CN1434703A - Delayed release compositions and combinations - Google Patents
Delayed release compositions and combinations Download PDFInfo
- Publication number
- CN1434703A CN1434703A CN00819010.0A CN00819010A CN1434703A CN 1434703 A CN1434703 A CN 1434703A CN 00819010 A CN00819010 A CN 00819010A CN 1434703 A CN1434703 A CN 1434703A
- Authority
- CN
- China
- Prior art keywords
- biological activity
- activity protein
- combination
- fibrinogen
- rpst
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Detergent Compositions (AREA)
Abstract
The present invention relates to a delayed release composition of a physiologically active protein, which comprises an effective amount of the physiologically active protein, and fibrin glue in an amount effective to delay the release of the physiolgoically active protein. The present invention further relates to a delayed release combination of a physiologically active protein, which comprises an effective amount of the physiologically active protein, and fibrinogen and thrombin in an amount effective to delay the release of the physiologically active protein.
Description
Invention field
The present invention relates to a kind of delayed release compositions and combination of biological activity protein, the biological activity protein that it contains effective dose presents in an amount at least sufficient to postpone the fibrin glue that this biological activity protein discharges, or fibrinogen and thrombin.
Background of invention
How animal husbandry is avoided the institute domesticated animal is injected as far as possible, its purpose be to reduce to raising animal produce stress probability, and reduce the human cost of raising simultaneously.During before general pig sells from extremely going on the market from breast, the stock farmer only proceeds to many twice injection usually to it.
Yet, keeping good growth conditions and can further promote its growth even raise animal for making, the dealer may need provide some physiologically active protein matter again in its growth course.For example, known pig growth hormone can stimulate the growth of pig in the specific period.According to reports, RPST (rPST) can make pig do sth. in advance to reach the hundred required kg body weight that list marketing more than about ten days, and economic interests are most considerable.
But, for reaching above-mentioned effect, the dealer must begin to inject every day one time rPST when the pig body weight is about 25 kilograms, reaches till about 75 kilograms to its body weight.The related human cost of every day injection is to hard iron, for pig may cause again stress, therefore, hindered the industry utilization of the method for above-mentioned stimulation pig growth.
For taking into account feeding manner, cost and economic interests, this area is needed the method that can effectively prolong biological activity protein effective dose in animal body badly, and the phase makes single agent injection can reach the available maximum effect of this biological activity protein.
Fibrin glue (" fibringlue ") or title fibrin adhesive (" fibrinsealant ") industry are used for many years by surgical operation, it is to make fibrinogen change into fibrin in the presence of thrombin, by the final step of artificial animal body thrombin mechanism, and reach purposes such as thrombin, promotion wound healing.Please refer to as The Journal ofLaryngology and Otology November 1987, Vol.101.pp.1182-1186; Br.J.Surg.1991, Vol.78, July, 841-843; And Ann.Thorac Surg 1993:56:387-9.
Exp Brain Res 1995:104 (2): 199-206 discloses, and it is the transmission of derivatization neurotrophic factor (GDNF) in central nervous system tissue that fibrin glue can prolong cellula adhesiae.In addition, Biol.Pharm.Bull.20 (3) 278-281 (1997) teaching is utilized fibrin glue and is carried out the location specific transmission of hydroxyl daunoblastin with the compositions of sodium alginate, can prolong this medicine in tumor cell extracellular fluid body during.Moreover, Cell Transplant 1998Jan-Feb; 7 (1): 53-61 then discloses a kind of slow releasing preparation that contains fibrin glue-GDNF, it is said that fibrin glue makes that GDNF is short to be limited to the position of using in can be between given period, and does not enter in ambient body fluid or the CSF circulation.
Above-mentioned three documents are not pointed out the systemic effect of fibrin glue.
Summary of the invention
The purpose of this invention is to provide a kind of method that prolongs the effective blood level of biological activity protein.Further, the invention provides a kind of delayed release compositions and combination of biological activity protein, this biological activity protein can be kept the effective blood level of prolongation in animal body after using.
Detailed Description Of The Invention
Be surprised to find that now fibrin glue can make biological activity protein slowly and regularly discharge, reach the effect that prolongs the effective blood level of this protein and produce the systemic effect of prolongation.
