CN1074825A - The delayed release device that is used for transition metal/protein complexes - Google Patents
The delayed release device that is used for transition metal/protein complexes Download PDFInfo
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- CN1074825A CN1074825A CN 93100374 CN93100374A CN1074825A CN 1074825 A CN1074825 A CN 1074825A CN 93100374 CN93100374 CN 93100374 CN 93100374 A CN93100374 A CN 93100374A CN 1074825 A CN1074825 A CN 1074825A
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Abstract
本发明涉及用于缓释过渡金属-蛋白质络合物 的可植入缓释装置。该络合物与一种提高络合物在 生理pH下溶解度的物质相结合。还公开了一种改 进过渡金属-蛋白质络合物在生理pH下的溶解度的 方法，以及向靶动物释放过渡金属-蛋白质络合物的 方法。在一项优选的实施方案中，过渡金属是锌，蛋 白质是猪生长激素。The present invention relates to a transition metal-protein complex for slow release implantable sustained-release device. The complex and an enhanced complex in the Substances with solubility at physiological pH are combined. also disclosed a modified Study on Solubility of Transition Metal-Protein Complexes at Physiological pH method, and release of transition metal-protein complexes to target animals method. In a preferred embodiment, the transition metal is zinc, egg White matter is porcine growth hormone.
Description
The present invention relates to can be to the proteinic delayed release device of target animals release with transition metal complex in long-time.
Known have various types of delayed release devices can be used for administration, comprises protein.For example, United States Patent (USP) 4,522,625 relate to a kind of oral medication dispenser, and it comprises the wall that is made of semi-transparent material and enteral absorbing material, and this patent is quoted as a reference in this article.The enteral absorbing material comprises that isoelectric point, IP is lower than the aminoacid of pH7.Confirm that also aminoacid can be used as the excipient that control protein (comprising growth hormone) discharges.
Though these devices can use, existing people is reported in the proteinic burst size of some type and speed and the protein dissolubility aspect in vivo that discharges like this has problems.When protein is when existing with the complex form with transition metal, often undissolved transition metal-protein complex under physiological pH (7.4) for example, this class problem is especially serious.Transition metal can be used for reclaiming protein by precipitation from aqueous solution such as cell culture fluid.Transition metal and protein form insoluble complex, and this complex can be separated from solution by centrifugal or the sedimentation method.Therefore, problem is to make protein rework solution attitude in the aqueous physiological environment.
In addition, discharging proteinic mode from some device is initial " explosion type ", and then quantity reduces.A kind of delayed release device is preferably arranged, and it can discharge protein with improved constant speed, makes it still solvable after release.Have found that the problems referred to above are for the growth hormone especially severe.
Therefore, the purpose of this invention is to provide a kind of delayed release device, it discharges transition metal-protein complex with controlled and lasting speed, and protein wherein is still solvable after release.
The present invention relates to be used for the delayed release device of delivery of biologically active transition metal-protein complex and the method for taking this complex.This device can be implanted, and wherein comprises the transition metal-protein compositions that combines with the excipient that can produce slow releasing function.
Fig. 1 is the sketch map of an implant embodiment of the present invention.
Fig. 2 is the sketch map of another implant embodiment of the present invention.
The present invention relates to a kind of delayed release device, have bioactive transition metal-protein complex for after this device is implanted target animals, discharging. The transition metal solubilizer that the device of implanting includes transition metal-protein complex and the biology that makes up with it can tolerate, this composition is called later on " matrix ".
A kind of preferred protein that is used for the present invention is growth hormone. Here used " protein " word that comprises such as specified proteins such as growth hormone comprises the protein of natural, synthetic or recombinant forms. In addition, any other variant for example has the bioactive fragment of corresponding native protein, analog or other polypeptide, is all included. Therefore, any transition metal-protein complex can contain any in the above-mentioned variation of this protein. A kind of particularly preferred protein is pig growth hormone.
The transition metal that adopts among the present invention can be any suitable transition metal.These metals are that those skilled in the art understand, and comprise for example Zn, Mn and Cu.It is known reclaiming protein with these metals from aqueous solution.For example quote as a reference european patent application 0216485A1 referring to this paper.When using with pig growth hormone, a kind of particularly preferred transition metal is a zinc.
The application's remainder only for for the purpose of the example explanation, will adopt zinc-pig growth hormone (Zn-pST) as example.Should be clear, make example and do not mean that the extensive scope of application of the present invention is restricted to transition metal-protein complex with Zn-pST.
As what be described in more detail below, have found that aminoacid is the suitable solubilizing agent of transition metal.The combined dissolubility that improves Zn-pST of aminoacid and Zn-pST of the present invention, thus its release from device promoted.These aminoacid can be natural or synthetic aminoacid.If natural amino acid preferably contains basic side chain in the aminoacid.
By slow release in the device is to realize by a part with the diffusion barrier constituent apparatus, and the remainder of device can not be saturating to substrate, water and other excipient.The cross-sectional view of an embodiment of the present invention is shown in Fig. 1.In a kind of implanting device of being made by nontoxic safe material, the form of packing into is the Zn-pST substrate of pill 6,8 and 10.Should be understood that this is an exemplary that contains three pills.Other embodiment can contain the pill that desired any number contains Zn-pST substrate.The biological side 2 and 4 that can tolerate material can not be saturating for substrate, water or body fluid and other excipient.Here employed biology can tolerate a speech and be meant any material that can be implanted to safely in the biologic artifact.In this embodiment, the silicone rubber tube of an opening has constituted the suitable substance of making this device.Other suitable substance comprises various polymer well known by persons skilled in the art, for example wax or polyethylene.
As shown in Figure 1, implanting device has terminal 11 and 12.Preferably, an end 11 of device also can not be saturating for host material, prevents that host material from spilling.End at silicone rubber tube inserts a kind of effective means that one or more beades are realization this purpose.If wish to discharge more quickly, two ends can be saturating, but an end 12 of common just device constitutes diffusion barrier.In general, diffusion barrier can be made by leucine or microporous polyethylene (" MPPE ") disk.Preferred leucine barrier.These barriers are made with the simple pressed disc method that those skilled in the art understand easily.
The cross-sectional view of second embodiment of the present invention is shown in Fig. 2.Implanting device is equipped with Zn- pST substrate pill 6,8 and 10.Its side and an optional end 14 can not be saturating for substrate, water, body fluid and other excipient.Can not partly make thoroughly in this embodiment with wax.Suitable wax comprises animal wax, for example Cera Flava, lanoline, shellac wax and white beeswax; Vegetable wax, for example oil with hydrogenated soybean, cotmar, Brazil wax, candelilla wax, bayberry wax and sugarcane wax; And mineral wax, for example fossil waxes or ceresine (ceresine, ceresin(e)wax, montan wax) and pertroleum wax (paraffin, microwax, slack wax or crude scale); Or their compositions.The wax material that uses among the present invention is Cera Flava, vegetable wax, Brazil wax or their combination preferably.
As mentioned above, at least one end 12 of device constitutes diffusion barrier.
The Zn-pST that uses among the present invention can be the Zn-pST of any biologically active form.Here that employed term Zn-pST comprises is natural, synthetic, the zinc complex of reorganization or other form pig growth hormone.In addition, have the complex of the bioactive any variant of natural pig growth hormone, fragment, analog or other polypeptide, be also included within the term Zn-pST.For example, in △ 7-rpST will be included in, it was to lack 7 amino acid whose known pST reorganization variants at N-terminal, and it is open and claimed in all disclosed european patent applications 104,920 of genus Biogen.
Zn-pST preferably mixes with a kind of amino acid excipient.Here used " aminoacid " speech comprises natural and synthetic aminoacid.Zn-pST under physiological pH (7.4) aqueous solution such as body fluid in poor solubility.Therefore, these amino acid whose necessary characteristics are it has solubilising Zn-pST under physiological pH abilities,, need to produce the aminoacid of Zn-pST solubilization that is.Though do not think bound by theoryly, it is believed that the ionic aminoacid of chelated zinc is specially adapted to the present invention.Known Zn-pST is solvable in alkaline aqueous solution.Therefore, the natural amino acid that preferably has basic side chain.Particularly preferably be arginine.Arginine can use with free alkali form or with arginine monohydrochloride (AHCl) form.AHCl is effective especially aspect solubilising reorganization Zn-pST, assembles hardly.Should be understood that the introduction according to this description, those skilled in the art determine the proteinic best excipient-transition metal of any appointment-protein matrix easily.
In another particularly preferred embodiment, can make a kind of synthetic aminoacid, for example ethylenediaminetetraacetic acid (EDTA) mixes mutually with Zn-pST.Preferably use the EDTA trisodium salt.Table 1 explanation, the required EDTA of solubilising Zn-pST compares with natural basic amino acid and wants much less.Should be clear, can use other synthesizing amino acid in the present invention, as long as these aminoacid can solubilising Zn-pST under physiological pH.
In addition, disclosed in 568 as United States Patent (USP) 4,816, once used the stabilizing agent of sucrose as pST, this patent is quoted as a reference in this article.Preferably contain sucrose in the substrate of the present invention.
When using natural amino acid, find that preferably aminoacid or sucrose are excessive.The preferred proportion of Zn-pST and aminoacid and sucrose is from about 1: 3: 1 to about 1: 1: 3, and is preferred especially with 1: 3: 1.When using EDTA, can comprise the Zn-pST of larger amt in the device.Zn-pST can be from about 2: 1 to about 10: 1 with the ratio of EDTA.In the embodiment of using EDTA, preferably about by weight 6 parts to about 30 parts of the amount of sucrose.
Usually, each material that uses in the substrate was sieved to granularity earlier less than about 250 microns before mixing.Mixing can be a physical mixed, will do component and put into sterile vials in desired ratio and stir.The method of stirring is that those skilled in the art understand, and comprises using the vortex agitator.The suitable stirring time normally about 5 was by about 10 minutes.If desired, after about 3 minutes, can in prescription, add 1% magnesium stearate as the tablet lubricant.
Second kind of ideal preparation method comprises common lyophilization.In the method, the Zn-pST of institute's requested number is added in the aqueous solution of aequum aminoacid and sucrose.With the solution supersound process a few minutes that form, normally about 5 to 10 minutes.After 0.22 micron filter filtration, with the solution lyophilization.
The mixed-powder pelleting that arbitrary blend step is formed preferably.Suitable pelleting method is that those skilled in the art understand, and comprises using Stoke pellet press or one-shot head pellet press.The weight of pill and size can be controlled with these technology.Have been found that diameter has preferred release feature from about 3.0 to 4.0 millimeters pill.Particularly preferably be the about 4 millimeters pill of diameter.The length of pill can change, but is about 7 millimeters usually.
Just as understood by those skilled in the art, all material sterilization that importantly will in implant, use.The suitable sterile method is known, does not constitute a part of the present invention.
The above-mentioned pill of requisite number purpose is inserted in the delayed release device that is fit to the implantation target animals.This number partly depends on the quantity and the persistent period of the dosage that requires.In general, delayed release device is only bigger than the pill number that it will hold.The implantable device that any biology can tolerate all can use.But as noted above, for simplicity, silicone rubber tube is a preferable material.Particularly preferably be the about 4 millimeters silicone rubber tube of internal diameter.Preferably can continue some days implanting device of delivery of biologically active growth hormone.
The present invention also comprises the method for taking Zn-pST to target animals.As previously mentioned, the implanting device that will contain aequum Zn-pST is implanted in the target animals.Implanted prosthetics is that those skilled in the art understand, and any this class implanted prosthetics all is suitable for use among the present invention.Substrate is dissolved in target animals body fluid, and the growth hormone Zn-pST of biologically active is discharged in the animal body from implant.Rate of release is controlled by diffusion barrier.Growth hormone preferably discharges from device in some days time with the speed that continues, preferably at least about 14 days.
The invention still further relates to the method for a kind of Zn-pST of improvement release feature from implantable delayed release device.Make Zn-pST with can solubilising under physiological pH the material of Zn-pST mix, the mixture of aequum is packed in the delayed release device.Suitable material comprises natural amino acid and the salt thereof with basic side chain, for example arginine, histidine and AHCl.Preferably, natural amino acid is AHCl, and Zn-pST is the pST of reorganization.Zn-pST is mixed mutually with synthetic aminoacid (for example EDTA).
The present invention has done general introduction, and following specific embodiment is used as example explanation usefulness, never will think it is limitation of the present invention by mistake.
Embodiment 1: the preparation of implant
With married operation independently separately, each composition of quantity shown in the table 1 is mixed.Except as otherwise noted, reagent is all obtained by commercial source.Submitted to January 30 according to european patent application 0277043(1987) preparation Zn-pST, this application is quoted as a reference in this article.
Histidine and monosodium glutamate are sterilized through 0.2 micron Gelman Acrodiscs with 3.3% and 10% W/V aqueous solution form respectively, and lyophilization.Arginine and AHCl sterilized.Alanine and sucrose autoclaving 15 minutes and 40 ℃ of vacuum dryings (76 millimeters hydrargyrum) 36 hours.Arginine aquation to water content is 17%.Each composition was crossed 60 mesh sieves earlier before mixing.Each component is directly being removed weighing in the sterile vials of tare weight.Add pST earlier, add aminoacid then, at last with sucrose.
The prescription that table 1 is identified is formed
Group number code name substrate and composition (milligram)
1 ARG ZnpST/ arginine/sucrose
360/1080/360
2 HCL ZnpST/ arginine monohydrochloride/sucrose
360/1080/360
3 ALA ZnpST/ alanine/sucrose
360/1080/360
4 HIS ZnpST/ histidine/sucrose
360/1080/360
5 MSG ZnpST/L-glutaminate sodium salt/sucrose
360/1080/360
6 SUHC-A ZnpST/ sucrose
383/1532
7 EDTA ZnpST/EDTA/ salt/sucrose
400/50/50/1300
With bottle sealing, be placed on and be located at 10 grades on the Vortex-Genie blender and stir, rotate by hand simultaneously.After 3 minutes, add 1% magnesium stearate that autoclaving and vacuum drying are crossed, continue again to stir 2 minutes.The powder of gained crossed be sieved to granularity,, obtain heavy 101 milligrams, 4.0 millimeters of diameters, long 7 millimeters pill with being furnished with one-shot head tablet machine (the Key International company) pelleting of plane punch less than 250 microns.Before pelleting, all contact surfaces were all sterilized with 70% ethanol wiping, flame heat and ultraviolet irradiation in 15 minutes.After each tabletting, that instrument is lubricated with aseptic magnesium stearate.In the silicone rubber tube of the one section sterilization that cuts in advance, insert the pill that three balls weigh 101 milligrams.One end of pipe is lived with two 4 millimeters solid glass bead seal, and bead is in advance 160 ℃ of sterilizations in xeothermic 6 hours.The other end of pipe is loaded onto one 25 milligrams the disk made from the L-leucine (4 millimeters of diameters).Each implant contains 60 milligrams of pST.
Embodiment 2: release in vitro research
The implant of embodiment 1 is placed in 20 * 125 millimeters the aseptic culture pipe, be equipped with in the pipe 8 milliliters of 10mM phosphate buffers (PBS, pH7.4).Add gentamycin sulfate (100ppm) to prevent germ contamination.Culture tube is bathed continuous oscillation under 5 grades of speed in (New Brunswick Scientific Co., Edison, NJ, G76 type) in the Gyrotory vibration.Day by day change solution, use the ultraviolet spectral analysis protein concentration.Use the light absorption at Perkin-Elmer Lambda-7 spectrophotometric determination 276nm place.Measure the light absorption at 320nm place, from the absorption value of 276nm, deduct this value and carry out the random scatter correction.Adopt 0.73 milligram for Zn-pST solution
-1The milliliter centimetre
-1Extinction coefficient.
14 days inner growth hormone (ST) burst size increase according to the order of MSG＜SUC＜His＜Ala＜Arg＜AHCl or EDTA.Therefore, AHCl or EDTA discharge the ST of maximum.Equal the carrying out and descend of rate of release in all cases with research.Each group discharges data rows at table 2.Arg, EDTA and AHCl discharge maximum pST, with gel permeation chromatography (GPC) they are done further test.GPC is a kind of known technology, does not constitute a part of the present invention.The GPC test shows that AHCl only discharges monomer pST, and Arg substrate then forms a large amount of dimers.The GPC data rows is in table 3.
2(is continuous for table) the 7th group release data
Accumulated time discharges milligram number/sky cumulative release %
(natural law) meansigma methods SD meansigma methods SD
0.4 23.2 4.1 9.8 1.7
1.0 11.6 1.1 18.8 2.3
2.0 7.8 0.9 28.1 3.2
3.0 5.9 0.4 35.2 3.6
4.0 4.5 0.3 46.0 4.1
5.0 4.4 0.5 46.0 4.1
6.0 3.6 0.3 50.3 4.2
7.0 3.2 0.2 54.1 4.0
8.0 3.1 0.3 58.0 4.3
9.0 2.2 0.3 60.6 4.6
10.0 1.8 0.3 62.7 4.9
11.0 1.5 0.2 64.5 5.2
12.0 1.3 0.2 66.1 5.5
13.0 1.1 0.2 67.4 5.7
14.0 0.9 0.2 68.5 5.8
Annotate: the SD=standard deviation
The GPC data of the ST solution of table 3. the 1st day and recovery in the 6th day
Monomer: dimer: aggregation area %
Group number the 1st day the 6th day
#
1 67:33:0 54:45:0
2 100:0:0 100:0:0
3 100:0:0 100:0:0
4 100:0:0 100:0:0
5 100:0:0 100:0:0
6 100:0:0 100:0:0
7 100:0:0 100:0:0
Annotate: the meansigma methods of two samples of *
Claims (32)
1, a kind of proteinic implantable delayed release device of delivery of biologically active that is used for, this device comprises a kind of substrate, and this substrate comprises by the complex of above-mentioned biological activity protein and transition metal and a kind of mixture that can the material of the described complex of solubilising constitutes under physiology PH.
2, the device of claim 1, wherein said protein comprises growth hormone.
3, the device of claim 2, wherein said transition metal comprises zinc.
4, the device of claim 3, wherein said growth hormone comprises pig growth hormone.
5, the device of claim 1, wherein said substrate also comprises sucrose.
6, the device of claim 5, wherein said material comprise natural amino acid, synthesizing amino acid or their salt that contains the basic side chain group.
7, the device of claim 6, wherein said natural amino acid comprises arginine, histidine or arginine monohydrochloride.
8, the device of claim 7, wherein said natural amino acid comprises arginine monohydrochloride.
9, the device of claim 6, wherein said synthesizing amino acid comprises EDTA.
10, the device of claim 8, the weight ratio of wherein said growth hormone, arginine monohydrochloride and sucrose is about 1: 3: 1 to 1: 1: 3.
11, the device of claim 9, the weight ratio of wherein said growth hormone, EDTA and sucrose is about 2: 1: 30 to 10: 1: 6.
12, the device of claim 6, this device contains the zinc-pig growth hormone of capacity, so that the zinc-pig growth hormone slow release that makes biologically active was at least about 14 days.
13, the device of claim 1, its mesostroma are included in the container that biology can tolerate, and this container comprises one section silicone rubber tube or a wax cover.
14, the device of claim 13, this device also comprise a diffusion barrier, and this barrier comprises at least one leucine or microporous polyethylene disk, and described disk is positioned at the one or both ends of described container.
15, the device of claim 5, the form of wherein said zinc, pig growth hormone substrate is one or more pills.
16, the device of claim 15, wherein the diameter of each described pill is about 3 millimeters to about 4 millimeters.
17, the device of claim 13, wherein said wax cover is selected from various waxes, comprises animal wax, as Cera Flava, lanoline, shellac wax or white beeswax; Vegetable wax is as oil with hydrogenated soybean, cotmar, Brazil wax, candelilla wax, bayberry wax or sugarcane wax; Mineral wax as fossil waxes or ceresine, comprises ceresine, ceresin(e)wax or montan wax; Or pertroleum wax, comprise paraffin, microwax, slack wax or crude scale; Or their compositions.
18, a kind of implantable device that is used for slow releasing bioactivity zinc-pig growth hormone, this device comprises
A) one section silicone rubber tube, it has at least one bead to be inserted in an end of pipe, and the internal diameter of wherein said pipe equates substantially with the diameter of described bead, so that make bead seal the end of pipe basically;
B) a kind of zinc-pig growth hormone substrate, wherein contain zinc-pig growth hormone, can chelated zinc aminoacid and the mixture of sucrose, its weight ratio is about 1: 3: 1 to about 1: 1: 3, described substrate forms one or more pills, and described pill is inserted into presses close to described bead in the described pipe;
C) one is inserted in the diffusion barrier that described Guan Zhongyu contains an end opposite end of described bead, and described diffusion barrier comprises a leucine disk.
19, the device of claim 18, wherein said aminoacid comprises arginine monohydrochloride.
20, the device of claim 18, wherein said aminoacid comprises EDTA, described weight ratio is about 8: 1: 16.
21, a kind of method of improving zinc in the implantable delayed release device-pig growth hormone release feature, this method comprises, described zinc-pig growth hormone can be mixed at the aminoacid of solubilising zinc-pig growth hormone under the physiological pH with a kind of, in the described delayed release device of then described mixture being packed into.
22, the method for claim 21, wherein said zinc-pig growth hormone comprises RPST.
23, the method for claim 21, wherein said aminoacid comprises arginine monohydrochloride.
24, the method for claim 21, wherein said aminoacid comprises EDTA.
25, a kind of in target animals the method for slow releasing bioactivity zinc-pig growth hormone, this method comprises, be implanted into the delayed release device that a biology can tolerate at described target animals body, this device comprises the substrate that contains a kind of mixture, contain zinc-pig growth hormone in the mixture and can solubilising under physiological pH the aminoacid of described zinc-pig growth hormone, described device provides limited Permeability to described substrate.
26, the method for claim 25, wherein said aminoacid comprises arginine monohydrochloride or EDTA, described device comprises one section silicone rubber tube, the end sealing of pipe, the other end has a diffusion barrier.
27, a kind of method that makes bioactive zinc-pig growth hormone at the target animals sustained release profile in vivo test, this method comprise, implant the implantable device of claim 18 in described animal.
28, a kind ofly promote the method for the zinc-pig growth hormone of increment to the target animals slow release, this method comprises, implants the implantable device of claim 22 in described animal.
29, a kind of method to target animals slow release zinc-pig growth hormone, this method comprise, implant the implantable device of claim 23 in described animal.
30, a kind of method to target animals slow release zinc-pig growth hormone, this method comprises, in described animal, implant an implantable delayed release device, this device comprises a kind of substrate that is made of the mixture of zinc-pig growth hormone, arginine monohydrochloride and sucrose, its weight ratio is about 1: 3: 1 to about 1: 1: 3, or a kind of substrate that constitutes by zinc-pig growth hormone, EDTA and sucrose, its weight ratio is about 8: 1: 16, this substrate be in one to described substrate basically can not be saturating container in, described container also contains a diffusion barrier.
31, the method for claim 30, wherein said container comprises wax, described diffusion barrier comprises the leucine disk.
32, the method for claim 30, wherein said container comprise one section silicone rubber tube, and it has at least a bead to seal an end of described pipe basically, and the other end of described pipe has a diffusion barrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82017692A | 1992-01-13 | 1992-01-13 | |
| US820,176 | 1992-01-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1074825A true CN1074825A (en) | 1993-08-04 |
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ID=25230092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93100374 Pending CN1074825A (en) | 1992-01-13 | 1993-01-12 | The delayed release device that is used for transition metal/protein complexes |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1074825A (en) |
| AU (1) | AU3582893A (en) |
| MX (1) | MX9300139A (en) |
| WO (1) | WO1993013792A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0946169B1 (en) * | 1996-12-20 | 2003-02-26 | Takeda Chemical Industries, Ltd. | Method of producing a sustained-release preparation |
| KR20080011353A (en) | 2000-02-24 | 2008-02-01 | 몬산토 테크놀로지 엘엘씨 | Non-aqueous injections for the sustained release of somatotropin |
| WO2002000261A2 (en) | 2000-06-26 | 2002-01-03 | Monsanto Technology Llc | Surfactant-containing formulations for extended release of somatotropin |
| US6664234B1 (en) | 2000-06-30 | 2003-12-16 | Monsanto Technology Llc | Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin |
| MXPA03001092A (en) | 2000-08-07 | 2003-09-25 | Nektar Therapeutics Al Corp | Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation. |
| MX2012006980A (en) | 2009-12-21 | 2012-07-17 | Ambrx Inc | Modified porcine somatotropin polypeptides and their uses. |
| EP2805964A1 (en) | 2009-12-21 | 2014-11-26 | Ambrx, Inc. | Modified bovine somatotropin polypeptides and their uses |
| ITBO20120368A1 (en) | 2012-07-06 | 2014-01-07 | Alfa Wassermann Spa | COMPOSITIONS INCLUDING RIFAXIMINA AND AMINO ACIDS, RIFAXIMINE CRYSTALS DERIVING FROM SUCH COMPOSITIONS AND THEIR USE. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5008112A (en) * | 1985-12-16 | 1991-04-16 | International Minerals & Chem. Corporation | Device for the extended delivery of diffusible agents |
| US4765980A (en) * | 1986-04-28 | 1988-08-23 | International Minerals & Chemical Corp. | Stabilized porcine growth hormone |
| US4917685A (en) * | 1986-05-16 | 1990-04-17 | International Minerals & Chem. Corp. | Delivery device for the administration of stabilized growth promoting hormones |
| DE68924808D1 (en) * | 1988-07-26 | 1995-12-21 | Univ Rutgers | Devices and methods for promoting growth in fried poultry. |
| JPH04504122A (en) * | 1989-03-17 | 1992-07-23 | ピットマン―ムーア・インコーポレイテッド | Controlled release devices for macromolecular proteins |
| WO1991005548A1 (en) * | 1989-10-10 | 1991-05-02 | Pitman-Moore, Inc. | Sustained release composition for macromolecular proteins |
-
1993
- 1993-01-08 WO PCT/US1993/000274 patent/WO1993013792A1/en active Application Filing
- 1993-01-08 AU AU35828/93A patent/AU3582893A/en not_active Abandoned
- 1993-01-12 CN CN 93100374 patent/CN1074825A/en active Pending
- 1993-01-12 MX MX9300139A patent/MX9300139A/en unknown
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| Publication number | Publication date |
|---|---|
| AU3582893A (en) | 1993-08-03 |
| MX9300139A (en) | 1994-07-29 |
| WO1993013792A1 (en) | 1993-07-22 |
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