• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Prolonged parenteral release of a bioactive polypeptide at desirably effective levels can be achieved using novel compositions in which the polypeptide is present in a biocompatible oil in an unusually high proportion such as at least about 10% by weight. Also disclosed are certain metal-associated somatotropins that are useful for prolonged parenteral release of such somatotropins.
    公开号:SU1595330A3
    申请号:SU853963358
    申请日:1985-10-03
    公开日:1990-09-23
    发明作者:Виллиам Митчел Джеймс
    申请人:Монсанто Компани (Фирма)；
    IPC主号:
    专利说明:

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    The invention relates to biologically active polypeptide compositions that can be administered parenterally to animals, and which are characterized by an increased release period, as well as to methods of using such compositions.
    The aim of the invention is to provide compositions that are suitable for providing an increased period of release of the biologically active polypeptide in the organism of animals and which consist of components that are biologically compatible with the given animal.
    Another object of the invention is to provide such compositions that have a sufficiently rapid release in order to provide the desired biological effect in the animal's body.
    The aim of the invention is also the creation of such compositions, which have a sufficiently slow release, in order to maintain the desired biological effect in the animal's body for a sufficiently long period of time.
    In addition, it is an object of the invention to provide such compositions that contain a highly effective amount of a polypeptide (effective dose) in order to maintain the required rate of release of the drug in the animal's body for such an extended period of time.
    The aim of the invention is also to provide such compositions which are characterized by a sufficiently low volume in order to ensure the convenience of parenteral administration into the body. This is a particularly important factor in cases where the dose of the polypeptide to be introduced into the animal is really large.
    In most cases, somatotropin (bovine somatotropin) can be dissolved in a variety of buffer solutions.
    It is preferred to dissolve somatotropin in an aqueous solution of urea, buffered with tris (oxymethyl) aminomethane (TRiS) or another suitable buffering agent. The necessary upper limit of urea concentration is usually about 6 M, but in some cases it is preferable to about 4 M urea. The lower limits of the urea, equal to 3 M, are as low as 2 M and even 1 M , can be




    used, but with lower solubility at the same time somatotropin.
    The pH of the urea buffer solution is preferably in the range of from 7 to about 10.5 units. pH Within these limits of the pH value, extraction of somatotropin as a precipitate from a solution is generally at least about 60%, however, a higher recovery can be achieved, for example, at least equal to 90%, in cases where the indicator is in the range of about 9 to 9.5 units. pH
    The temperature of the solution during the precipitation operation should be low enough to avoid the oligomerization of the self-trotropin. In general, such temperatures should be less than 10 and more than 5 ° C.
    To produce a polypeptide bound to monovalent meta. scrap, the solution subjected to depyrogenation and sterilization, as mentioned above, is treated by diafiltration (or dialysis) in order to replace the urea with a solution of metal bicarbonate (for example, 25 mM NaHCOa solution, the pH value is 9.5 pH units) or other suitable salt. Repeated exchange with the metal bicarbonate solution is preferably carried out to ensure complete urea exchange. The resulting solution is further processed by additional filtration with water in order to remove excess amounts of CaNOS3, as indicated by the beginning of precipitation of the biologically active somatotropin bound to the metal. Extraction of sodium-somatotropin using a lyophilization process results in a powder that is the somatotropin sodium salt.
    To produce a polyvalent polypeptide bound to a polyvalent metal, the solution subjected to depyrogenation and sterilization, as mentioned above, is contacted with a salt of a polyvalent metal, such as, for example, zinc. The use of a zinc chloride solution having a concentration of 1M has been shown to produce zinc somatotropin in the form of a somatotropin urea solution having a 4.5 M urea concentration, although higher or lower concentrations of zinc chloride can be used. It is preferred to perform slow
    515
    adding a solution of zinc chloride, for example, by titration while stirring a solution of somatotropin.
    As the zinc chloride solution is added, the self-trotropine solution initially has a whitish color and then a pearl white color after all the stoichiometric amount of zinc has been added. For example, by adding 4 ml of zinc chloride solution having a W concentration to 400 ml of a solution having a pH of 9.5 pH and containing about 20 mg of somatotropin in 1 ml and 0.09 M tris- ( oxymethyl) aminomethane in urea, having a concentration of 4.5 M, a homogeneous pearl-white suspension of zinc-somatotropin will be obtained. An additional amount of zinc chloride (for example, up to about 10 ml of a zinc chloride solution having a concentration of 1 M) may be added in order to ensure complete precipitation.
    The slurry is then often, as necessary, diluted in order to reduce the tendency to increase the size of the sediment particles. Dilution with approximately 3.5 volumes of water to a urea concentration of approximately 1 M has been found to satisfactorily protect the zinc-somatotropin particle from agglomeration. Removing by diafiltration (or multiple centrifugation and washing) to remove urea, tris (oxymethyl) aminomethane, and zinc and chlorine ions, followed by lyophilization, provides a powder having a particle size generally less than 10 to microns.
    In cases where bovine somatotropin is used, the particles usually contain about 0.3-1% zinc (in the range of about 1-4 zinc molecules per 1 somatotropin molecule). If the rate of zinc addition increases, large amounts precipitate, up to 4-5%. Such high amounts may be due to the fact that there is an additional addition of zinc to the active acid sites on somatotropin, i.e. on additional fragments of aspartic and / or glutamic acids or, possibly, histidine debris, or on terminal carboxy groups of the polypeptide. The inventor does not believe that this zinc addition theory should be considered as limiting the scope of the present invention. In general, precipitation using really mi
    A minimum amount of zinc should be considered as preferred.
    Example 1 Preparation of bovine somatotropin bound to zinc.
    N-terminated methionine bovine somatotropin (MBS) is obtained by a known method by lysine of bacterial cells and subsequent separation of somatotropin from bacterial cell debris.
    Bacteria are destroyed by treatment with 50% sulfuric acid, which is sufficient to reduce the pH of the fermentation broth to 1.7 ppb. The broth is neutralized by adding sodium hydroxide and then centrifuged to obtain a cell paste, which is then suspended in urea, homogenized, cooled to about 4 ° C (this temperature was maintained until the bovine somatotropin N was lyophilized -terminal methionine, as will be described below), and then centrifuging and 3-fold washing are performed, dissolving in a solution of guanidine hydrochloride having a concentration of 7M. Centrifugation is performed in order to remove insoluble impurities, then filtration is performed and the resulting substance is passed through a column filled with G 25, in which guanidine is replaced with urea, then filtered and the resulting substance is then passed through an ion exchange column of type E 52. Volume effluent from the column is reduced by about 30 times by ultrafiltration through hollow fibers. The concentrated solution is then passed through a chromatographic column filled with Sephadex G 75, and then another volume reduction step is performed by passing through a hollow fiber and the resulting substance is then exchanged, in which the urea is first replaced with NaHCOs, and then with distilled water in order to ensure the deposition of bovine somatotropin N-terminated methionine.
    The resulting precipitate is lyophilized to give a white solid, poorly soluble in water and containing a polypeptide that is a bovine somatotropin N-terminated methionine containing NH2-meth-fe (l) - pro (2) ... lei (126) .. fe (190) -COOH
    amino acid sequence. Such a polypeptide — bovine somatotropin N-terminated methionine — is subjected to dissolution in a 4.5 M urea solution, a 0.09 M tris (oxymethyl) aminomethane solution at a concentration of 21.5 mg of the indicated polypeptide per 1 ml, 4 ° C; equal to 9.5 e. pH. The resulting solution of N-terminated methionine bovine somatotropin polypeptide is depyrogenated by mixing 0.2 grams of mixed anion-exchange / cation-exchange resin of the Biorac / Ag-501X8 type per milliliter of a sterile polypeptide solution from 0.2 g. The mixture thus obtained is agitated for approximately 10 minutes at 4 ° C and then filtered using a nylon filter having openings of 1 micron to remove the ion exchange resin granules containing adsorbed pyrogens.
    The resulting depyrogenated polypeptide — bovine N-terminated methionine (MBS) bovine somatotropin — is sterilized by passing the solution through a radiation-sterilized (irradiated) corrugated capsular filter having openings with a diameter of 0.2 µm to remove non-sterile foreign bodies, such as bacteria or contamination from previous processing stages.
    The MBS polypeptide is converted to the zinc salt of the polypeptide (ZnMBS) by adding 1 M zinc chloride while stirring the depyrogenated MBS polypeptide solution. The precipitated ZnMBS contains about 1% zinc. The solution containing the solid material (ZnMBS) is further diluted with sterile depyrogenated water to a urea concentration of 1 M.
    The ZnMBS polypeptide is extracted by centrifuging at an acceleration of 10,000 g for 30 minutes, while the temperature is maintained at 4 ° C. This polypeptide is then suspended in sterile depyrogenated water at a concentration of 50 mg ZnMBS / ml, using high shear forces at displacement. The ZnMBS polypeptide is again recovered by centrifugation at an acceleration of 10,000 g for 30 minutes, then resuspended in sterile depyrogenated water at a concentration of 50 mg ZnMBS / ml using high shear forces when mixed, and the resulting substance is subjected to lyophilization, resulting in white loose powder sterile ZnMBS.
    15953308
    Example 1A. An alternative method of preparing ZnMBS is illustrated.