Therefore, the present invention at first provides a kind of delayed release compositions of biological activity protein, and its biological activity protein and amount thereof that contains effective dose is enough to postpone the fibrin glue that this biological activity protein discharges.
Any the useful protein of economic animal all is applicable to the present invention, it includes but not limited to growth hormone, insulin, interferon and intracellular hormone.It is obtained that these biological activity proteins can be any method, comprises the recombinant protein that utilizes the genetic engineering mode made, for example RPST (rPST).
The effective dose of the biological activity protein that the present composition is contained, according to different biological activity protein kind and hope the effect of reaching and decide, those of ordinary skills can judge according to ordinary technology.For example, when using rPST as biological activity protein, the present composition can contain the rPST of the 20-50 mg/ml of having an appointment, and is preferably the rPST of about 25 mg/ml.
Similarly, be enough to postpone the effective dose of the Fibrin Glue that biological activity protein discharges, also according to the proteinic kind of use and hope the effect of reaching to decide.By and large, more preferably, contain in the present composition and be equivalent to use 30-60 gram fibrinogen/milliliter and fibrin glue that the 10-100 iu/the milliliter thrombin is produced.Best for being equivalent to use 50 milligrams of fibrinogen/milliliters and fibrin glue that 60 ius/the milliliter thrombin is produced.
The contained fibrin glue of the present composition also can original position form when using, and prolongs the effect that biological activity protein discharges and reach.Therefore, the delay that the present invention further provides a kind of biological activity protein discharges combination, and the biological activity protein that it contains effective dose presents in an amount at least sufficient to postpone fibrinogen and the thrombin that this biological activity protein discharges.
By and large, the delay of biological activity protein of the present invention discharges the contained composition of combination and is contained in individually in the isolating container, and mixes in the injection site original position when using, and forms and prolongs the fibrin glue that biological activity protein discharges.Perhaps, this biological activity protein places same container in advance with fibrinogen through mixing, thrombin then is contained in another and divides in other container, when using, mix with the mixture original position of fibrinogen with biological activity protein, form and prolong the fibrin glue that biological activity protein discharges in the injection site.
The present invention's combination no matter wherein fibrinogen system is contained in separately in other container of branch, or mixes with biological activity protein in advance, and it more preferably contains the fibrinogen/milliliter of 30-60 milligram, and the thrombin of 10-100 iu/milliliter.Most preferably contain 50 milligrams the fibrinogen/milliliter and the thrombin/milliliter of 60 ius.
Form fibrin glue for subsidiary book invention postpones to discharge to be combined in when using in original position, the present invention's combination also can contain IIa family alkaline-earth metal composition, as ionized calcium composition, for example calcium chloride.
Delayed release compositions of the present invention or combination can postpone the release of contained biological activity protein, make this biological activity protein keep long effective blood level after using.More preferably, delayed release compositions of the present invention or combination can postpone the release of contained biological activity protein, make this biological activity protein can keep effective blood level at least about 21 days after using.Be more preferably and keep about 30 days effective blood level.
According to the difference of contained biological activity protein, delayed release compositions of the present invention or combination can reach the effect of multiple beneficial.For example, when this biological activity protein was growth hormone, it can be in order to promote the growth of economic animal, and for example growth of aquatic biologicals such as pig, cattle, horse, camel, birds, fish, shrimp reduces feed cost, and the improvement meat quality.
Now further specify the present invention with following example.Should be appreciated that these examples are not restriction of the present invention, the variation that any those skilled in the art knew by inference includes within the scope of the invention.
Example one
Get totally 30 of the rats of heavily about 200 grams, be divided into three groups at random: test group (FG+pST), fibrin glue matched group (FG) and inject matched group (DI) every day.
In test the 1st day, rat with the solution A test injection group (FG+pST) of 100 microlitres, it contains 10 milligrams the fibrinogen and the pST of 110 micrograms, be included in that 80 microlitre Hanks buffer and 20 microlitres (100KIU) pulmonis Bovis seu Bubali are dirty to be pressed down in the protease (aprotinin), the then solution B of injecting 100 microlitres immediately at same position, it contains the CaCl of 40mM
2And the thrombin of 4.9-11.1 mg/ml.Raised totally 21 days, and weighed in the 14th and 21 day.
In test the 1st day, inject the rat of fibrin glue matched group (FG) with the solution A of 100 microlitres, it contains 10 milligrams fibrinogen, be included in that 80 microlitre Hanks buffer and 20 microlitres (100KIU) pulmonis Bovis seu Bubali are dirty to be pressed down in the protease, the then solution B of injecting 100 microlitres immediately at same position, it contains the CaCl of 40mM
2And the thrombin of 4.9-11.1 mg/ml.Raised totally 21 days, and weighed in the 14th and 21 day.
In test the 1st day, inject the rat of matched group (DI) every day and then accept the Hanks buffer injection that 12.5 microlitres contain 5 microgram pST, totally 21 days every day.Raised totally 21 days, and weighed in the 14th and 21 day.
The composition of aforementioned Hanks buffer is as follows: 5.4mM KCl, 0.3mM Na
2HPO
4, 0.4mMKH
2PO
4, 4.2mM NaHCO
3, 1.3mM CaCl
2, 0.5mM MgCl
2, 0.6mM MgSO
4, 137mMNaCl, 5.6mM D-glucose, and adjustment pH is 7.4.Three groups of rats are as shown in the table in testing the body weight of being surveyed in the 14th and 21 day:
The 14th day (gram number) the 21st day (gram number)
FG DI FG+pST FG DI FG+pST
20 40 30 35 60 55
25 40 30 50 75 50
50 20 45 65 35 65
40 45 35 60 60 45
45 20 45 55 50 65
35 15 50 55 30 70
30 20 40 50 35 60
10 40 25 25 55 40
45 25 25 60 40 40
30 45 average 33 30 36 51 49 54
Example two
16 average weights of picked at random are 50 kilograms pig, are divided into test group and matched group.2.5 milliliters solution A are mixed with 0.4 milliliter solution B, wherein solution A contains pig growth hormone (available from Parlow ' the s laboratory of UCLA medical center) and 300 milligrams of porcine blood plasma that contain about 150 milligrams of fibrinogen of 70 milligrams, be included in PBS solution (20mM phosphate, 230mMNaCl, pH7) in; Solution B then contains 2MCaCl
2And derive from the 500IU/ milliliter thrombin of porcine blood serum.The hemicolloid thing that mixes gained is injected in the scapula place of each pig of test group.Matched group does not then use pig growth hormone and biogum.
Use is suitable for the general commercial feedstuff feeding pig of this stage pig use.The body weight of each pig of weighing every other week, totally seven weeks, and when weighing, take a blood corpse or other object for laboratory examination and chemical testing.
The pH value of an analyzing blood corpse or other object for laboratory examination and chemical testing, blood urea nitrogen, glucose and pig growth hormone concentration.Butcher the matched group of half and be subjected to examination group pig the time in the 3rd week, and in test at the end (the 7th week) butcher the pig of residue half, when butchering, take the sample of either side of the small of the back position and back fat.And carry out the sense analysis of carcass with expert judging group, comprise meat color and luster, fatty tissue content and other meat index.Other writes down feedstuff meat change rate, lean meat gain in weight, average feedstuff intake and total augment weight amount.Carry out gained result's statistical analysis.
Claims (24)
1. the delayed release compositions of a biological activity protein, it contains the biological activity protein of effective dose, and amount is enough to postpone the fibrin glue that this biological activity protein discharges.
2. compositions according to claim 1, wherein said biological activity protein is selected from growth hormone, insulin, interferon and cytokine.
3. compositions according to claim 2, wherein said biological activity protein are pig growth hormone.
4. compositions according to claim 3, wherein said pig growth hormone are RPST (rPST).
5. compositions according to claim 4, the effective dose of wherein said RPST are the 20-50 mg/ml.
6. compositions according to claim 5, the effective dose of wherein said RPST are 25 mg/ml.
7. according to any described compositions of claim 1-6, it contains and is equivalent to use 30-60 milligram fibrinogen/milliliter and fibrin glue that the 10-100 iu/the milliliter thrombin is produced.
8. compositions according to claim 7, it contains and is equivalent to use 50 milligrams of fibrinogen/milliliters and fibrin glue that 60 ius/the milliliter thrombin is produced.
9. compositions according to claim 1, it can keep the effective blood level at least about 21 days described biological activity protein.
10. compositions according to claim 9, it can keep about 30 days effective blood level of described biological activity protein.
11. the delay of a biological activity protein discharges combination, it contains the biological activity protein of effective dose, and presents in an amount at least sufficient to postpone fibrinogen and the thrombin that described biological activity protein discharges.
12. combination according to claim 11, wherein said biological activity protein is selected from growth hormone, insulin, interferon and cytokine.
13. combination according to claim 12, wherein said biological activity protein are pig growth hormone.
14. combination according to claim 13, wherein said pig growth hormone are RPST.
15. combination according to claim 14, the effective dose of wherein said RPST are the 20-50 mg/ml.
16. combination according to claim 15, the effective dose of wherein said RPST are 25 mg/ml.
17. according to any described combination among the claim 11-16, it contains the fibrinogen/milliliter of 30-60 milligram and the thrombin of 10-100 iu/milliliter.
18. combination according to claim 17, it contains 50 milligrams the fibrinogen/milliliter and the thrombin of 60 iu/milliliters.
19. according to any described combination among the claim 11-16, wherein said biological activity protein and fibrinogen system is in advance through mixing, and is contained in the same container.
20. according to any described combination among the claim 11-16, wherein said biological activity protein and fibrinogen are included in the different vessels.
21. according to the total any described combination of claim 11-16, it contains IIa family alkaline-earth metal composition in addition.
22. combination according to claim 21, wherein said IIa family alkaline-earth metal composition is a calcium chloride.
23. combination according to claim 11, it can keep the effective blood level of described biological activity protein at least about 21 days.
24. combination according to claim 23, it can keep about 30 days effective blood level of described biological activity protein.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2000/020799 WO2002015882A1 (en) | 2000-08-24 | 2000-08-24 | Delayed release compositions and combinations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1434703A true CN1434703A (en) | 2003-08-06 |
Family
ID=21741635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00819010.0A Pending CN1434703A (en) | 2000-08-24 | 2000-08-24 | Delayed release compositions and combinations |
Country Status (5)
| Country | Link |
|---|---|
| CN (1) | CN1434703A (en) |
| AU (1) | AU2000270527A1 (en) |
| BR (1) | BR0017324A (en) |
| MX (1) | MXPA03001653A (en) |
| WO (1) | WO2002015882A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102872450A (en) * | 2012-10-17 | 2013-01-16 | 中国人民解放军总医院 | Composition for composite drug administration |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9304075A (en) * | 1992-07-08 | 1994-04-29 | Applied Research Systems | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OR PROPHYLAXIS OF CONSUMPTIVE THROMBOHEMORRHAGIC DISORDERS. |
| US5338836A (en) * | 1992-07-29 | 1994-08-16 | American Cyanamid Company | Biologically active porcine somatotropin polypeptides and methods of using the same |
| WO1995009607A1 (en) * | 1993-10-04 | 1995-04-13 | Maurizio Tonetti | Pharmaceutical composition to enhance tissue healing and regeneration and application kit comprising it |
| WO1998046588A2 (en) * | 1997-04-11 | 1998-10-22 | Neorx Corporation | Compounds and therapies for the prevention of vascular and non-vascular pathologies |
-
2000
- 2000-08-24 MX MXPA03001653A patent/MXPA03001653A/en unknown
- 2000-08-24 BR BR0017324-0A patent/BR0017324A/en not_active IP Right Cessation
- 2000-08-24 AU AU2000270527A patent/AU2000270527A1/en not_active Abandoned
- 2000-08-24 CN CN00819010.0A patent/CN1434703A/en active Pending
- 2000-08-24 WO PCT/US2000/020799 patent/WO2002015882A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102872450A (en) * | 2012-10-17 | 2013-01-16 | 中国人民解放军总医院 | Composition for composite drug administration |
| CN102872450B (en) * | 2012-10-17 | 2014-09-03 | 中国人民解放军总医院 | Composition for composite drug administration |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA03001653A (en) | 2004-09-10 |
| BR0017324A (en) | 2003-07-29 |
| WO2002015882A8 (en) | 2002-03-28 |
| AU2000270527A1 (en) | 2002-03-04 |
| WO2002015882A1 (en) | 2002-02-28 |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |