prescription Raw Material Dosage Polydatin 25.0 g Meglumine 50.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Take 25.0g of polydatin and 50.0g of meglumine and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is ultrafiltrated with 0.21am microporous membrane before the final product is encapsulated into 1000 ampoules. 5 [Example 2] 1. Prescription Raw Material Dosage Polydatin 50.0 g P3-cyclodextrin 250.0 g Buffer of pH 9.0 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Take 50.0g of polydatin and 250.0g of 1-cyclodextrin and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is ultrafiltrated with 10 0.2pm microporous membrane before the final product is encapsulated into 1000 ampoules. [Example 3] 1. Prescription Raw Material Dosage Polydatin 100.0 g hydroxypropyl-3-cyclodextrin 600.0 g Buffer of pH 7.5 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Take 100.0g of polydatin and 600.0g ofhydroxypropyl-p-cyclodextrin and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is ultrafiltrated with 0.2ptm microporous membrane before the final product is encapsulated into 5 1000 ampoules. [Example 4] 1. Prescription Raw Material Dosage Polydatin 75.0 g sulfobutylether-o-cyclodextrin 400.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Take 75.0g of polydatin and 400.0g of sulfobutylether-p-cyclodextrin and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. 10 Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is ultrafiltrated with 0.2km microporous membrane before the final product is encapsulated into 1000 ampoules. [Example 5] 1. Prescription Raw Material Dosage Polydatin 75.0 g Meglumine 75.0 g P-cyclodextrin 250.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Take 75.0g of polydatin, 100.0 g of meglumine and 200.0g of 3-cyclodextrin and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is roughly filtrated with 0.45 pm microporous membrane and then filtrated again with 0.22ptm 5 microporous membrane. It is depyrogenated with a plate-frame ultrafilter with PES ultrafiltration membrane of 10000 Molecular Weight Cutoff before the final product is encapsulated into brown bottles with nitrogen gas. [Example 6] 1. Prescription Raw Material Dosage Polydatin 400.0 g Meglumine 400.0 g hydroxypropyl-p3-cyclodextrin 1500.0 g Buffer of pH 7.5 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 10 2. Method Take 400.0g of polydatin, 400.0 g of meglumine and 1250.0g of hydroxypropyl-3-cyclodextrin and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is roughly filtrated with 0.45pm microporous membrane and then filtrated again with 0.22jim microporous membrane. It is depyrogenated with PES 15 ultrafiltration membrane of 1000 Molecular Weight Cutoff before the final product is encapsulated into brown bottles with nitrogen gas. Preparation of yIvophilized polydatin powder for injection [Example 7] 1. Prescription Raw Material Dosage Polydatin 25.0 g Meglumine 50.0 g Mannitol 50.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2. Method Preparation of the pre-cryodesiccation solution: Take 25.0g of polydatin, 50.0g of meglumine and 50.0g of mannitol and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in 5 to metered volume of 5.0 L, which is ultrafiltrated with 0.2pm microporous membrane before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -35°C and product temperature to be decreased to -300C for cryodesiccation for 3 hours, when the temperature reaches up to -40°C. 10 After vacuumization, along with the plate temperature rises slowly back to 400C, the temperature of the product will be increased and the product will be dried. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. [Example 8] 1. Prescription Raw Material Dosage Polydatin 75.0 g P3-cyclodextrin 400.0 g Mannitol 100.0 g Buffer of pH 9.0 Na 2
HPO
4 -NaH 2
PO
4 to 10.0 L Finalized into 1000 tube 2. Method Preparation of the pre-cryodesiccation solution: Take 75.0g of polydatin, 400.0g of 0-cyclodextrin and 100.0g of mannitol and add them into 9.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 10.0 L, which is ultrafiltrated with 0.2gm microporous membrane 5 before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -35°C and product temperature to be decreased to -30°C for cryodesiccation for 3 hours, when the temperature reaches up to -40°C. 10 After vacuumization, along with the plate temperature rises slowly back to 40'C, the temperature of the product will be increased and the product will be dried. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. [Example 9] 1. Prescription Raw Material Dosage Polydatin 75.0 g hydroxypropyl-p-cyclodextrin 500.0 g Mannitol 50.0 g Buffer of pH 7.5 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 15 2. Method Preparation of the pre-cryodesiccation solution: Take 750.0g of polydatin, 500.0g of hydroxypropyl-p3-cyclodextrin and 50.0g of mannitol and add them into 4.8L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0 L, which is ultrafiltrated with 0.2pm microporous membrane before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -35°C and product temperature to be 5 decreased to -30 0 C for cryodesiccation for 3 hours, when the temperature reaches up to -400gC. After vacuumization, along with the plate temperature rises slowly back to 400C, the temperature of the product will be increased and the product will be dried. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. [Example 10] 10 1. Prescription Raw Material Dosage Polydatin 100.0 g sulfobutylether-p3-cyclodextrin 800.0 g Mannitol 100.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 10.0 L Finalized into 1000 tube 2. Method Preparation of the pre-cryodesiccation solution: Take 50.0g of polydatin, 400.0g of sulfobutylether-p-cyclodextrin and 100.0g of mannitol and add them into 9.