    Depyrogenated and sterilized solution containing 21 mg of MBS per 1 ml in a solution of urea with a concentration of 4.5 M, containing 0.05 M tris (oxymethyl) aminomethane, having a temperature of 10 ° C, and is characterized by the value of equal to 8.8 units The pH is recirculated through the tank using a plunger pump. A solution of zinc chloride with a concentration of 1 M is introduced into the pump suction line until the concentration of zinc chloride in the solution becomes 0.01 M, which leads to precipitation of ZnMBS. Water is then added to dilute in order to provide a concentration of 10 mg MBS per ml, resulting in further precipitation of ZnMBS. The ZnMBS suspension thus obtained is then circulated at a temperature of 25 ° C through a diafiltration membrane consisting of a hollow fiber that has openings that allow molecules with a molecular weight up to 10,000 to pass through. This operation is carried out until the concentration reaches equal to 40 mg MBS per 1 ml; water is further added in order to adjust the filtration rate through the membrane so as to remove practically all of the zinc, urea and tris (oxymethyl) aminomethyl from the suspension. The addition of water is stopped in order to ensure a concentration of approximately 80 mg MBS / ml. The concentrated suspension thus obtained is then lyophilized to obtain a dry, white ZnMBS powder, having a particle size of 0.5 to 11 microns.
    Example 1B Illustrates a method for producing bovine somatotronin associated with sodium.
    A depyrogenated and sterilized solution containing 21.5 mg / MBS per ml in a solution of urea with a concentration of 4.5 M, containing 0.05 M tris (oxymethyl) aminomethane, having a temperature of 4 ° C, characterized by the value of hydrogen 9.5 units. pH, dialyzed to replace urea first with NaHCOa solution and then with distilled water. Water exchange is stopped at that point in time when MBS precipitation begins to occur. The solution thus obtained is further filtered with a filter having an opening size of 0.2 µm to remove precipitated MBS.
    and then lyophilized to obtain the sodium salt (NaMBS), which can be used in the compositions of the present invention.
    Example 2: Preparation of compositions containing somatotropin bound to zinc. A certain amount of sesame oil (variety FISHER NF) is added to a three-neck flask with a round base. Aluminum monostearate is added as an antihydration agent in an amount equal to 5% of the total weight of aluminum monostearate and sesame oil. This flask is then placed in an oil bath having a temperature of 155 ° C and is stirred to disperse the aluminum monostearate as quickly as possible. The stirring process is continued for 20 minutes, and during this period of time, the aluminum monostearate is completely dissolved in oil. The flask is then removed from the oil bath, kept under vacuum, and subjected to cooling to 25 ° C. After cooling, the resulting solution turns into a thick gel. The cooled gel is then discharged into a ball mill having a stirrer providing high shear forces in the layer, consisting of stainless steel balls having diameters of 1/8 inch, 3/18 inch and 1/4 inch (0.32 0.48 and 0.64 cm, respectively). In the working space of the mill, a vacuum is created, and ZnMBS powder, obtained as described in Example 1, is slowly fed into the working space of the mill using a screw feeder until the amount of ZnMBS reaches 40% (weight ratio between ZnMBS and monostearate aluminum is 13.3). The stirring process is continued for 6 hours and during this period the average particle diameter of ZnMBS is reduced from 20 to 5 microns. The resulting practically anhydrous gel-like ZnMBS oil suspension is separated from the stainless steel balls by filtration.
    Example 3. Efficacy of using the composition.
    A substantially anhydrous composition was prepared as described in Example 2, by dissolving 5% aluminum monostearate in sesame oil heated to 155 ° C. This oil is then cooled to form a ZnMBS gelatinous oil, subjected to dispersion and grinding in oil until the amount of ZnMBS in the composition reaches 327 ° in the continuous phase of the oil (9.4 is the weight ratio
    between ZnMBS and monostearate aluminum). Syringes equipped with a 18 gauge needle and having a length of 1.5 inches (3.8 cm) filled 2.54 g (2.5 ml) with a composition to form a dose containing 805 mg of ZnMBS. This composition is characterized by an injection ability of 0.36 ml / s. Pure compositions of sesame oil with 5% aluminum monostearate, but without a polypeptide, are also prepared and similar syringes of 2.4 g of these compositions are filled. These compositions are administered by injection of 23 Holstein dairy cows in the second or third three months of their second or subsequent lactation. Cows are randomly grouped into four groups containing 5 or 6 animals. Two groups of cows were injected intramuscularly (1 M) into the area of the stomach, one group being given a composition containing ZnMBS, and the other control group of animals was given a composition that did not contain a polypeptide. Similarly, the two groups of animals are administered as a composition containing the ZnMBS polypeptide, as well as a composition not containing the polypeptide, subcutaneously in the suprascapular region. The cumulative values obtained by the least squares method for the average milk yield (covariantly calculated through the differences of the input values when pre-processing the milk productivity values) are shown in Table. 1, where milk yield is expressed in kilograms of milk per day. As shown in the table. 1, single injection, intramuscular or subcutaneous, the composition is the subject of the present invention and leads to a rapid and long-lasting improvement in milk production with very high values of statistical significance.
    Blood samples are analyzed to determine bovine somatotropin, which, without input in accordance with the present invention, is usually present in the cattle circulatory system. The results of the analyzes carried out using radioimmunoassay experiments are presented in Table. 2, where the concentrations of bovine somatotropin are expressed in nanograms per milliliter (ng / ml). Example 4: Efficacy of the composition for an extended release period of a polypeptide (MBS) in animals. These compositions contain a variety of different materials. ZnMBC compositions are prepared as indicated in Example 3, using combinations of the following components: Biologically Co 111595330
    oil capacity (seed oil of sesame or peanut); antihydration agent (aluminum monostearate) at concentration
    Traction 3 or 5% of oil plus aluminum monostearate; The polypeptide (ZnMBS) at a concentration of 20, 30 or 40% of the total composition.
    Aluminum monostearate is dispersed in oil. Dispersion after heating and holding at 155 ° C for 15 minutes. subjected to cooling to 25 ° C to obtain a gel-like oil. Next, ZnMBS is added and the resulting mixture is dispersed in a mixer, providing high shear, resulting in a suspension of ZnMBS in gel oil. Tuberculin syringes equipped with 18-gauge hypodermic needles are filled with this suspension.
    The compositions listed in table. 3, are injected subcutaneously in the dorsal (dorsal) supraspinal region to rats of Sprogue Dawliy breed, which are divided into 16 groups, 8 pieces each (female), in rats they suppress the immune system.
    Blood samples are analyzed by radioimmunological experiments on somatotropin bovine. The data listed in the table. 4, expressed in nanograms per 1 ml of blood plasma. These plasma levels are presented in table. 4 for blood samples taken before injection on day 0 (on the day of injection). Some measurements of the main line (reference point) for the rats in Examples 4-7 are higher than some of the main lines and measurements of the isolated blood polypeptide in Example 3. This is due to the fact that there are differences in the normal levels of self-absorption. - ropina and due to the fact that the radioimmuno-genetic analyzes in example 3 are more accurate.
    The mean concentrations for the control groups of 1, 5, 9, and 13 are in the range of 5-12 ng / ml for each of the days indicated above.
    Example 5. The example illustrates the effectiveness of the composition being the subject of the present invention and providing an extended polypeptide release period (MBS) using other fatty acid aluminum salts as anti-hydration agents. In these compositions, aluminum monopalmitate and aluminum monolaurate are used as anti-hydrating agents along with sesame oil and peanut oil.
    In this example, gelatinous oils containing 3% aluminum monolaurate and
    12
    aluminum monopalmitate, is obtained practically as shown in measurement 4. ZnMBS is suspended in gel-like oils at a concentration of 30% by weight of the whole composition (the weight ratio between ZnMBS and aluminum monolaurate or aluminum monopalmitate was 14.3). Each composition was administered by injection to rats of IFS-D breeds, each group consisting of 8 animals. Doses are listed below in the table. five.
    By analyzing blood samples taken from rats on the indicated days after injection, it is established that the concentrations of bovine somatotropin are as shown below in Table. 6, where the values relating to day O were the reference point for the analyzes.
    Example 6: Efficacy of the composition of the present invention, characterized by an extended polypeptide release period (MBS), in which olive or corn oil is used.
    In this example, the gelatinous oils are radiated practically as described in Example 4, using 3% aluminum monostearate based on the weight of aluminum monostearate and oil. Suspensions containing 30 or 40% MBS were injected into two groups of rats of the IFS-D breeds, in each group there were 8 animals. Concentrations of injected doses are listed below in table. one.
    As a result of the analysis of blood samples taken from rats, the concentrations of bovine somatotropin are as shown below in Table. 8, where values relating to Day O are the starting point for the analyzes.
    Example 7. The example illustrates compositions containing about 10% of polypeptides of the type MBS and ZnMBS found in peanut oil. The example further illustrates the fact that an extended release period of a polypeptide can be further increased by the use of an anti-hydration agent. Compositions, as indicated below in the table. 9, intended for injection, get almost as indicated in example 4.
    Each composition was administered by subcutaneous injection to groups of rats of the IFS-D breed, each of which consists of 8 animals, the dose is 300 µl. As a result of the analysis of blood samples taken from rats on the indicated days after the injection, it was determined that the concentrations of bovine somatotros 1315
    Pins in plasma are as shown below in Table. 10, where the values relating to Day O were the starting point for the analyzes.
    A comparison of the results obtained for groups 30 and 31 illustrates an improvement in the ability to increase the MBS release time by at least 7 days by using a bound polyvalent metal.
    A comparison of the results obtained for groups 32 and 33 illustrates the improvement in the ability to increase the MBS release time by using an anti-hydration agent in cases where MBS is associated with such a polyvalent metal.
    Example 8. The example illustrates compositions that are yush; the subject of the present invention contains 10% bovine somatotropin, without using an anti-hydration agent in each of such oils as sesame, peanut, corn, olive, safflower, cotton, palm, rapeseed and soy butter. The separate volumes of each of these oils are stored at the following temperatures: 4, 25, 50, 75, 100 and 125 ° C. ZnMBS is dispersed and milled in each of the oils, as indicated in Example 2, until the concentration becomes 10%. The grinding process continues until the average particle diameter of the somatotropin becomes less than 15 microns. Each of the compositions is characterized by the ability to extrude in excess of 0.1 ml / sec.
    Example 9. The example illustrates the compositions of the present invention and those obtained as indicated in Example 8, except that before adding somatotropin, the aluminum monostearate is dispersed in each of the oils to a concentration of 5 % relative to the weight of the oil plus aluminum monostearate. These compositions are characterized by the ability to extrude in excess of 0.1 ml / s.
    Example 10 The example illustrates compositions prepared as indicated in example 8, except that the process of adding somatotropin continues until the content of bovine somatotropin reaches 40%. The dispersion and grinding process is continued until the average particle diameter of the somatotropin becomes less than 15 microns. These compositions have a shpitz ability greater than 0.03 ml / s.
    0
    14
    Example 11. The example illustrates the composition as indicated in example 10, except that before adding somatotropin, the aluminum monosterate is dispersed in each of the oils at a concentration of 5% by weight: oil plus aluminum monostearate. These compositions have the ability to extrude in excess of 0.03 ml / s.
    Example 12. In the example, compositions containing 10% bovine somatotropin are dissolved, which are dissolved in each of such oils as sesame, maize, olive, safflower, cottonseed, palm, rapeseed and soybean. Each oil is heated to 160 ° C and stirred to improve the dissolution of aluminum monostearate. After the dissolution of 1% aluminum monostearate is achieved, each of the oils is cooled to 25 ° C. ZnMBS is subjected to dispersion and grinding in chilled oil, as indicated in Example 2, and this process is continued until the concentration of this polypeptide becomes 10% and the average particle diameter is no more than 15 µm. Each of the compositions has a syringe ability greater than 0.1 ml / s.
    Example 13. In the example and. lustration compositions prepared as indicated in example 12, except that the process of adding somatotrin is continued until the somatotropin content reaches 40%. These compositions are milled as indicated in Example 2, and the milling process is continued until the average particle diameter exceeds 15 microns. Each composition is characterized by the ability to extrude more than 0.03 ml / s.
    Example 14. The example illustrates the compositions of the present invention containing 10% bovine somatotropin in oils in which aluminum monostearate was dissolved, its concentration was 5% relative to the weight of the oil plus aluminum monostearate. These oils are sesame, peanut, maize, safflower, cotton, palm, rapeseed and soybean. Each oil is heated to 160 ° C and stirred to improve the dissolution of aluminum monostearate. After the aluminum monostearate is dissolved, each of the oils is cooled to 25 ° C. ZnMBS is further subjected to dispersion and grinding in chilled oil, as indicated in Example 2, until the concentration
    this polypeptide in oil does not become equal to 10%. The resulting dispersion is further milled until the average particle diameter of the somatotropin becomes less than 15 microns. Each of the compositions is characterized by the ability to extrude in excess of 0.1 ml / sec.
    Example 15. In accordance with this composition example, which is the subject of the present invention and containing 42% bovine somatotropin, is prepared by the continuous addition of somatotropin to the compositions indicated in Example 14, and this addition is made until the content of somatotropin in the composition does not reach 42%. While maintaining the oil in the form of a continuous phase, somatotropin is subjected to dispersion and grinding, as indicated in Example 2, and this operation is carried out until the average particle diameter of the somatotropin becomes less than 15 microns. Each of the obtained compositions containing the polypeptide and which are the subject of the present invention, is characterized by the ability to extrude in excess of 0.03 ml / s.
    Example 16. The example illustrates compositions that are the subject of the present invention and contain 20% bovine somatotropin in oils similar to those similar to those used in example 9, but in these compositions as an anti-hydration agent instead of aluminum monostearate uses one of such agents as aluminum distearate or aluminum tristearate, aluminum monopalmitate, aluminum dipalmitate or aluminum tripalmitate, as well as calcium monostearate, calcium distearate, calcium laurate, palmitate ltsi, magnesium monostearate, distearate, magnesium laurate, magnesium palmitate, and magnesium. The antihydration agent is added to the oil before adding somatotropin. ZnMBS is added, as indicated in Example 2, until its concentration becomes 20%. Dispersing and grinding processes continue until the average particle diameter of the somatotropin particles does not exceed 15 µm. Each of the compositions is characterized by the ability to extrude in excess of 0.03 ml / s.
    Example 17. The example illustrates compositions containing other concentrations of bovine somatotropin in oils, similar to those used in example 20, and in which types of oils
    correspond to the types of oils used in example 16, but with the exception that the process of adding somatotropin continues until the concentration of self-trotropin becomes 25, 30 or 35%. The grinding and dispersing processes continue until the mean particle diameter of the self-trotropine becomes less than 15 microns. Each of the compositions is characterized by the ability to extrude in excess of 0.03 ml / s.
    Example 18. In accordance with this example, results similar to those obtained in examples 8-17 are obtained in cases where the bovine somatotropin used was a chemically unbound form or was chemically bound to potassium or sodium cations.
    Example 19. The results obtained in accordance with this example are similar to those obtained in Examples 8-18 for those cases where other bovine somatotropins, i.e. somatotropins characterized by the following amino acid sequence:
    LN2-met-fe (1) -pro (2) ... shaft (126) ... fe (19 0) -COOH
    MH2-ala-fe (1) -pro (2) ... shaft (126) ... fe (180) -COOH
    MH2-ala-fe (1) -pro (2) ... lei (126) ... fe (19 0) -COOH
    MH2-fe- (1) -pro (2) ... lei (126) ... fe (190) soon
    MH2-fe- (1) -pro (2) ... shaft (126) ... fe (190) soon
    HH2-met-asp-glu-fe (1) -pro (2) ... lei (126) ... fe (190) -COOH
    MH2-met-asp-glu-fe (1) -pro (2) ... shaft (126) ... fe (190) -COOH
    MH2-met- (4) ... lei (126) ... fe (190) -COOH
    HH2-met (4) ... shaft (126) ... fe (190) -COOH.
    Examples 20-30. In cases where bovine somatotropin is replaced by porcine somatotropin in the procedures described in examples 8-18, the results are almost the same, since bovine and porcine somatotropin are similar.
    Example 31. Pork somatotropin is prepared with N-terminal alanine (APS) by expression of recombinant DNA. The light emitting bodies containing APS are isolated and solubilized, folded and acidified in an aqueous solution of urea. The remainder of the purification process is similar to that used in Example 1 for purifying MBS. The composition of the APS is prepared mainly as described in example 3, using 17
    a mixture of sesame oil (SO) and AIMS at an AIMS concentration of 2.5 or 5% per SO / AIMS. The content of the polypeptide (APS) in the composition is 10 or 20%, respectively. The amounts of each obtained composition with an APS content of 80 mg are used for injection into fat on the dorsal side of crossbred hogs weighing 68-77 kg at the beginning of the experiment. Two injections were performed at a 2-week interval, with an average daily weight gain for 4 weeks being observed. The degree of feed utilization is calculated by dividing the average daily feed intake by the average daily weight gain. At the same time, a lower degree value, utilization of feed means indicates an improved result. Untreated hogs serve as controls. The results are shown in Table. P.
    CLAIM
    权利要求:
    Claims (2)
    [1]
    1. The composition for stimulating lactation in cows and increasing the degree of digestibility of feed, and somatotropin and vegetable oil, characterized in that bovine or porcine somatotropin is used as somatotropin in the following ratio, wt.%:
    Bovine or pork somatotro10 - 42 Vegetable oil58 - 90
    [2]
    2. A composition according to claim 1, characterized in that it further comprises an agent
    1595330
    18
    Example 32. Prepare APS according to the method described in example 31 in a carrier containing 95% sesame oil and 5% AIMS. A sufficient amount of APS is added to obtain a concentration of 39%. This mixture is injected into the fat on the dorsal side of the neck with crossbred hogs weighing approximately 54-63 kg at the beginning of the experiment. One group of hogs was administered 30 mg APS every 7 days, and the other 60 mg APS every 14 days. The experience continued for 6 weeks. During this time, the degree of utilization of fodder in the untreated control hog group is 3.61, and in the group that received 60 mg every 14 days, it is 3.53, and the value of the degree of utilization in the case of the group that received 30 mg every 7 days is 3.17.
    protivogidratatsii selected from the group vklyuchayushy monostearate, distearate and aluminum tristearate, sorbitan monopalmitate, dipal- tripalmitate palmitate and aluminum monolaurate, aluminum, magnesium distearate, magnesium monolaurate, monopalmitate, distearate and calcium, calcium monolaurate, monopalmitate calcium, wherein the agent is contained protivogidratatsii in the composition in the amount of 0.6 - 4.5 wt.%.
    19159533020
    Table I
    Cumulative milk yield values
    cows (MP, kg / day)
    Method I 7 days I 14 days j 21 days j 30 days Dose I input 1 MP 1% MP% Ci
    Cont-Intra Role Muscle 23.3 - 22.4 - 22.0 - 21 I 2n1Sh Same 26.6 16.2 26.0 17.1 13.7
    Cont-Subcutaneously 22.5 - 21.1 - 21.8 - 20.6 - Riel
    Z /, MBS Same 25.1 9.6 24.8 11.7 24.0 9.6 22.1 5.7 Connection of intramuscular and subcutaneous injections
    (1) control 22.9 - 22.2 - 21.9 - 20.9 (2) 2l, 25.9 13.1 25.4 14.4 24.4 11.4 8.1 Comparison of Significance Levels
    (2) with respect to (i)
    .0001 .0001 .0004, 0187% characterizes the percentage relative improvement to the average control value
    table 2
    Injection Formulations
    to)
    In relation to weight: oil + aluminum monostearate.
    Table 3
    25159533026
    Table 4
    Table 5
    Table b
    Mean values of bovine somatotropin concentrations
    in plasma, lg / ml
    Compositions for injection
     Polypeptide Oil}} polypeptide,% |
    k) p
    relation to weight: oil + aluminum monostearate.
    Table 7
    Table 8
    Table 9
    i Monostearate aluminum,%
    )
    Feed utilization rate
    ten
    Recycling rate
    feed means 3.09 3.30 3.37 3.07 3.53
    Table 10
    TABLE II
    20
    ten
    20
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1595330A3|1990-09-23|Composition for stimulating cow lactation and better feed absorption
    US5411951A|1995-05-02|Prolonged release of biologically active somatotropin
    EP0278103B1|1992-10-28|Sustained release growth hormone compositions for parenteral administration and their use
    JPH08510721A|1996-11-12|Isolation of the compound of interest from milk
    EP0540582A1|1993-05-12|Growth hormone crystals and a process for production of these gh-crystals.
    EP0289186A2|1988-11-02|Process for increasing the growth rate and enhancing the feed efficiency of meat producing livestock
    US5474980A|1995-12-12|Prolonged release of biologically active somatotropins
    JP2620417B2|1997-06-11|Compositions for sustained release of biologically active polypeptides
    RU2493873C1|2013-09-27|Injection preparation for higher sperm production in farm breeders and cocks, and method for using it
    CA1285874C|1991-07-09|Injectable sustained release formulation
    US5086041A|1992-02-04|Methods of using prolonged release somatotropin compositions
    EP0639984A1|1995-03-01|Lyophilized somatotropin formulations
    EP0343696B1|1996-01-03|Zinc-associated somatotropins
    US6605594B2|2003-08-12|Aqueous glycerol formulations of somatotropin
    JP2000506509A|2000-05-30|Aqueous sustained release formulation
    Sinha et al.1979|Serum and pituitary concentrations of growth hormone and prolactin in pygmy mice
    WO1998029131A9|1998-11-05|Aqueous glycerol formulations of somatotropin
    KR100355517B1|2003-03-04|Aqueous Sustained Release Agent
    MXPA02008261A|2002-11-29|Non aqueous injectable formulations for extended release of somatotropin.
    AU716492B2|2000-02-24|Somatotropin compositions mixed with vitamins
    KR920005688B1|1992-07-13|Composition of polypeptide which releasing continously
    CN1253472C|2006-04-26|Polyglycol-human growth hormone conjugate and its prepn process and medicinal use
    BG62038B1|1999-01-29|Medicamentous form based on biostimulator
    同族专利:
    公开号 | 公开日
    AU573904B2|1988-06-23|
    PT81248A1|1988-08-01|
    AU1439088A|1988-09-29|
    BG47039A3|1990-04-16|
    JPS6191130A|1986-05-09|
    US5013713A|1991-05-07|
    CZ284472B6|1998-12-16|
    PL152711B1|1991-01-31|
    PT81248B1|1992-10-30|
    UA8352A1|1996-03-29|
    CN85109638A|1986-07-30|
    ZA857642B|1986-08-27|
    IL76554D0|1986-02-28|
    KR890002631B1|1989-07-21|
    CN1044761A|1990-08-22|
    JPH0745409B2|1995-05-17|
    PT81248A|1985-11-01|
    AU601272B2|1990-09-06|
    HUT38839A|1986-07-28|
    NO173975C|1994-03-02|
    CN1031038C|1996-02-21|
    NO853909L|1986-04-07|
    IL76554A|1990-04-29|
    DK449585D0|1985-10-03|
    KR870003791A|1987-05-04|
    ES547489A0|1986-12-16|
    IE852422L|1986-04-04|
    EP0177478A2|1986-04-09|
    EP0177478B1|1991-04-17|
    DE3588074D1|1996-02-15|
    AU4823785A|1986-04-10|
    PL261273A1|1987-08-10|
    EP0177478B2|1997-03-05|
    NZ213701A|1988-08-30|
    CS711885A2|1987-11-12|
    CN1007124B|1990-03-14|
    CA1309018C|1992-10-20|
    IE65392B1|1995-10-18|
    ES8702440A1|1986-12-16|
    GR852398B|1986-02-03|
    DD244914A5|1987-04-22|
    AT132372T|1996-01-15|
    PL255622A1|1986-12-30|
    CZ815687A3|1998-09-16|
    DE3582548D1|1991-05-23|
    NO173975B|1993-11-22|
    EP0177478A3|1987-04-01|
    US5739108A|1998-04-14|
    HU196714B|1989-01-30|
    PT81248B|1987-10-20|
    YU158485A|1988-12-31|
    YU45281B|1992-05-28|
    DK449585A|1986-04-05|
    CS274717B2|1991-10-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2491537A|1947-06-03|1949-12-20|Welch Henry|Liquid injectable oil-pectin-drug therapeutic compositions|
    US2807569A|1953-01-17|1957-09-24|Organon|Adrenocorticotropic hormone composition|
    GB807692A|1957-05-07|1959-01-21|Lilly Co Eli|Corticotropin reaction complexes|
    US2964448A|1959-01-27|1960-12-13|Anschel Joachim|Relaxin composition and process for preparing same|
    US3118815A|1959-09-28|1964-01-21|Upjohn Co|Growth hormone and recovery thereof|
    FR3597M|1963-02-15|Organon Nv|New preparations with adrenocorticotropic hormone activity and their manufacture.|
    US3810881A|1971-06-18|1974-05-14|Ciba Geigy Corp|Peptides having d-alpha-phenylglycine,l-lysine and l-ornithine in positions 1,17 and 18,respectively|
    BE795516A|1972-02-17|1973-08-16|Ciba Geigy|PREPARATIONS OF OILY AND INJECTABLE PEPTIDES AND PROCESS FOR THEIR PREPARATION|
    GB1454105A|1972-11-04|1976-10-27|Hoechst Ag|Preparation containing luteinizing hormone-releasingfactor|
    US4172138A|1977-03-23|1979-10-23|Rhodes Russell E|Method and composition of matter for the treatment of dry cows for mastitis|
    US4256737A|1979-06-11|1981-03-17|Syntex Inc.|Long acting depot injectable formulations for LH-RH analogues|
    US4328214A|1979-07-04|1982-05-04|Ciba-Geigy Corporation|Cyclopeptides and pharmaceutical preparations thereof and also processes for their manufacture|
    CA1146866A|1979-07-05|1983-05-24|Yamanouchi Pharmaceutical Co. Ltd.|Process for the production of sustained releasepharmaceutical composition of solid medicalmaterial|
    DE3378250D1|1982-04-22|1988-11-24|Ici Plc|Continuous release formulations|
    US4659696A|1982-04-30|1987-04-21|Takeda Chemical Industries, Ltd.|Pharmaceutical composition and its nasal or vaginal use|
    US4452775A|1982-12-03|1984-06-05|Syntex Inc.|Cholesterol matrix delivery system for sustained release of macromolecules|
    KR890002631B1|1984-10-04|1989-07-21|몬산토 캄파니|Composition of prolonged release of biologically active somatotropin|
    EP0177342A3|1984-10-04|1987-12-02|Genentech, Inc.|Oral formulation of therapeutic proteins|
    US5474980A|1984-10-04|1995-12-12|Monsanto Company|Prolonged release of biologically active somatotropins|
    US5086041A|1984-10-04|1992-02-04|Monsanto Company|Methods of using prolonged release somatotropin compositions|
    US5411951A|1984-10-04|1995-05-02|Monsanto Company|Prolonged release of biologically active somatotropin|US5086041A|1984-10-04|1992-02-04|Monsanto Company|Methods of using prolonged release somatotropin compositions|
    US5474980A|1984-10-04|1995-12-12|Monsanto Company|Prolonged release of biologically active somatotropins|
    US5411951A|1984-10-04|1995-05-02|Monsanto Company|Prolonged release of biologically active somatotropin|
    KR890002631B1|1984-10-04|1989-07-21|몬산토 캄파니|Composition of prolonged release of biologically active somatotropin|
    US5037806A|1985-02-22|1991-08-06|Monsanto Company|Biologically active method using somatotropins|
    US4775659A|1985-08-19|1988-10-04|Eli Lilly And Company|Injectable semi-solid formulations|
    IL79765A|1985-08-23|1992-02-16|Lilly Co Eli|Injectable sustained release formulations of bovine somatotropin|
    US4977140A|1985-08-23|1990-12-11|Eli Lilly And Company|Injectable sustained release formulation|
    US4857506A|1987-01-12|1989-08-15|American Cyanamid Company|Sustained release growth hormone compositions for parenteral administration and their use|
    EP0279616A3|1987-02-17|1990-03-07|International Minerals And Chemical Corporation|Swine growth promotion|
    US4863736A|1987-03-16|1989-09-05|Monsanto Company|Somatotropin prolonged release|
    GB8725427D0|1987-10-30|1987-12-02|Lilly Industries Ltd|Somatotropin formulations|
    US5021554A|1989-02-24|1991-06-04|Eli Lilly And Company|Process for protein particle size reduction using a fluid-energy mill|
    DK168790D0|1990-07-13|1990-07-13|Novo Nordisk As|
    US5780599A|1990-07-13|1998-07-14|Novo Nordisk A/S|Growth hormone crystals and a process for production of growth hormone crystals|
    US6894023B1|1990-07-13|2005-05-17|Novo Nordisk A/S|Growth hormone crystals and a process for production of these GH-crystals|
    YU87892A|1991-10-01|1995-12-04|Eli Lilly And Company Lilly Corporate Center|INJECTIBLE LONG TERM RELEASE FORMULATIONS AND PROCEDURES FOR THEIR OBTAINING AND USE|
    US6063910A|1991-11-14|2000-05-16|The Trustees Of Princeton University|Preparation of protein microparticles by supercritical fluid precipitation|
    WO1994006452A1|1992-09-21|1994-03-31|The Upjohn Company|Sustained-release protein formulations|
    SI0690864T1|1993-03-12|2001-10-31|Upjohn Co|Crystalline ceftiofur free acid|
    US6284727B1|1993-04-07|2001-09-04|Scios, Inc.|Prolonged delivery of peptides|
    US6087324A|1993-06-24|2000-07-11|Takeda Chemical Industries, Ltd.|Sustained-release preparation|
    ZA949350B|1994-01-25|1996-05-24|Upjohn Co|Aqueous prolonged release formulation|
    CN1157562A|1994-09-09|1997-08-20|武田药品工业株式会社|Sustained release preparation containing metal salt of peptide|
    NZ326953A|1996-01-11|2001-03-30|Upjohn Co|Aqueous prolonged release bovine somatotropinformulation|
    US5767080A|1996-05-01|1998-06-16|Cargill, Incorporated|Enhanced milk production in dairy cattle|
    AU3854001A|2000-02-24|2001-09-03|Monsanto Technology Llc|Non-aqueous injectable formulations for extended release of somatotropin|
    AU7149101A|2000-06-26|2002-01-08|Monsanto Technology Llc|Non-aqueous surfactant-containing formulations for extended release of somatotropin|
    US6664234B1|2000-06-30|2003-12-16|Monsanto Technology Llc|Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin|
    KR20030038690A|2000-08-07|2003-05-16|인헤일 테라퓨틱 시스템즈 인크.|Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation|
    US7829100B2|2000-09-12|2010-11-09|Teagarden Dirk L|Pharmaceutical composition having modified carrier|
    DE10161078A1|2001-12-12|2003-08-28|Achim Goepferich|Matrices for the stabilization and controlled release of problem drugs|
    US7659061B2|2002-11-19|2010-02-09|Pharmacia & Upjohn Company|Pharmaceutical compositions having a modified vehicle|
    JP2006199589A|2003-09-03|2006-08-03|Ltt Bio-Pharma Co Ltd|Nanoparticle containing physiologically active protein or peptide, method for producing the same and external preparation comprising the nanoparticle|
    US20090156545A1|2005-04-01|2009-06-18|Hostetler Karl Y|Substituted Phosphate Esters of Nucleoside Phosphonates|
    WO2006137953A1|2005-04-01|2006-12-28|The Regents Of The Univerisity Of California|Phosphono-pent-2-en-1-yl nucleosides and analogs|
    GB0511269D0|2005-06-02|2005-07-13|Creative Peptides Sweden Ab|Sustained release preparation of pro-insulin C-peptide|
    ES2664086T3|2005-12-30|2018-04-18|ZensunScience & Technology, Co., Ltd.|Extended release of neurregulin to improve cardiac function|
    DK2383271T3|2006-03-13|2013-10-07|Kyorin Seiyaku Kk|Aminoquinolones as GSK-3 Inhibitors|
    US20070232671A1|2006-03-13|2007-10-04|Given Bruce D|Methods and compositions for treatment of diastolic heart failure|
    WO2007106468A2|2006-03-13|2007-09-20|Encysive Pharmaceuticals, Inc.|Formulations of sitaxsentan sodium|
    US20080026061A1|2006-06-22|2008-01-31|Reichwein John F|Crystalline N--2-[2-methyl-4.5-phenylacetyl]-thiophene-3-sulfonamide|
    KR20090068263A|2006-09-21|2009-06-25|액티브스 바이오사이언시즈, 인크.|Serine hydrolase inhibitors|
    JP2010507585A|2006-10-19|2010-03-11|オースペックス・ファーマシューティカルズ・インコーポレイテッド|Substituted indole|
    WO2008057604A2|2006-11-08|2008-05-15|The Regents Of The University Of California|Small molecule therapeutics, syntheses of analogues and derivatives and methods of use|
    WO2008106167A1|2007-02-28|2008-09-04|Conatus Pharmaceuticals, Inc.|Combination therapy comprising matrix metalloproteinase inhibitors and caspase inhibitors for the treatment of liver diseases|
    AU2008219622A1|2007-02-28|2008-09-04|Conatus Pharmaceuticals, Inc.|Methods for the treatment of liver diseases using specified matrix metalloproteinaseinhibitors|
    WO2008140859A1|2007-03-15|2008-11-20|Auspex Pharmaceuticals, Inc.|Deuterated venlafaxines and 0-desmetylvenlafaxines with serotoninergic and / or norepinephrinergic activity|
    US7892776B2|2007-05-04|2011-02-22|The Regents Of The University Of California|Screening assay to identify modulators of protein kinase A|
    JP2010533205A|2007-07-12|2010-10-21|トラガラファーマシューティカルズ，インク．|Methods and compositions for treating cancer, tumors, and tumor-related disorders|
    EP2203458B1|2007-09-11|2011-11-02|Kyorin Pharmaceutical Co., Ltd.|Cyanoaminoquinolones as gsk-3 inhibitors|
    WO2009035684A1|2007-09-12|2009-03-19|Activx Biosciences, Inc.|Spirocyclic aminoquinolones as gsk-3 inhibitors|
    US8618289B2|2008-03-17|2013-12-31|Ambit Biosciences Corporation|RAF kinase modulator compounds and methods of use thereof|
    WO2009139880A1|2008-05-13|2009-11-19|Celgene Corporation|Thioxoisoindoline compounds and compositions and methods of using the same|
    AU2009249600A1|2008-05-20|2009-11-26|Cerenis Therapeutics Holding S.A.|Niacin and NSAID for combination therapy|
    RU2519947C2|2008-07-02|2014-06-20|Айденикс Фармасьютикалз, Инк.|Compounds and pharmaceutical compositions for treatment of viral diseases|
    WO2010020871A2|2008-08-22|2010-02-25|Orchid Chemicals & Pharmaceuticals Limited|Crystalline sodium salt of cephalosporin antibiotic|
    JP5780969B2|2008-12-31|2015-09-16|サイネクシス，インコーポレーテッド|Cyclosporine A derivative|
    WO2010088450A2|2009-01-30|2010-08-05|Celladon Corporation|Methods for treating diseases associated with the modulation of serca|
    US8568793B2|2009-02-11|2013-10-29|Hope Medical Enterprises, Inc.|Sodium nitrite-containing pharmaceutical compositions|
    US8349851B2|2009-02-27|2013-01-08|Ambit Biosciences Corp.|JAK kinase modulating compounds and methods of use thereof|
    US8193372B2|2009-03-04|2012-06-05|Idenix Pharmaceuticals, Inc.|Phosphothiophene and phosphothiazole HCV polymerase inhibitors|
    MX2011009414A|2009-03-11|2011-10-19|Kyorin Seiyaku Kk|7-cycloalkylaminoquinolones as gsk-3 inhibitors.|
    MX2011009413A|2009-03-11|2011-10-21|Ambit Biosciences Corp|Combination of an indazolylaminopyrrolotriazine and taxane for cancer treatment.|
    WO2010110686A1|2009-03-27|2010-09-30|Pathway Therapeutics Limited|Pyrimidinyl and 1,3,5 triazinyl benzimidazoles and their use in cancer therapy|
    CA2756067A1|2009-03-27|2010-09-30|Pathway Therapeutics, Inc.|Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy|
    MY162440A|2009-04-22|2017-06-15|Axikin Pharmaceuticals Inc|2,5-disubstituted arylsulfonamide ccr3 antagonists|
    SG175748A1|2009-04-22|2011-12-29|Axikin Pharmaceuticals Inc|2,5-disubstituted arylsulfonamide ccr3 antagonists|
    NZ595838A|2009-04-22|2014-03-28|Axikin Pharmaceuticals Inc|Arylsulfonamide ccr3 antagonists|
    WO2011003870A2|2009-07-06|2011-01-13|Creabilis S.A.|Mini-pegylated corticosteroids, compositions including same, and methods of making and using same|
    EP3072890B1|2009-07-07|2018-10-17|MEI Pharma, Inc.|Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy|
    CA2767168C|2009-07-08|2019-04-09|Hope Medical Enterprises, Inc. D.B.A. Hope Pharmaceuticals|Sodium thiosulfate-containing pharmaceutical compositions|
    WO2011009961A1|2009-07-24|2011-01-27|Virologik Gmbh|Combination of proteasome inhibitors and anti-hepatitis medication for treating hepatitis|
    WO2011089166A1|2010-01-19|2011-07-28|Virologik Gmbh|Semicarbazone proteasome inhibitors for treating hiv and hepatitis infection|
    TW201117812A|2009-08-05|2011-06-01|Idenix Pharmaceuticals Inc|Macrocyclic serine protease inhibitors|
    BR112012003661A2|2009-08-19|2017-04-25|Ambit Biosciences Corp|"Biaryl compounds and methods of use thereof."|
    US8470817B2|2009-10-26|2013-06-25|Sunesis Pharmaceuticals, Inc.|Compounds and methods for treatment of cancer|
    WO2011056764A1|2009-11-05|2011-05-12|Ambit Biosciences Corp.|Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles|
    WO2011064769A1|2009-11-24|2011-06-03|Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.|Methods and pharmaceutical compositions for the treatment of hot flashes|
    US20110301235A1|2009-12-02|2011-12-08|Alquest Therapeutics, Inc.|Organoselenium compounds and uses thereof|
    TW201136942A|2009-12-18|2011-11-01|Idenix Pharmaceuticals Inc|5,5-fused arylene or heteroarylene hepatitis C virus inhibitors|
    WO2011087810A1|2009-12-21|2011-07-21|Ambrx, Inc.|Modified porcine somatotropin polypeptides and their uses|
    MX349301B|2009-12-21|2017-07-21|Ambrx Inc|Modified bovine somatotropin polypeptides and their uses.|
    EP2515654A4|2009-12-23|2013-04-24|Map Pharmaceuticals Inc|Novel ergoline analogs|
    CN102834409A|2009-12-30|2012-12-19|西尼克斯公司|Cyclosporine analogues|
    WO2011094890A1|2010-02-02|2011-08-11|Argusina Inc.|Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators|
    WO2011097525A1|2010-02-05|2011-08-11|Tragara Pharmaceuticals, Inc.|Solid state forms of macrocyclic kinase inhibitors|
    PL3202460T3|2010-02-11|2019-12-31|Celgene Corporation|Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same|
    US8999995B2|2010-03-02|2015-04-07|Axikin Pharmaceuticals, Inc.|Isotopically enriched arylsulfonamide CCR3 antagonists|
    WO2011112689A2|2010-03-11|2011-09-15|Ambit Biosciences Corp.|Saltz of an indazolylpyrrolotriazine|
    AU2011227232B2|2010-03-17|2015-07-09|Axikin Pharmaceuticals Inc.|Arylsulfonamide CCR3 antagonists|
    WO2011150201A2|2010-05-27|2011-12-01|Ambit Biosciences Corporation|Azolyl amide compounds and methods of use thereof|
    WO2011150198A1|2010-05-27|2011-12-01|Ambit Biosciences Corporation|Azolyl urea compounds and methods of use thereof|
    JP6019015B2|2010-06-01|2016-11-02|ビオトヘルイク， インコーポレイテッド|Method for treating hematological malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2-pyridone|
    CN103038216A|2010-06-01|2013-04-10|拜欧赛里克斯公司|Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases|
    CA2801778C|2010-06-07|2018-06-05|Novomedix, Llc|Furanyl compounds and the use thereof|
    EP2595615A1|2010-07-19|2013-05-29|Summa Health System|Vitamin c and chromium-free vitamin k, and compositions thereof for treating an nfkb-mediated condition or disease|
    EP2611793A1|2010-09-01|2013-07-10|Ambit Biosciences Corporation|2-cycloquinazoline derivatives and methods of use thereof|
    EP2611795B1|2010-09-01|2016-05-04|Ambit Biosciences Corporation|An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof|
    WO2012030944A2|2010-09-01|2012-03-08|Ambit Biosciences Corporation|Quinoline and isoquinoline compounds and methods of use thereof|
    JP5901634B2|2010-09-01|2016-04-13|アムビト ビオスシエンセス コルポラチオン|Quinazoline compounds and methods of use thereof|
    US20130225578A1|2010-09-01|2013-08-29|Ambit Biosciences Corporation|7-cyclylquinazoline derivatives and methods of use thereof|
    US20130303533A1|2010-09-01|2013-11-14|Ambit Biosciences Corporation|Azolopyridine and azolopyrimidine compounds and methods of use thereof|
    CA2809983A1|2010-09-01|2012-03-08|Ambit Biosciences Corporation|Hydrobromide salts of a pyrazolylaminoquinazoline|
    EP2611794A1|2010-09-01|2013-07-10|Ambit Biosciences Corporation|4-azolylaminoquinazoline derivatives and methods of use thereof|
    US20130317045A1|2010-09-01|2013-11-28|Ambit Biosciences Corporation|Thienopyridine and thienopyrimidine compounds and methods of use thereof|
    WO2012030918A1|2010-09-01|2012-03-08|Ambit Biosciences Corporation|Adenosine a3 receptor modulating compounds and methods of use thereof|
    WO2012044641A1|2010-09-29|2012-04-05|Pathway Therapeutics Inc.|1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy|
    US20120088769A1|2010-10-11|2012-04-12|Axikin Pharmaceuticals, Inc.|Salts of arylsulfonamide ccr3 antagonists|
    CN103298474B|2010-11-10|2016-06-29|无限药品股份有限公司|Heterocyclic compound and application thereof|
    US20140079686A1|2010-12-06|2014-03-20|Shikha P. Barman|Methods For Treating Baldness And Promoting Hair Growth|
    WO2012080050A1|2010-12-14|2012-06-21|F. Hoffmann-La Roche Ag|Solid forms of a phenoxybenzenesulfonyl compound|
    AU2012205669B2|2011-01-10|2015-08-20|Infinity Pharmaceuticals Inc.|Processes for preparing isoquinolinones and solid forms of isoquinolinones|
    EP2670396A1|2011-01-31|2013-12-11|Celgene Corporation|Pharmaceutical compositions of cytidine analogs and methods of use thereof|
    AR085352A1|2011-02-10|2013-09-25|Idenix Pharmaceuticals Inc|MACROCICLIC INHIBITORS OF SERINA PROTEASA, ITS PHARMACEUTICAL COMPOSITIONS AND ITS USE TO TREAT HCV INFECTIONS|
    AR085651A1|2011-03-11|2013-10-16|Celgene Corp|METHODS TO TREAT CANCER USING 3--PIPERIDIN-2,6-DIONA|
    CA2831590A1|2011-03-28|2012-10-04|Mei Pharma, Inc.| pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases|
    BR112013024907A2|2011-03-28|2016-12-20|Mei Pharma Inc|compound, pharmaceutical composition, method for treating, preventing or attenuating one or more symptoms of a pi3k-mediated disorder, disease or condition in a subject, method for modulating pi3k enzymatic activity|
    WO2012135166A1|2011-03-28|2012-10-04|Pathway Therapeutics Inc.| pyrimidynyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases|
    JP2014514295A|2011-03-31|2014-06-19|アイディニックスファーマシューティカルズインコーポレイテッド|Compounds and pharmaceutical compositions for the treatment of viral infections|
    US20120252721A1|2011-03-31|2012-10-04|Idenix Pharmaceuticals, Inc.|Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor|
    US8604035B2|2011-06-23|2013-12-10|Map Pharmaceuticals, Inc.|Fluoroergoline analogs|
    WO2013012915A1|2011-07-19|2013-01-24|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|
    CA2842190A1|2011-07-19|2013-01-24|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|
    AU2012302197B2|2011-08-29|2016-01-07|Infinity Pharmaceuticals Inc.|Heterocyclic compounds and uses thereof|
    WO2013039920A1|2011-09-12|2013-03-21|Idenix Pharmaceuticals, Inc.|Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections|
    CN103906759A|2011-09-12|2014-07-02|埃迪尼克斯医药公司|Compounds and pharmaceutical compositions for the treatment of viral infections|
    US9630979B2|2011-09-29|2017-04-25|Infinity Pharmaceuticals, Inc.|Inhibitors of monoacylglycerol lipase and methods of their use|
    US8507460B2|2011-10-14|2013-08-13|Idenix Pharmaceuticals, Inc.|Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections|
    MX368081B|2011-10-14|2019-09-19|Ambit Biosciences Corp|Heterocyclic compounds and use thereof as modulators of type iii receptor tyrosine kinases.|
    AU2012355982A1|2011-12-19|2014-07-10|Map Pharmaceuticals, Inc.|Novel iso-ergoline derivatives|
    EP2793583A4|2011-12-21|2015-08-12|Map Pharmaceuticals Inc|Novel neuromodulatory compounds|
    WO2013130600A1|2012-02-29|2013-09-06|Ambit Biosciences Corporation|Solid forms comprising optically active pyrazolylaminoquinazoline, compositions thereof, and uses therewith|
    WO2013138617A1|2012-03-16|2013-09-19|Axikin Pharmaceuticals, Inc.|3,5-diaminopyrazole kinase inhibitors|
    US8940742B2|2012-04-10|2015-01-27|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|
    WO2013177219A1|2012-05-22|2013-11-28|Idenix Pharmaceuticals, Inc.|D-amino acid compounds for liver disease|
    WO2013177188A1|2012-05-22|2013-11-28|Idenix Pharmaceuticals, Inc.|3',5'-cyclic phosphoramidate prodrugs for hcv infection|
    US9296778B2|2012-05-22|2016-03-29|Idenix Pharmaceuticals, Inc.|3′,5′-cyclic phosphate prodrugs for HCV infection|
    US9012640B2|2012-06-22|2015-04-21|Map Pharmaceuticals, Inc.|Cabergoline derivatives|
    IN2015DN00885A|2012-08-09|2015-06-12|Celgene Corp|
    NZ628077A|2012-08-09|2017-04-28|Celgene Corp|Treatment of immune-related and inflammatory diseases|
    CA2922849A1|2012-08-31|2014-03-06|Ixchel Pharma, Llc|Agents useful for treating obesity, diabetes and related disorders|
    BR112015004959A2|2012-09-07|2017-07-04|Axikin Pharmaceuticals Inc|isotopically enriched compound, pharmaceutical composition, method for treating, preventing or alleviating one or more symptoms of a basal, mast cell-related or mast cell-related eosinophil-related ccr3-related disease, disorder or condition in a subject, method for treat, prevent or alleviate one or more symptoms of an inflammatory disease in a subject and method for modulating ccr3 activity.|
    WO2014055647A1|2012-10-03|2014-04-10|Mei Pharma, Inc.| pyrimidines and triazines, pharmaceutical compositions thereof, and their use for treating proliferative diseases|
    AP2015008384A0|2012-10-08|2015-04-30|Univ Montpellier Ct Nat De La Rech Scient|2'-Chloro nucleoside analogs for hcv infection|
    WO2014063019A1|2012-10-19|2014-04-24|Idenix Pharmaceuticals, Inc.|Dinucleotide compounds for hcv infection|
    EP2909222B1|2012-10-22|2021-05-26|Idenix Pharmaceuticals LLC|2',4'-bridged nucleosides for hcv infection|
    MX2015005536A|2012-11-01|2015-10-29|Infinity Pharmaceuticals Inc|Treatment of cancers using pi3 kinase isoform modulators.|
    KR20160013204A|2013-05-30|2016-02-03|인피니티 파마슈티칼스, 인코포레이티드|Treatment of cancers using pi3 kinase isoform modulators|
    CA2890177A1|2012-11-08|2014-05-15|Summa Health System|Vitamin c, vitamin k, a polyphenol, and combinations thereof for wound healing|
    US20140140951A1|2012-11-14|2014-05-22|Idenix Pharmaceuticals, Inc.|D-Alanine Ester of Rp-Nucleoside Analog|
    WO2014078436A1|2012-11-14|2014-05-22|Idenix Pharmaceuticals, Inc.|D-alanine ester of sp-nucleoside analog|
    CN104955801B|2012-11-30|2017-10-31|诺沃梅迪科斯有限公司|Substituted diaryl sulfonamide and application thereof|
    US9211300B2|2012-12-19|2015-12-15|Idenix Pharmaceuticals Llc|4′-fluoro nucleosides for the treatment of HCV|
    SG11201504931SA|2012-12-21|2015-07-30|Map Pharmaceuticals Inc|Novel methysergide derivatives|
    NZ630746A|2013-01-11|2017-02-24|Summa Health System|Vitamins c and k for treating polycystic diseases|
    US9339541B2|2013-03-04|2016-05-17|Merck Sharp & Dohme Corp.|Thiophosphate nucleosides for the treatment of HCV|
    EP2970358B1|2013-03-04|2021-06-30|Idenix Pharmaceuticals LLC|3'-deoxy nucleosides for the treatment of hcv|
    WO2014151386A1|2013-03-15|2014-09-25|Infinity Pharmaceuticals, Inc.|Salts and solid forms of isoquinolinones and composition comprising and methods of using the same|
    US9187515B2|2013-04-01|2015-11-17|Idenix Pharmaceuticals Llc|2′,4′-fluoro nucleosides for the treatment of HCV|
    US10005779B2|2013-06-05|2018-06-26|Idenix Pharmaceuticals Llc|1′,4′-thio nucleosides for the treatment of HCV|
    WO2015017713A1|2013-08-01|2015-02-05|Idenix Pharmaceuticals, Inc.|D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease|
    RU2016111675A|2013-08-30|2017-10-04|Эмбит Байосайенсиз Корпорейшн|COMPOUNDS OF BIARILACETAMIDE AND METHODS OF USE|
    NZ631142A|2013-09-18|2016-03-31|Axikin Pharmaceuticals Inc|Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors|
    EP3046924A1|2013-09-20|2016-07-27|IDENIX Pharmaceuticals, Inc.|Hepatitis c virus inhibitors|
    US9700549B2|2013-10-03|2017-07-11|David Wise|Compositions and methods for treating pelvic pain and other conditions|
    PE20160685A1|2013-10-04|2016-07-23|Infinity Pharmaceuticals Inc|HETEROCYCLIC COMPOUNDS AND USES OF THEM|
    US9751888B2|2013-10-04|2017-09-05|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|
    WO2015061204A1|2013-10-21|2015-04-30|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|
    WO2015061683A1|2013-10-25|2015-04-30|Idenix Pharmaceuticals, Inc.|D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv|
    US20160271162A1|2013-11-01|2016-09-22|Idenix Pharmacueticals, Llc|D-alanine phosphoramide pronucleotides of 2'-methyl 2'-fluro guanosine nucleoside compounds for the treatment of hcv|
    BR112016011949A8|2013-11-27|2020-04-28|Idenix Pharmaceuticals Llc|compound, pharmaceutical composition, and use thereof ”|
    US20170198005A1|2013-11-27|2017-07-13|Idenix Pharmaceuticals Llc|2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection|
    WO2015095419A1|2013-12-18|2015-06-25|Idenix Pharmaceuticals, Inc.|4'-or nucleosides for the treatment of hcv|
    CN103746201B|2013-12-18|2016-04-20|宁波意欧迅网络通信有限公司|High-frequency data plug and electrical harnesses cable|
    WO2015134560A1|2014-03-05|2015-09-11|Idenix Pharmaceuticals, Inc.|Solid forms of a flaviviridae virus inhibitor compound and salts thereof|
    CA2943075A1|2014-03-19|2015-09-24|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders|
    WO2015143161A1|2014-03-20|2015-09-24|Capella Therapeutics, Inc.|Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer|
    EP3922630A4|2014-03-20|2021-12-15|Capella Therapeutics Inc|Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer|
    AU2015243437B2|2014-04-09|2019-08-29|Siteone Therapeutics, Inc.|10',11'-modified saxitoxins useful for the treatment of pain|
    WO2015161137A1|2014-04-16|2015-10-22|Idenix Pharmaceuticals, Inc.|3'-substituted methyl or alkynyl nucleosides for the treatment of hcv|
    WO2015168079A1|2014-04-29|2015-11-05|Infinity Pharmaceuticals, Inc.|Pyrimidine or pyridine derivatives useful as pi3k inhibitors|
    MX2016014731A|2014-05-12|2017-05-04|Conatus Pharmaceuticals Inc|Treatment of the complications of chronic liver disease with caspase inhibitors.|
    JP2017516779A|2014-05-28|2017-06-22|アイデニクス・ファーマシューティカルズ・エルエルシー|Nucleoside derivatives for cancer treatment|
    US9527815B2|2014-06-18|2016-12-27|Biotheryx, Inc.|Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases|
    AU2015277786B2|2014-06-19|2019-04-18|Takeda Pharmaceutical Company Limited|Heteroaryl compounds for kinase inhibition|
    US9499514B2|2014-07-11|2016-11-22|Celgene Corporation|Antiproliferative compounds and methods of use thereof|
    EP3191100A4|2014-09-12|2018-05-30|Tobira Therapeutics, Inc.|Cenicriviroc combination therapy for the treatment of fibrosis|
    US9708348B2|2014-10-03|2017-07-18|Infinity Pharmaceuticals, Inc.|Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof|
    CN111825717A|2014-10-21|2020-10-27|阿瑞雅德制药公司|Crystalline forms of 5-chloro-N4- [2-phenyl ] -N2- { 2-methoxy-4- [4-piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine|
    EP3209658A1|2014-10-24|2017-08-30|Biogen MA Inc.|Diterpenoid derivatives and methods of use thereof|
    ES2805528T3|2014-12-23|2021-02-12|Sma Therapeutics Inc|3,5-diaminopyrazole kinase inhibitors|
    EP3253753A4|2015-01-20|2018-06-27|Xoc Pharmaceuticals, Inc|Ergoline compounds and uses thereof|
    MX2017009406A|2015-01-20|2018-01-18|Xoc Pharmaceuticals Inc|Isoergoline compounds and uses thereof.|
    EP3303361A1|2015-05-27|2018-04-11|Idenix Pharmaceuticals LLC|Nucleotides for the treatment of cancer|
    KR20180015260A|2015-06-23|2018-02-12|뉴로크린 바이오사이언시즈 인코퍼레이티드|VMAT2 inhibitors for the treatment of neurological diseases or disorders|
    RS59158B9|2015-08-17|2020-09-30|Kura Oncology Inc|Methods of treating cancer patients with farnesyl transferase inhibitors|
    US10112953B2|2015-09-30|2018-10-30|Siteone Therapeutics, Inc.|11,13-modified saxitoxins for the treatment of pain|
    EP3368534B1|2015-10-30|2021-01-27|Neurocrine Biosciences, Inc.|Valbenazine ditosylate and polymorphs thereof|
    WO2017079566A1|2015-11-05|2017-05-11|Conatus Pharmaceuticals, Inc.|Caspase inhibitors for use in the treatment of liver cancer|
    US10112924B2|2015-12-02|2018-10-30|Astraea Therapeutics, Inc.|Piperdinyl nociceptin receptor compounds|
    CN108925135A|2015-12-23|2018-11-30|纽罗克里生物科学有限公司|Prepare - -3- isobutyl group -9,10- dimethoxy -2,3,4,6,7,11b- hexahydro -1H- pyrido [2,1-a] isoquinolin-2-yl 2- amino -3 Methylbutanoic acid ester twosynthetic method|
    AU2016381974A1|2015-12-31|2018-07-12|Conatus Pharmaceuticals Inc.|Methods of using caspase inhibitors in treatment of liver disease|
    KR20180095094A|2016-01-08|2018-08-24|셀진 코포레이션|The use of biomarkers as predictors of clinical susceptibility to treatment methods and therapies for cancer|
    TWI733734B|2016-01-08|2021-07-21|美商西建公司|Solid forms of 2--n--1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses|
    CN108430473B|2016-01-08|2021-08-31|细胞基因公司|Antiproliferative compounds and pharmaceutical compositions and uses thereof|
    WO2017161116A1|2016-03-17|2017-09-21|Infinity Pharmaceuticals, Inc.|Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors|
    WO2017180589A1|2016-04-11|2017-10-19|Auspex Pharmaceuticals, Inc.|Deuterated ketamine derivatives|
    US10047077B2|2016-04-13|2018-08-14|Skyline Antiinfectives, Inc.|Deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams|
    WO2017184968A1|2016-04-22|2017-10-26|Kura Oncology, Inc.|Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors|
    CN109476635B|2016-04-29|2021-07-13|Fgh生物科技公司|Disubstituted pyrazoles for treatment of diseases|
    CN109476600A|2016-05-16|2019-03-15|拜欧赛里克斯公司|The therapeutical uses of pyrithione, its pharmaceutical composition and its disease for treating proliferative, inflammatory, neurodegeneration or immune-mediation|
    US10919914B2|2016-06-08|2021-02-16|Infinity Pharmaceuticals, Inc.|Heterocyclic compounds and uses thereof|
    US20190194167A1|2016-09-07|2019-06-27|Fgh Biotech, Inc.|Di-substituted pyrazole compounds for the treatment of diseases|
    MX2019003134A|2016-09-19|2019-08-29|Mei Pharma Inc|Combination therapy.|
    HUE053927T2|2016-11-03|2021-07-28|Kura Oncology Inc|Farnesyltransferase inhibitors for use in treating cancer|
    US10988442B2|2016-11-09|2021-04-27|Novomedix, Llc|Nitrite salts of 1,1-dimethylbiguanide, pharmaceutical compositions, and methods of use|
    US10106521B2|2016-11-09|2018-10-23|Phloronol, Inc.|Eckol derivatives, methods of synthesis and uses thereof|
    EP3548007A4|2016-12-01|2020-08-12|Ignyta, Inc.|Methods for the treatment of cancer|
    EP3548027A1|2016-12-02|2019-10-09|Neurocrine Biosciences, Inc.|Use of valbenazine for treating schizophrenia or schizoaffective disorder|
    US10993941B2|2017-10-10|2021-05-04|Neurocrine Biosciences, Inc.|Methods for the administration of certain VMAT2 inhibitors|
    AU2017395701A1|2017-01-27|2020-06-18|Neurocrine Biosciences, Inc.|Methods for the administration of certain VMAT2 inhibitors|
    US10137121B2|2017-02-21|2018-11-27|Kura Oncology, Inc.|Methods of treating cancer with farnesyltransferase inhibitors|
    EP3542800A1|2017-02-21|2019-09-25|Kura Oncology, Inc.|Methods of treating cancer with farnesyltransferase inhibitors|
    WO2018164996A1|2017-03-06|2018-09-13|Neurocrine Biosciences, Inc.|Dosing regimen for valbenazine|
    EP3601326A4|2017-03-20|2020-12-16|The Broad Institute, Inc.|Compounds and methods for regulating insulin secretion|
    EP3601290B1|2017-03-29|2021-11-24|Siteone Therapeutics, Inc.|11,13-modified saxitoxins for the treatment of pain|
    KR20200012833A|2017-03-29|2020-02-05|사이트원 테라퓨틱스, 인코포레이티드|11,13-modified saxitoxin for pain treatment|
    WO2018200605A1|2017-04-26|2018-11-01|Neurocrine Biosciences, Inc.|Use of valbenazine for treating levodopa-induced dyskinesia|
    US10085999B1|2017-05-10|2018-10-02|Arixa Pharmaceuticals, Inc.|Beta-lactamase inhibitors and uses thereof|
    WO2018213810A1|2017-05-19|2018-11-22|Nflection Therapeutics, Inc.|Pyrrolopyridine-aniline compounds for treatment of dermal disorders|
    CN111093658A|2017-05-19|2020-05-01|恩福莱克逊治疗有限公司|Fused heteroaromatic-aniline compounds for the treatment of skin diseases|
    AU2018275873A1|2017-06-01|2019-12-19|Xoc Pharmaceuticals, Inc.|Ergoline derivatives for use in medicine|
    US10806730B2|2017-08-07|2020-10-20|Kura Oncology, Inc.|Methods of treating cancer with farnesyltransferase inhibitors|
    JP2020534305A|2017-09-21|2020-11-26|ニューロクライン バイオサイエンシーズ，インコーポレイテッド|High-dose valbenazine formulations and related compositions, methods and kits|
    WO2019074492A1|2017-10-10|2019-04-18|Obrien Christopher F|Methods for the administration of certain vmat2 inhibitors|
    WO2019113269A1|2017-12-08|2019-06-13|Kura Oncology, Inc.|Methods of treating cancer patients with farnesyltransferase inhibitors|
    US20210052529A1|2018-01-10|2021-02-25|Cura Therapeutics, Llc|Pharmaceutical compositions comprising dicarboxylic acids and their therapeutic applications|
    US20210052525A1|2018-01-10|2021-02-25|Cura Therapeutics, Llc|Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications|
    MA52896A|2018-06-14|2021-04-21|Neurocrine Biosciences Inc|VMAT2 INHIBITOR COMPOUNDS, ASSOCIATED COMPOSITIONS AND METHODS|
    CA3105352A1|2018-06-29|2020-01-02|Histogen, Inc.|-3--3-oxopiperazin-1-yl)acetamido)-4-oxo-5-pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases|
    TW202021585A|2018-08-15|2020-06-16|美商紐羅克里生物科學有限公司|Methods for the administration of certain vmat2 inhibitors|
    US20220009938A1|2018-10-03|2022-01-13|Siteone Therapeutics, Inc.|11,13-modified saxitoxins for the treatment of pain|
    JP2022506463A|2018-11-01|2022-01-17|クラ オンコロジー， インコーポレイテッド|How to Treat Cancer with Farnesyltransferase Inhibitors|
    JP2022515739A|2018-12-19|2022-02-22|シャイ・セラピューティクス・エルエルシー|Compounds that interact with the RAS superfamily for the treatment of cancer, inflammatory disease, RAS disease, and fibrous disease|
    WO2020132700A1|2018-12-21|2020-06-25|Fgh Biotech Inc.|Methods of using inhibitors of srebp in combination with niclosamide and analogs thereof|
    EP3897638A1|2018-12-21|2021-10-27|Kura Oncology, Inc.|Therapies for squamous cell carcinomas|
    WO2020163554A1|2019-02-06|2020-08-13|Dice Alpha, Inc.|Il-17a modulators and uses thereof|
    WO2021055376A1|2019-09-16|2021-03-25|Dice Alpha, Inc.|Il-17a modulators and uses thereof|
    WO2020180663A1|2019-03-01|2020-09-10|Kura Oncology, Inc.|Methods of treating cancer with farnesyltransferase inhibitors|
    TW202100506A|2019-03-07|2021-01-01|美商柯納特斯製藥公司|Caspase inhibitors and methods of use thereof|
    TW202108170A|2019-03-15|2021-03-01|美商庫拉腫瘤技術股份有限公司|Methods of treating cancer patients with farnesyltransferase inhibitors|
    KR20210144778A|2019-03-29|2021-11-30|쿠라 온콜로지, 인크.|Method of treatment of squamous cell carcinoma using farnesyltransferase inhibitor|
    WO2020205387A1|2019-04-01|2020-10-08|Kura Oncology, Inc.|Methods of treating cancer with farnesyltransferase inhibitors|
    WO2020223583A1|2019-05-02|2020-11-05|Kura Oncology, Inc.|Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors|
    CA3146157A1|2019-07-11|2021-01-14|Cura Therapeutics, Llc|Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications for the treatment of neurodegenerative diseases|
    CA3146159A1|2019-07-11|2021-01-14|Cura Therapeutics, Llc|Phenyl compounds and pharmaceutical compositions thereof, and their therapeutic applications|
    US10940141B1|2019-08-23|2021-03-09|Neurocrine Biosciences, Inc.|Methods for the administration of certain VMAT2 inhibitors|
    WO2021059023A1|2019-09-26|2021-04-01|Abionyx Pharma Sa|Compounds useful for treating liver diseases|
    WO2021242970A1|2020-05-29|2021-12-02|Boulder Bioscience Llc|Methods for improved endovascular thrombectomy using 3,3'-diindolylmethane|
    WO2021257828A1|2020-06-18|2021-12-23|Shy Therapeutics, Llc|Substituted thienopyrimidines that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease|
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    US65771384A| true| 1984-10-04|1984-10-04|LV930221A| LV5186A3|1984-10-04|1993-04-02|Composition for stimulating bovine lactation and increasing the use of bundles for bovine use|
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