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 10.0 L, which is ultrafiltrated with 15 0.2pm microporous membrane before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -35°C and product temperature to be decreased to -30 0 C for cryodesiccation for 3 hours, when the temperature reaches up to -40'C. After vacuumization, along with the plate temperature rises slowly back to 40°C, the temperature of the product will be increased and the product will be dried. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. 5 [Example 11] 1. Prescription Raw Material Dosage Polydatin 50.0 g Meglumine 50.0 g P3-cyclodextrin 200.0 g Mannitol 50.0 g Buffer of pH 8.5 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 2.Method Preparation of the pre-cryodesiccation solution: Take 50.0g of polydatin, 50.0g of meglumine, 200.0g of P-cyclodextrin and 100.0g of mannitol and add them into 4.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the 10 Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0L, which is ultrafiltrated with 0.2pm microporous membrane before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -50°C and product temperature to be 15 decreased to -45 0 C for cryodesiccation for 3 hours, when the temperature reaches up to -55°C. After vacuumization, along with the plate temperature rises slowly back to -20 0 C. Then the procedure shall be repeated 3 times as said above before the plate temperature is increased slowly back to 400C and the product will be dried and finalized. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. [Example 12] 1. Prescription Raw Material Dosage Polydatin 300.0 g Meglumine 300.0 g sulfobutylether-3-cyclodextrin 1500.0 g Mannitol 50.0 g Buffer of pH 7.5 Na 2
HPO
4 -NaH 2
PO
4 to 5.0 L Finalized into 1000 tube 5 2. Method Preparation of the pre-cryodesiccation solution: Take 300.0g ofpolydatin, 300.0g of meglumine, 1000.0g of sulfobutylether-3-cyclodextrin and 50.0g of mannitol and add them into 4.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 5.0L, which is roughly filtrated with 0.45pm microporous membrane and then filtrated again with 0.22 tm microporous 10 membrane. It is depyrogenated with PES ultrafiltration membrane of 10000 Molecular Weight Cutoff before the final product is packed into 1000 penicillin bottles that are used specially for lyophilized product. Finalization of the preparation: The penicillin bottles are placed into a freeze-drying cabinet with the plate temperature to be reduced to -50'C and product temperature to be 15 decreased to -45'C for cryodesiccation for 3 hours, when the temperature reaches up to -550. After vacuumization, along with the plate temperature rises slowly back to -20'C. Then the procedure shall be repeated 3 times as said above before the plate temperature is increased slowly back to 40°C and the product will be dried and finalized. Then the freeze dryer is opened before the penicillin bottles are tamponaded and capped. Preparation of Polydatin Oral Liquid [Example 13] 5 1. Prescription Raw Material Dosage Polydatin 100.0 g Meglumine 100.0 g 3-cyclodextrin 450.0 g Buffer of pH 8.5 Na 2
HPO
4 -NaH 2
PO
4 to 10.0 L Finalized into 1000 bottle 2. Method Take 100.0g of polydatin, 100.0g of meglumine and 450.0g of P-cyclodextrin and add them into 9.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 10.0L, which is ultrafiltrated with 0.45gm microporous membrane before the final product is packed into 1000 10 glass bottles for oral liquid. Preparation of Polydatin Spraying Agent [Example 14] 1. Prescription Raw Material Dosage Polydatin 500.0 g Meglumine 500.0 g P-cyclodextrin 3000.0 g Buffer of pH 8.0 Na 2
HPO
4 -NaH 2
PO
4 to 20.0 L Finalized into 1000 tube 2. Method Take 500.0g of polydatin, 500.0g of meglumine and 3000.0g of 0-cyclodextrin and add them into 19L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C. Then the Na 2
HPO
4 -NaH 2
PO
4 buffer is added in to metered volume of 20.0L, which is roughly filtrated with 0.45pm microporous membrane and then filtrated again with 0.22[tm 5 microporous membrane. The polydatin spraying agent is finalized after the filtrate is filled into the ultrasonic nebulizers. The diameters of the mists are mostly less than 5[im and they could be inhaled into bronchi and pulmonary alveoli. Preparation of Polydatin Aerosol [Example 15] 10 1. Prescription Raw Material Dosage Polydatin 100.0 g hydroxypropyl-3-cyclodextrin 600.0 g pH 7.5 Na 2
HPO
4 -NaH 2
PO
4 3.5 L Freon Fl2 to 5000.0 g Finalized into 1000 bottle 2. Method Take 100.0g of polydatin and 600.0g of meglumine and add them into 3.5L of Na 2
HPO
4 -NaH 2
PO
4 buffer with ultrasonic promotion of solubility at 40 0 C, which is then roughly filtrated with 0.45tm microporous membrane and then filtrated again with 0.22tm microporous membrane. The polydatin aerosol is finalized after the filtrate is filled according to required 15 dosage with F12 injected by pressure after being connected to the dose-valve system and shaken to uniformity. The solubilization of meglumine and 0-cyclodextrin on polydatin [Example 16] The solubilization of meglumine on polydatin 10 ml of meglumine solution at different concentrations of 0, 2.5, 5, 10, 20, 40 and 80mg/ml, respectively is prepared before each of the solution is added in with polydatin to the volume of 50 ml. After promotion of solubility by ultrasound at 40 0 C for 30 min, the solution is placed at room temperature for 3 hours. The concentration of polydatin in filtrate is then determined with HPLC after it is filtrated with 0.20.m microporous membrane and the results are read in table 1 as 5 follows: Table 1: Saturated solubility of polydatin in meglumine solutions at different concentrations (mg/ml) Meglumine 0 2.5 5 10 20 40 80 solution Solubility of 0.25 2.51 5.69 6.51 9.68 16.82 22.68 polydatin When the concentration of meglumine exceeds 10 Omg/ml, the pH values of the saturated solution of polydatin prepared with it may vary between 9 and 12. However, the solubility of 10 polydatin in meglumine solution may be tens times higher than that in NaOH solution at the same pH value (see patent No. CN 1709269A). Moreover, in the saturated solution of polydatin prepared with the meglumine solution at concentration of 7.5mg/ml according to the method mentioned above, the solubility of polydatin is measured as about 5.12mg/ml while the pH value is about 8.7; and in the saturated solution of 15 polydatin prepared with the meglumine solution at concentration of 7.5mg/ml, which is prepared with phosphate buffer at pH 7.5, the solubility of polydatin is measured as about 14.83mg/ml while its pH value is about 8.94. Obviously, (1) the solubilizing action of meglumine on polydatin should not be contributed to adjustment of pH values. (2) Meglumine solution at 7.5 to 60mg/ml may be used in 20 preparation of aqueous solution of polydatin with pH value lower than 9 and concentration of polydatin being in a scope of 5 to 15mg/ml. [Example 171] The solubility of polydatin in P3-cyclodextrin solution Take 0, 25, 50, 100, 200, 300 and 450mg of P3-cyclodextrin respectively and add each of them together with 100 mg of polydatin into 10ml of distilled water, the solubility of which is promoted by ultrasound at 40 0 C for 30 min. After being placed for 3 hours at room temperature, it is filtrated with 0.20ptm microporous membrane. The filtrate is then checked with HPLC method for the concentration of polydatin and the results are read in table 2 as follows. Table 2: Saturated solubility ofpolydatin in 3-cyclodextrin solutions at different concentrations 5 (mg/ml) Dosage of 1-cyclodextrin 0 2.5 5.0 10.0 20.0 30.0 45.0 Solubility ofpolydatin 0.25 0.91 1.35 2.35 3.76 5.81 10.14 The results show that when concentration of 1-cyclodextrin in the solution exceeds 30mg/ml, the solubility of polydatin can be more than 5mg/ml. As the literature and results from laboratory measurement all show that the solubility of P3-cyclodextrin in pure water is about 18mg/ml at room temperature, it may be happened that in the operation said above for preparing 10 high-concentration 3-cyclodextrin solution, the 3-cyclodextrin added in the solution may not be dissolved completely. That is to say the amount of P3-cyclodextrin in the filtrate may not reach the calculated concentration of P3-cyclodextrin listed in Table 2. Besides, the pH values in the aforesaid saturated solutions of polydatin may be checked as being lower than 7. In order to determine the actual solubleness of -cyclodextrin in presence of polydatin and the influence of 15 P3-cyclodextrin at different pH values over the solubility of polydatin, further tests are carried out for preparing following solutions with phosphate buffer at pH 9.0: Take 200, 400 and 600mg of P-cyclodextrin respectively and add each of them together with 50, 100 and 200mg of polydatin into 10 ml of phosphate buffer, the solubility of which is promoted by ultrasound at 40 0 C for 30 min. After being placed for 3 hours at room temperature, it is checked that the solutions obtained 20 are all clear solutions without filtration, indicating that P3-cyclodextrin and polydatin can be completely dissolved in them, among which the solubility of -cyclodextrin can be above 60mg/ml. From the above results it can be seen that (1) the water solubility of polydatin can be increased along with the increment of the existing amount of 3-cyclodextrin, but without obvious 25 linear relationship between the concentrations of both; (2) in the presence of polydatin, the self-solubility of P-cyclodextrin can be raised greatly, which provides a fundamental condition for application of 1-cyclodextrin in preparing high-concentration polydatin solution that is useful in clinical practice; (3) the polydatin solution with concentration of up to 5-20mg/ml and pH less than 9.0 can be prepared using 1-cyclodextrin with concentration of 20-60mg/ml. [Example 181 The solubility of polydatin in hydroxypropyl-P3-cyclodextrin solution Take 0, 25, 50, 100, 200, 300, 400, 500, 700, 900, 1200, 1500, 2000, 3000 and 5000mg of 5 hydroxypropyl-p- cyclodextrin respectively and add to each of them with polydatin to over saturation and then 10ml of distilled water, the solubility of which is promoted by ultrasound at 40 0 C for 30 min. After being placed for 3 hours at room temperature, it is filtrated with 0.20pm microporous membrane. The filtrate is then checked with HPLC method for the concentration of polydatin and the results are read in table 3 as follows. 10 Table 3: Saturated solubility of polydatin in hydroxypropyl-P3-cyclodextrin solutions at different concentrations (mg/ml) Dosage of cyclodextrin 0 2.5 5.0 10.0 30.0 60.0 Solubility of polydatin 0.25 0.83 1.56 2.88 6.25 11.53 Dosage of cyclodextrin 90 120 150 200 300 500 Solubility of polydatin 16.34 22.60 29.12 39.18 50.12 56.32 The results show that hydroxypropyl-p-cyclodextrin may produce solubilizing activity on polydatin similar to that of 3-cyclodextrin and form a aqueous solution of polydatin at much 15 higher concentration due to the better aqueous solubility of itself. The water solubility of polydatin may be increased along with the increment of the existing amount of hydroxypropyl-p3-cyclodextrin, but without obvious linear relationship between the increments of the concentrations of both. When concentration of hydroxypropyl-P3-cyclodextrin in the solution exceeds 30mg/ml, the solubility of polydatin can be more than 6mg/ml and when concentration 20 of hydroxypropyl-P-cyclodextrin in the solution exceeds 300mg/ml, the solubility of polydatin can be more than 50mg/ml. Further tests are carried out for preparation of following two solutions with phosphate buffer at pH 9.0: Take 200 and 4500mg of hydroxypropyl-13-cyclodextrin and add to each of them together with 50 and 600 of polydatin into 10 ml of phosphate buffer, the solubility of which is promoted by ultrasound at 40 0 C for 30 min.
After being placed for 3 hours at room temperature, it is checked that the solutions obtained are all clear solutions without filtration, indicating that hydroxypropyl-p3-cyclodextrin and polydatin can be completely dissolved in them. The tests also show it is possible to use the hydroxypropyl-p3-cyclodextrin solution at the concentration of no less than 20mg/ml to prepare 5 the polydatin solution at the concentration of no less than 5mg/ml. At the pH value less than 9.0, it is possible to use hydroxypropyl-p-cyclodextrin to prepare the polydatin solution at the concentration up to 60mg/ml. The tests also prove that sulfobutylether-13-cyclodextrin has similar solubilizing action on polydatin. [Example 191 Synergistic solubilization of meglumine and -cyclodextrin on polydatin 10 Take 0, 50, 100 and 150mg of meglumine and add to each of them 0, 150, 300 and 450mg of p-cyclodextrin respectively, then add to all of them with 200 mg of polydatin and 10 ml of distilled water, the solubility of which is then promoted by ultrasound at 40 0 C for 30 min. After being placed for 3 hours at room temperature and filtrated with 0.2km microporous membrane, the filtrate is checked with HPLC method for concentration of polydatin and the results are read 15 in Table 4 as follows: Table 4: The solubility of polydatin in solutions of meglumine and P3-cyclodextrin at different concentrations (mg/ml) Dosage of 0 5 meglumine Dosage of 0 15 30 45 0 15 30 45 P3-cyclodextrin Solubility of 0.25 2.97 5.73 10.09 3.42 7.89 11.25 15.46 polydatin Dosage of 10 15 meglumine Dosage of 0 15 30 45 0 15 30 45 P-cyclodextrin Solubility of 5.69 10.09 13.11 17.86 7.24 12.25 15.92 19.37 polydatin Obviously, without the presence of meglumine, 15, 30 and 45 mg/ml of 3-cyclodextrin can increase the solubility of polydatin by 2.72, 5.48 and 9.48 mg/ml, respectively, while without the presence of 3-cyclodextrin, 5, 10 and 15 mg/ml of meglumine can increase the solubility of polydatin by 3.71, 5.44 and 6.99 mg/ml, respectively. It is also obviously demonstrated that with the 5 presence of both meglumine and 1-cyclodextrin at different concentrations, the solubilizing action on polydatin is all stronger than the simple sum of the corresponding solubilizing action on polydatin when each of them is in presence alone. For example, meglumine at 5mg/ml may increase the solubility of polydatin by 3.17mg/ml and P3-cyclodextrin at 15mg/ml may increase the same by 2.72mg/ml, the sum of both being 5.89 mg/ml. However, in the mixed solution of meglumine and 10 P3-cyclodextrin with the same concentrations correspondingly, the solubility of polydatin increased by 7.64mg/ml, being 30% higher than the value of the simple summation. Similarly, hydroxypropyl-3-cyclodextrin or sulfobutylether-p3-cyclodextrin can also produce much stronger synergistic action of solubilization when they are respectively used along with meglumine. In addition, after adding 450mg of meglumine and 600mg of 03-cyclodextrin to 400mg of 15 polydatin and then dissolving them with 10 ml of phosphate buffer at pH 8.5, clear aqueous solution of polydatin can be harvested, indicating that the combination of using meglumine and P3-cyclodextrin may be helpful in preparation of polydatin aqueous solution with the concentration up to 40mg/ml (pH value less than 9). After adding 1 g of meglumine and 3 g of P3-cyclodextrin to 1 g of polydatin and then dissolving them with 10 ml of phosphate buffer at pH 20 8.5, clear aqueous solution of polydatin can be also harvested, indicating that the combination of using meglumine and P-cyclodextrin may be helpful in preparation of polydatin aqueous solution with the concentration up to 1 00mg/ml (pH value less than 9). Study on safety and stability of the pharmaceutical composition of polydatin [Example 201 Exploration on storage stability of polydatin injection and lyophilized 25 powder for injection 1. Test samples The polydatin injection and lyophilized powder for injection prepared in examples 1 to 12. 2 . Test method Storage condition: the test samples are stored away from light in thermostated containers at 30 0 C and refrigerators at 4 0 C, respectively. 5 Examination for clarity: the samples for test are examined for clarity before storage and 3 months after storage. The lyophilized powder for injection is checked for its clarity after it is diluted with normal saline in the volume as designed (5mlor 10ml). Content detection: high-performance liquid chromatography. chromatographic condition: High Performance Liquid Chromatograph Agilent 1100, Agilent DAD Detector, YWG C18 10 Chromatographic Column with 10itm 4.6x250mm from Dalian, and the mobile phase is the methanol-6% acetic acid solution (25:75) with flow rate of 1.0ml/min, wave length of 306nm, column temperature of 30 0 C and sample size of 20 gl. 3 . Results The results shown in Table 5 demonstrate that clarity of both polydatin injection and 15 lyophilized powder for injection is up to standard. 3 months after the test samples have been stored at 30 0 C or at 4oC, their contents of effective components still remain stable (with change not exceeding + 10%). Table 4: Storage stability of polydatin injection and lyophilized powder for injection (mg/ml) Clarity examination Content detection 3 months after 3 months after Samples for test Before Before storage storage storage storage 30 0 C 4 0 C 30 0 C 4 0 C Injection from Example Qualified Qualified Qualified 4.953 4.743 4.951 1 Injection from Example Qualified Qualified Qualified 9.883 9.664 9.823 2 Injection from Example Qualified Qualified Qualified 20.07 19.29 20.10 3 Injection from Example Qualified Qualified Qualified 14.96 14.91 14.95 4 Injection from Example Qualified Qualified Qualified 15.02 14.22 15.00 5 Injection from Example Qualified Qualified Qualified 79.51 75.40 79.52 6 lyophilized powder for injection from Example Qualified Qualified Qualified 4.893 4.682 4.886 7 lyophilized powder for injection from Example Qualified Qualified Qualified 7.492 7.403 7.429 8 lyophilized powder for injection from Example Qualified Qualified Qualified 14.75 14.60 14.77 9 lyophilized powder for injection from Example Qualified Qualified Qualified 9.852 9.731 9.826 10 lyophilized powder for injection from Example Qualified Qualified Qualified 10.16 9.635 10.23 11 lyophilized powder for injection from Example Qualified Qualified Qualified 58.63 55.36 57.98 12 [Example 21] Detection on hemocytolysis, allergy and vascular stimulation of polydatin injection and lyophilized powder for injection. 1. Samples for test Sample 1, polytatin injection from Exmple 3. Sample 2, lyophilized powder for injection from Example 11 .Dissolved with 5ml of normal 5 saline before using. 2. Method Hemolytic test: Blood is sampled from ear veins in New Zealand rabbits. After defibrinogen and washed with normal saline, it is diluted into 2% suspension for use in test. After 0(control), 0.1, 0.2, 0.3, 0.4 and 0.5ml of polydatin injection or lyophilized powder for 10 injection are taken respectively, they are added with normal saline to the volume of 2.5ml with the aforesaid 2% blood cell suspension. After being shaken slightly to uniformity, it is placed at the room temperature of 270C for observation and record hemolytic results at the time of 30, 60 and 180min. Test for systemic anaphylaxis: 24 healthy guinea pigs (250-350g) are grouped randomly by 15 6 in each of the group. All animals are injected intraperitoneally with normal saline (for negative control), polydatin injection or lyophilized powder for injection that is re-dissolved with water and egg albumen (for positive control) by Iml/each for 3 times. On the 14 th day after first injection, 3 pigs of each group are chosen once more for injection of the control solutions or testing solutions respectively by 2.5ml/each for observation on the response of test animals after 20 injection, while the other remaining 3 guinea pigs of each group are injected with the same control solutions or testing solutions on the 2 1 st day after first injection respectively by 2.5ml/each for observation on the response of test animals. Vessel stimulation test: 6 New Zealand rabbits, half male and half female, are injected with polydatin injection or lyophilized powder for injection that is re-dissolved with water by 5mg/kg 25 through their ear veins once daily for 3 times to observe the changes of the vessels and tissues around them after injection. 30 min after the last injection, the animals are put to death by cutting off their carotid arteries and their ears are sheared off for fixation of the injection sites on them, while the corresponding sites of the ears on the other side are also cut off and fixed for normal control. Pathological sections are made to observe the pathological changes on the ears of the rabbits. 2. Results Hemolysis test: No hemolytic crisis and red cell agglutination is observed at 30, 60 and 5 180min after the administration of polydatin injection or lyophilized powder for injection that is re-dissolved with water. Test for systemic anaphylaxis: After last injection of polydatin injection or lyophilized powder for injection that is re-dissolved with water, only a few animals shows slightly reaction to scratch their noses slightly, but without allergic symptoms such as shivering, dyspnea or spasm. 10 In positive control group, it is observed that some test animals die due to fierce allergic reactions. Vessel stimulation test: Polydatin injection or lyophilized powder for injection that is re-dissolved with water administrated through ear veins of the rabbits witness no phlebectasia and hyperemia of veins and edema of tissues around them. Pathological examination sees no damage of the skin of the rabbit ears or hypodermic hyperemia and edema. No phlebectasia and 15 hyperemia is found veins on the edge of ears and no change appears in vascular endothelial cells. On the walls of blood vessels, no mural thrombosis and inflammatory cell infiltration are observed. Around the veins, no bleeding is found. Conclusions: (1) The testing polydatin injection and lyophilized powder for injection have no exhibition of in vitro hemoclasis and agglutination. (2) The testing polydatin injection and 20 lyophilized powder for injection have no irritation on the veins of ears in the rabbits. (3) The testing polydatin injection and lyophilized powder for injection cause no systemic anaphylaxis. The pharmacodynamic study on pharmaceutical composition of polydatin [Example 22] Effect of polydatin injection on myocardial blood flow in hemorrhagic shock dogs. 25 Test drug: polydatin injection from Example 5, provided by Shenzhen Neptunus Pharmaceutical Co., Ltd. Animal: Beagle dogs, weighing 8-12 kg, with certivicate numbered 001321 and permission numbered SYXK(YUE)2003-0007, provided by the Animal Institution, First Military Medical University. Test method: After anesthetized with 3% pentobarbital sodium, the dog is immobilized on its back on the operation table for tracheal intubation to have its breaths maintained (as 15 /min, 300-400 ml/min) by a respirator (Type E 100i, provided by American Newport Ven). Intubation is 5 performed from both femoral arteries for recording blood pressure (by Electrophysiolograph Marquette Eagle4000, made in USA) and for bleeding. Intravenous intubation is also performed for drug administration. Thoracotomy at the 2 nd 4 t h intercostal space is performed to expose the heart and to cut open the pericardium. An Ultrasonic blood flow meter (Type T206, provided by Transonic Systems Company in USA) is used to record the blood flow of left branch of anterior 10 descending coronary artery. Exsanguination is done through one of the arterial cannulas and the blood inflows into a sterile dripping bottle containing normal saline and heparin. By adjusting the blood flow of exsaguination, the mean arterial pressure is decreased to 40 mmHg within 15 min, which should be maintained for 120 min before drugs are administrated. After the polydatin injection is mixed with the normal saline, the volume of which is 1/3 of blood loss, it is infused 15 into the body through femoral veins within 120 min at the dose of 5.0 mg/kg. Coronary blood flows are recorded before and after the administration. For the control group, normal saline is used. Data of blood flow is standardized with normal blood flow being taken as 100% and multiple factor variance analysis (ANOVA) in statistical package of SPSS13.0 is adopted for statistic treatment. 20 Test results: In the experiment, the blood loss of dogs is 60% of their total blood volume. The results of tests demonstrated that in period of hemorrhagic shock, the blood flow of coronary artery in dogs decrease obviously, but after resuscitation administration of polydatin injection, their mean arterial pressures increase significantly (see Fig 1). The blood flow of coronary artery is also recovered obviously back to the normal level of 62.92±8.76%60 min after administration. 25 In following time of observation, the blood flows in polydatin group maintain at a higher level and even reach up to the normal level (101.96+15.87%) 120 min after the administration starts. Since the time 60 min after administration begins, the extent of increment of coronary arterial flow in polydatin group is higher at all time points than those in the control group of normal saline (see Table 6, Fig 2). Table 5 : Effect ofpolydatin treatment on coronary blood flow in hemorrhagic shock dogs (%, x±s) Nor Shock During administration After administration Nor Group mal 1' 60' 120' 30' 60' 120' 30' 60' 120' 31.86 32.11 35.62 48.20 59.31 60.87 51.06 52.04 40.20 Control 100 + ± + ± + + + 10.75* 7.31* 11.10* 16.46* 14.96* 9.85* 9.89* 9.73* 5.96* 27.09 30.12 32.98 62.92 91.09 101.96 85.92 78.97 82.00 Polydatin 100 + + ± + + + + + 9.18* 8.15* 2.87* 8.76 24.02' 15.87 ^ 6.66 ^ 3.12
^
# 5.25# 5 Self-comparison: * in comparison with normal group, p<0.05 ; ^ in comparison with shock group at 120', p<0.05 Group comparison: * in comparison with control group, p<0.05. Industrial applicability 10 The present invention provides a practical pharmaceutical composition of polydatin that has rather good effectiveness, safety and stability and can be administrated by direct injection in clinical application. This may provide not only a more convenient route for clinical application of polydatin, but also a condition to expand the scope for further clinical use of the drug. 15
Claims (27)
1. A pharmaceutical composition comprising high concentration of polydatin, wherein said pharmaceutical composition comprising polydatin as pharmacologically active component and 5 meglumine and/or cyclodextrin as solution adjuvant, said pharmaceutical composition is in the form of aqueous solution or lyophilized product which is to be prepared into aqueous solution before using, and the concentration of polydatin in said aqueous solution or in said aqueous solution prepared with the lyophilized product can reach 5mg/ml to 100mg/ml.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of polydatin 10 and meglumine and/or cyclodextrin is 1:0.5:1.5 to 1:20:100.
3. The pharmaceutical composition according to claim 2, wherein said pharmaceutical composition is polydatin aqueous solution.
4. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution comprises polydatin at 5mg/ml tol5mg/ml and meglumine at 7.5mg/ml to 60mg/ml. 15
5. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution comprises polydatin at 5mg/ml to 20mg/ml and P-cyclodextrin at 20mg/ml to 60mg/ml.
6. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution comprises polydatin at 5mg/ml to 60mg/ml and hydroxypropyl-3-cyclodextrin or sulfobutylether-p-cyclodextrin at 20mg/ml to 500mg/ml. 20
7. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution comprises polydatin at 5mg/ml to 40mg/ml, 3-cyclodextrin at 10mg/ml to 60mg/ml and meglumine at 2.5mg/ml to 45mg/ml.
8. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution comprises polydatin at 5mg/ml to 100mg/ml, hydroxypropyl-3-cyclodextrin or 25 sulfobutylether-p-cyclodextrin at 10mg/ml to 300mg/ml and meglumine at 2.5mg/ml to 1 00mg/ml.
9. The pharmaceutical composition according to claim 3to 8, wherein said polydatin aqueous solution is prepared by using injection water, normal saline or buffers at pH 7.0 to 9.0 as the solvents.
10. The pharmaceutical composition according to claim 3, wherein said polydatin aqueous solution is polydatin injection.
11. A method for preparing the pharmaceutical composition according to claim 3, 5 comprising the steps of: preparing said high-concentration polydatin aqueous solution by using injection water, normal saline or buffers at pH 7.0to 9.0 as solvents and meglumine and/or P3-cyclodextrin as solution adjuvant; sterilizing and/or depyrogenating the obtained high-concentration polydatin aqueous 10 solution; and encapsulating said high-concentration polydatin aqueous solution into ampoules.
12. The pharmaceutical composition according to claim 2, wherein said pharmaceutical composition is a lyophilized preparation which can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of polydatin can reach 15 5mg/ml to 100mg/ml.
13. The pharmaceutical composition according to claim 12, wherein said preparation comprises polydatin as active component and meglumine as solution adjuvant, the mass ratio of polydatin and meglumine isl:1.5 to 1:12, and said lyophilized preparation can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of 20 polydatin can reach 5mg/ml to 15mg/ml.
14. The pharmaceutical composition according to claim 13, wherein the mass ratio of polydatin and meglumine is 1:1.5 to 1:3.
15. The pharmaceutical composition according to claim 12, wherein said lyophilized preparation comprises polydatin and P-cyclodextrin, the mass ratio of polydatin and 25 P3-cyclodextrin is 1:3 to 1:12, and said lyophilized preparation can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of polydatin can reach 5mg/ml to 20mg/ml.
16. The pharmaceutical composition according to claim 15, wherein the mass ratio of polydatin and P3-cyclodextrin is 1:3 to 1:8.
17. The pharmaceutical composition according to claim 12, wherein said lyophilized preparation comprises polydatin and hydroxypropyl-13-cyclodextrin or sulfobutylether-3-cyclodextrin, the mass ratio of polydatin and hydroxypropyl-p3-cyclodextrin or 5 sulfobutylether-3-cyclodextrin is 1:4 to 1:60, and said lyophilized preparation can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of polydatin can reach 5mg/ml to 60mg/ml.
18. The pharmaceutical composition according to claim 17, wherein the mass ratio of polydatin and hydroxypropyl-p-cyclodextrin or sulfobutylether-3-cyclodextrin is 1:4 to 1:8. 10
19. The pharmaceutical composition according to claim 12, wherein said lyophilized preparation comprises polydatin, meglumine and P3-cyclodextrin, the mass ratio of polydatin and meglumine and 1-cyclodextrin is 1:0.5:1.5 to 1:9:12, and said lyophilized preparation can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of polydatin can reach 5mg/ml to 40mg/ml. 15
20. The pharmaceutical composition according to claim 19, wherein the mass ratio of polydatin and meglumine and P-cyclodextrin is 1:0.5:3 to 1:2:8.
21. The pharmaceutical composition according to claim 12, wherein said lyophilized preparation comprises polydatin, meglumine and hydroxypropyl-p-cyclodextrin or sulfobutylether-3-cyclodextrin, the mass ratio of them is 1: 0.5: 2 to 1: 20: 60, and said 20 lyophilized preparation can be prepared into aqueous solution with injection water or normal saline for injection, in which the concentration of polydatin can reach 5mg/ml to 100mg/ml.
22. The pharmaceutical composition according to claim 21, wherein the mass ratio of polydatin and meglumine and hydroxypropyl-p-cyclodextrin or sulfobutylether-3-cyclodextrin is 1: 0.5:4 to 1: 2: 8. 25
23. The pharmaceutical composition according to any of claims 12 to 22, wherein said lyophilized preparation is lyophilized powder for injection.
24. The pharmaceutical composition according to claim 12, wherein said lyophilized preparation further comprises pharmaceutical acceptable fillers.
25. A method for preparing the pharmaceutical composition according to claim 12, comprising the steps of: preparing said high-concentration polydatin aqueous solution by using injection water, normal saline or buffers at pH 7.0 to 9.0 as solvents and meglumine and/or P3-cyclodextrin as 5 solution adjuvant; adding optionally pharmaceutical acceptable fillers; depyrogenating the obtained solution with the method of ultrafiltration and sterilizing; and encapsulating into ampoules and capping after it is finalized by cryodesiccation.
26. The pharmaceutical composition according to claim 1, wherein the aqueous solution and 10 the aqueous solution prepared with the lyophilized product can be administered orally or parenterally by intravenous injection, intravenous drop infusion, intramuscular injection, subcutaneous injection and local administration.
27. A use of the pharmaceutical composition according to claim 1 in the treatment and/or prevention of cardiovascular diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610076175.6 | 2006-04-28 | ||
| CN2006100761756A CN101062044B (en) | 2006-04-28 | 2006-04-28 | Medicine combination including high-concentration polydatin |
| PCT/CN2007/001233 WO2007124668A1 (en) | 2006-04-28 | 2007-04-16 | Pharmaceutical composition comprising high concentrate of polydatin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2007246046A1 true AU2007246046A1 (en) | 2007-11-08 |
| AU2007246046B2 AU2007246046B2 (en) | 2010-04-22 |
Family
ID=38655061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2007246046A Active AU2007246046B2 (en) | 2006-04-28 | 2007-04-16 | Pharmaceutical composition comprising high concentrate of polydatin |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101062044B (en) |
| AU (1) | AU2007246046B2 (en) |
| WO (1) | WO2007124668A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791292A (en) * | 2010-04-13 | 2010-08-04 | 江庆澜 | Application of polygonin atomizing agent as asthma-treating medicine |
| CN103356476B (en) * | 2012-03-31 | 2016-02-17 | 昆药集团股份有限公司 | Dissolve the method for flavone compound, c-glycosides or stilbenes compound and the preparation method of injection or powder ampoule agent for injection |
| CN107625967B (en) * | 2016-07-15 | 2021-07-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Tecoviri injection pharmaceutical composition and preparation method thereof |
| CN107638571B (en) * | 2016-07-15 | 2021-07-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Tecoviri oral pharmaceutical composition and preparation method thereof |
| US10898420B2 (en) | 2016-10-31 | 2021-01-26 | L'oreal | Compositions containing phenolic compounds having synergistic antioxidant benefits |
| US10624830B2 (en) | 2017-11-30 | 2020-04-21 | L'oreal | Aqueous compositions with mangiferin for cosmetic applications |
| CN108670950B (en) * | 2018-06-29 | 2020-10-02 | 深圳海王医药科技研究院有限公司 | Polydatin pharmaceutical composition without organic solvent and preparation method thereof |
| CN113143861B (en) * | 2021-06-15 | 2022-09-13 | 华北制药股份有限公司 | Puerarin composition for injection and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1205938C (en) * | 2002-10-08 | 2005-06-15 | 深圳海王药业有限公司 | Medicine composition containing polydatin or its salt and its use in preparing medicine |
| CN1220486C (en) * | 2002-11-15 | 2005-09-28 | 董英杰 | resveratrol , piceid and its derivative and its preparation |
| CN1232251C (en) * | 2004-01-14 | 2005-12-21 | 江苏康缘药业股份有限公司 | Gingko lactone powder injection and its preparation method |
| CN100408043C (en) * | 2005-07-08 | 2008-08-06 | 深圳海王药业有限公司 | Medicinal composition containing polydatin and its use |
-
2006
- 2006-04-28 CN CN2006100761756A patent/CN101062044B/en active Active
-
2007
- 2007-04-16 WO PCT/CN2007/001233 patent/WO2007124668A1/en active Application Filing
- 2007-04-16 AU AU2007246046A patent/AU2007246046B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007124668A1 (en) | 2007-11-08 |
| CN101062044A (en) | 2007-10-31 |
| CN101062044B (en) | 2010-12-08 |
| AU2007246046B2 (en) | 2010-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2007246046B2 (en) | Pharmaceutical composition comprising high concentrate of polydatin | |
| KR101753131B1 (en) | Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use | |
| KR102465046B1 (en) | A composition comprising 5-cholestene-3, 25-diol, 3-sulfate (25HC3S) or a pharmaceutically acceptable salt thereof, and at least one cyclic oligosaccharide | |
| RU2643762C2 (en) | Lyophilized preparations of melphalan flufenamide | |
| KR20070110561A (en) | Pharmaceutical compositions for the treatment and prevention of ischemic reperfusion | |
| PL199652B1 (en) | Pharmacological agents containing cyclodextrins and taxoides | |
| CA2641393C (en) | Novel epoprostenol formulation and method of making thereof | |
| JP6879582B2 (en) | Solid pharmaceutical compositions containing biopterin derivatives and the use of such compositions | |
| US20130131174A1 (en) | Injectable pharmaceutical formulation of melphalan | |
| AU2002327307B2 (en) | Clathrates of butylphtualide with cyclodextrin or its derivatives, a process for their preparations and the use there of | |
| CN106692120A (en) | Medicine composition of lidocaine and application of medicine composition | |
| JP2022523712A (en) | Therapeutic compounds and compositions | |
| JP2012502932A (en) | Freeze-dried powder formulation for injectable pufferfish poison and its production method | |
| CN107019675B (en) | Adenosine cyclophosphate freeze-dried powder injection medicine composition for injection and quality control method and preparation method thereof | |
| CN109820820B (en) | Alprostadil injection and preparation method thereof | |
| CN111796043B (en) | Papaverine hydrochloride powder injection for injection and quality detection method thereof | |
| CN111789818B (en) | Papaverine hydrochloride pharmaceutical composition for injection and preparation method thereof | |
| CN1165305C (en) | Lyophilized composition of nimodipine | |
| CN109828046B (en) | Detection method of alprostadil injection | |
| CN111053743A (en) | Alprostadil liposome and preparation method thereof | |
| WO2019047812A1 (en) | Pharmaceutical composition of docetaxel conjugate and preparation method | |
| CN103330932B (en) | The pharmaceutical composition of a kind of MFG or its salt | |
| WO2023198704A1 (en) | Acetyl salicylic acid composition for intravenous administration, its storage, production and use | |
| WO2023209731A1 (en) | Injectable liquid or lyophilized powder dosage forms of selexipag and their method of preparation | |
| AU2006235847C1 (en) | Lyophilized pantoprazole preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |