CN1103601C - Release-controlled somatotropin composition and method for prepartion thereof - Google Patents
Release-controlled somatotropin composition and method for prepartion thereof Download PDFInfo
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- CN1103601C CN1103601C CN93101680A CN93101680A CN1103601C CN 1103601 C CN1103601 C CN 1103601C CN 93101680 A CN93101680 A CN 93101680A CN 93101680 A CN93101680 A CN 93101680A CN 1103601 C CN1103601 C CN 1103601C
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- growth hormone
- tocopherol
- alpha
- composition
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Dispersion Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method is processed by homogenous mixing of somatotropin with lecithin in an aqueous solution having a ratio of somatotropin-to-lecithin of from 7 : 3 to 8 : 2; lyophilisation of a lecithin solution with somatotropin and suspension of the lyophilised lecithin solution with somatotropin in a tocopherol derivative with a ratio of from 1 : 9 to 3 : 7.
Description
The present invention relates to a kind of growth hormone slow release (release-controlled) compositions that contains, it is long half time in animal body, does not have the usefulness of paying, and the invention still further relates to a kind of method for preparing said composition.
The growth hormone formulations of most biologically active all has the short relatively half-life in vivo.For sufficiently high biological agent being provided and keeping the biological activity of growth hormone to prolong, have in a large number and/or often supply medicine, may cause the damage serious like this to the administration animal.Therefore, in case supply with growth hormone in vivo, promptly need one to prolong its effect and the therapeutic regimen harmless again to animal.In order to address that need, to have developed various productions and had the interest for delinquency release characteristics and reduce administration frequency or the method for the somatotropin composition of dosage.
For example, United States Patent (USP) 4,985,440 disclose a kind of a kind of transition metal composite that contains, the compositions of particularly a kind of zinc one growth hormone complex, said composition is dissolved in vegetable or the mineral oil, and with adjuvant drug and the composite a kind of oils and fats suspending carrier of excipient.This method is very complicated, and needs a metal or the compound growth hormone of transition metal.For example, under the condition of strictness, in growth hormone solution, add zinc chloride and make zinc one growth hormone complex, but will through a plurality of steps centrifugal from the suspension that contains this complex the excessive zinc chloride of flush away.The solution that finally obtains then need carry out lyophilizing, and all processes that refines processing i.e. unusual tedium, when useless again.
The European patent open source literature has also been described a kind of containing for 216, No. 485 and has been suspended in such as the zinc in the oils and fats of Oleum Arachidis hypogaeae semen one growth hormonal composition.8mg said composition and 40mg growth hormone only show the 9 days drug effects in short ground exemplarily to the pig administration.In addition, this preparation method also with United States Patent (USP) 4,985, No. 404 are equally complicated.
United States Patent (USP) 4,863 discloses the method that a kind of preparation contains the implantable pill of growth hormone granule No. 736, this pill have as, Lac, Cera Flava and cellulosic polymer moieties barrier coatings.The release in vivo of this pill control growing hormone.Equally, the European patent open source literature also provides a kind of method for preparing the implantable medicament that contains growth hormone in penetration equipment for 374, No. 120.The European patent open source literature has also disclosed a kind of synthetic method that contains the implantable medicament of polypeptide and fatty acid for preparing for 246, No. 540.
In addition, United States Patent (USP) 4,786 has been put down in writing a kind of method for preparing implantable pill agent prescription No. 501, and this method comprises the mixed growth hormone, sucrose and ethyl cellulose, and apply this mixture with porous and atresia polyethylene.United States Patent (USP) 4,761 has also been discussed a kind of method for preparing implantable prescription No. 289, and it comprises mixed growth hormone and non-water-soluble polymer, adds a kind of non-water-soluble solvent and drying.Though these implantable prescriptions have the effect that keeps curative effect, they need underwent operative or special apparatus could implant or administration; Therefore, need relative complex and treatment sequence not too easily.
In addition, the European patent open source literature discloses a kind of compositions 193, No. 917, and it contains water dispersible and water miscible carbohydrate polymer, and a kind of tool biological activity growth hormone macromole.The European patent open source literature further discloses a kind of compositions that is dispersed in the peptide species in the oils and fats that contains for 314, No. 421, and its adopts a kind of carbohydrate polymer as dextran as support substance.The European patent open source literature also reported for 211, No. 691 and a kind ofly contained the compositions that is dispersed in the polypeptide in certain oils and fats with several Cera Flavas as support substance, but it has with the same shortcoming of above-mentioned those European patent open source literatures 193,917.In these compositionss, animal body usually is considered as antigen with carbohydrate polymers such as dextrans and induces reaction, and very sensitive, therefore is not suitable for life-time service.
A kind of compositions that is dispersed in the tocopherol and is furnished with the animal growth hormone of delay release action that contains has been described for Korean patent publication 91-15302 number.Because its high viscosity, this compositions are difficult to be used by injection, and have long tendency of holdup time in the administration tissue, can cause damage that tissue.
Therefore, the object of the present invention is to provide the method for a kind of somatotropin composition of preparation, said composition is long half time in living animal, does not have the effect of paying.
Another object of the present invention is to provide the somatotropin composition of a kind of the present invention's of employing method preparation.
According to the present invention, will provide a kind of method for preparing somatotropin composition, its release in vivo is that the time is controlled, this method comprises the steps: lecithin and growth hormone are dissolved in the aqueous solution, forms a kind of liposome growth hormone solution; The described liposome growth hormone solution of freezing drying under the conventional freezing drying condition; The liposome growth hormone that the described freezing drying that suspends in Tocopheryl derivatives is crossed is to make new compositions of the present invention.
Brief Description Of Drawings
The present invention is also by further being understood with reference to the following drawings, wherein:
Fig. 1 and Fig. 2 illustrate after injecting the present invention's compositions to milch cow, to the influence of milk crop;
Fig. 3 represents after the present invention's new compositions is injected pig to trophophase, the concentration of pig growth hormone in its serum;
After compositions with the present invention shown in Figure 4 is injected pig to trophophase, the concentration of blood urea nitrogen in its serum;
After Fig. 5 illustrates the present invention's compositions is injected pig to trophophase, the concentration of quasi-insulin growthing factor I in its serum.
According to of the present invention, growth hormone solution with lecithin at homogenizer The middle mixing, adopt then conventional method, it is suspended in tocopherol derives Obtain the present invention's composition in the thing. Being permitted eurypalynous growth hormone can both use In the present invention, as long as they possess desirable biologically active. This allusion quotation The growth hormone of type comprises: BGH, pig growth hormone, sheep growth Hormone etc. Although requiring, the present invention do not adopt metal one, or transition metal-composite growth hormone or with the growth hormone of the modified of low hydrogenation, But the growth hormone of these kinds also can use. The growth that can adopt Hormone also comprise those through recombinant DNA technologies from such as Escherichia coli and The growth hormone that makes in the contracting chief cells such as yeast, and from ox, sheep and pig Deng the spontaneous growth hormone that extracts in the heavy body of animal body brain.
Can be used for Tocopheryl derivatives of the present invention and comprise the d1-alpha-tocopherol, d1-α-tocopherol acetate, d1-α-butanedioic acid tocopherol, d1-alpha-phosphate tocopherol, 1-alpha-tocopherol, 1-α-tocopherol acetate, 1-α-butanedioic acid tocopherol, 1-alpha-phosphate tocopherol, and β, ξ1，ξ
2, a fertility amphyl; Preferably α-Tocopherol acetate. Tocopheryl derivatives keep as rat, mouse, cavy, The normal reproduction of the animal such as pig and ox; Help prevent animal muscle to send out Educate defective; In vivo the slowly-releasing of growth hormone plays the effect of carrier. In addition Outward, Tocopheryl derivatives prevents irregular muscular movement in vivo, perhaps Strengthen the intensity of muscle. Tocopherol can also prevent the irregular muscular movement of chicken, Or make muscle hardening, the pimelitis that also can prevent mink, pig or cat. The amount of the tocopherol that adopts in the present composition is to account for said composition weight 74～99%.
The bioactive growth hormone that has that the present invention adopts advances with lecithin Row mixes, and its mixing ratio is 7: 3 to 8: 2 (weight ratio). If The amount of growth hormone is less than lower bound (i.e. 70% weight), and it is difficult to show Go out biologically active. If the amount of growth hormone surpasses its upper limit (namely 80% Weight), then be difficult to form liposome growth hormone mixture.
Be present in the lecithin control growing hormone release time in animal body in the present composition.Typically being suitable for lecithin of the present invention comprises: phosphatidylcholine, lysophosphatide (Lysophospholipid), plasmalogen and sphingomyelins.
In addition, can add suitable excipient and/or adjuvant drug so that the present composition can be made various types of dosage forms.
As mentioned above, in some known compositions, growth hormone need be with metal or transition metal, and the technology by complexity comprises that dialysis forms composite form, because in vivo its dissolubility must be lower, purpose is to obtain slow release effect.Growth hormone also can overdosage, to cause the impact effect of beginning.
On the contrary, compositions by the present invention's preparation, comprise a kind of liposome growth hormone that is suspended in the freezing mistake in the tocopherol carrier, when it during to the animal body administration, needn't adopt the program of the sort of complexity, mode that promptly can slow release discharges the biologically active growth hormone, it is very simple and economical to refine processing whole recipe ingredient and treatment sequence, the more important thing is that the prescription of the present composition demonstrates growth hormone in vivo and is accompanied by lower initial release or impacts a kind of high-quality release type that discharges suddenly.
Metal in the prescription of the metal composite growth hormone of available technology adopting or transition metal can cause to make us so paying of considering acts on, and the present composition does not have the effect of paying.The used Tocopheryl derivatives of the present invention has certain pharmacology assosting effect in live body, and has and alleviate or prevent the repulsive interaction of live body to the present composition.
Further explain the present invention below with reference to embodiment, these embodiment do not have the intention of the restriction scope of the invention.
Embodiment 1
Get (with the bovine growth hormone solution 30.03mg/ml of recombinant DNA technology (Lucky Limited) production) bovine growth hormone solution 300ml, in homogenizer, mixed 20 minutes with L-α-phosphatidylcholine IV-S (L-α-lecithin) 3g that extracts in the Semen sojae atricolor, this solution was poured into a flask through a microfluidization instrument (microf luidizer) under 5 minutes, 4 ℃, quick freezing is to bearing 70 ℃, freezing then drying under dry ice-propanone is bathed.To contain powder 133.3mg after the freezing drying of L-α-phosphatidylcholine and bovine growth hormone in homogenizer with the alpha-tocopherol uniform mixing of 1ml 10 minutes.
Select for use 10 just to do experiment for Hao Sidun (Holstein) milch cow in suckling mid-term.Every per two weeks of cattle are injected compositions of the present invention totally 6 times.Wherein 5 cattle are experimental group, and 5 cattle are not injected said composition as matched group in addition.Shoulder first top subcutaneous injection said composition.After the injection, every day measure milk output, average every day, milk yield saw Table 1 and Fig. 1.
Embodiment 2
Method by embodiment 1 prepares the present composition, and the powder of just getting after the 333.5mg lyophilization mixes with α-tocopherol acetate of 1ml.
Select the Hao Sidun milch cow in 12 suckling mid-terms to experimentize.Every totally 6 times of injecting this compound composition of 2ml per two weeks of cattle.Wherein 6 cattle are as experimental group, and 6 cattle are matched group in addition.Experimentize by the identical method described in the embodiment 1, its experiment the results are shown in Table 2 and Fig. 2.Table 1 present composition is to the effect of milk production every day
Unit (kg)
Control group injection group injection front 21.50 23.91 is for the first time main penetrates 21.66 27.75 and injects 21.84 28.18 for the second time and inject for the third time 19.59 28.06 the 6th injections of 20.76 27.73 the 5th injections of 21.51 28.10 the 4th injections and inject two weekly forms, 2 present compositions after 17.94 23.45 for 18.51 27.17 the 6th times to the effect of every daily milk yield
Unit (kg)
Control group injection group injection front 26.14 25.50 is injected 22.6 23.8 for the first time and was injected for the second time for 23.8 25.6 two weeks of injecting for the third time 21.0 23.2 the 6th injections of 20.7 23.0 the 6th injections of 22.0 24.5 the 5th injections of 22.3 24.8 the 4th injections rear 18.9 19.3
Embodiment 3
Prepare the pig growth hormone compositions by embodiment 1 identical method.Select 14 hog, every nose heave about 60kg does experiment.Wherein every pigs are injected compound composition 1.5ml of the present invention per three weeks of 7 pigs, and totally twice, 7 pigs are used as matched group and do not inject said composition in addition.Injection back three their body weight of all weighings and foodstuff consumptions.Calculate frequency of administration (FE, feed efficiency kg/day).Increment number (ADG, average daily gain kg/day) and the frequency of administration (the FE=amount of eating/weight increase amount) of average every day shown in the table 3.
Table 3 average every day of increment and frequency of administration
FE 4.28 3.31 after 3.55 3.33 second three all ADG 0.81 0.96 of FE is organized after first three all ADG 0.94 0.97 in the matched group injection
Embodiment 4
Prepare the pig growth hormone compound composition by embodiment 1 identical method.Experimentize every heavily about 60kg of pig with 6 hog.Every said composition of injecting 1.5ml of 3 pigs wherein.Other 3 pigs not injectable composition are cooked matched group.Measure serum pig growth hormone concentration (PST), serum urea nitrogen (BUN) concentration and quasi-insulin growthing factor I concentration.
It records and the results are shown in Table 4, Fig. 4 and Fig. 5
Table 4 blood-serum P ST concentration, the concentration blood-serum P ST IGF-I BUN blood-serum P ST IGF-I of BUN and quasi-insulin growthing factor I BUN days (ng/ml) is (mg/dl) (ng/ml) (ng/ml) (mg/dl) 0 1.43 343 14.5 1.44 441 15.01 1.52. 306 15.7 325 891 4.53 1.15 308 17.4 46.9 1,135 8.06 1.42 356 15.0 8.30 1,018 6.010 1.44 351 19.8 3.10 692 16.514 1.46 354 19.7 1.02 506 19.021 1.80 348 23.3 1.10 438 17.7 (ng/ml)
As above show finding, the compositions for preparing by method of the present invention has the long half-life when supplying medicine to animal, and has no side effect, because its viscosity is hanged down the suitable injection of using, and is fit to use continuously.The very easy administration of said composition needn't be with performing the operation or special apparatus.In addition, its method for making is very simple and economical.
Can make amendment and change it about the description of the invention described above particular embodiment should be regarded as common existing these personnel in this area, limit within the protection domain but also fall into claim of the present invention.
Claims (8)
1, preparation contains the method for the slow releasing composition of growth hormone, comprises the steps:
With growth hormone and lecithin part by weight uniform mixing with 7: 3 to 8: 2;
With Lecithinized growth hormone solution lyophilizing; With
Freeze dried Lecithinized growth hormone is suspended in the Tocopheryl derivatives, thereby freeze dried Lecithinized growth hormone accounts for the 1-26% of suspension gross weight, the amount of Tocopheryl derivatives accounts for the 74-99% of suspension gross weight.
2, the method for claim 1, wherein said growth hormone is selected from bovine growth hormone, pig growth hormone and sheep growth hormone.
3, the method for claim 1, wherein said growth hormone prepares through recombinant DNA technology.
4, the method for claim 1, wherein said Tocopheryl derivatives is selected from the d1-alpha-tocopherol, d1-α-tocopherol acetate, d1-α-succinic acid tocopherol, d1-alpha-phosphate tocopherol, the 1-alpha-tocopherol, 1-α-tocopherol acetate, 1-α-succinic acid tocopherol, 1-alpha-phosphate tocopherol, and β, ξ
1, ξ
2-Tocopheryl derivatives.
5, method as claimed in claim 4, wherein said Tocopheryl derivatives are the d1-alpha-tocopherols.
6, the method for claim 1, wherein said lecithin is selected from phosphatidylcholine, lysophosphatide, plasmalogen and sphingomyelins.
7, a kind of growth hormone slow releasing composition by the described method preparation of claim 1.
8, compositions as claimed in claim 7 also contains excipient and/or adjuvant drug.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR22551/92 | 1992-11-27 | ||
| KR9222551 | 1992-11-27 | ||
| KR1019920022551A KR940011013A (en) | 1992-11-27 | 1992-11-27 | Method for preparing sustained release somatropin formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1087277A CN1087277A (en) | 1994-06-01 |
| CN1103601C true CN1103601C (en) | 2003-03-26 |
Family
ID=19344061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93101680A Expired - Lifetime CN1103601C (en) | 1992-11-27 | 1993-02-24 | Release-controlled somatotropin composition and method for prepartion thereof |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR940011013A (en) |
| CN (1) | CN1103601C (en) |
| CZ (1) | CZ280429B6 (en) |
| MY (1) | MY134714A (en) |
| SK (1) | SK279352B6 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103751769A (en) * | 2013-12-25 | 2014-04-30 | 楼秀余 | Lyophilized recombinant human growth hormone capsule and preparation method thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100365678B1 (en) * | 2000-03-24 | 2002-12-26 | 주식회사 엘지생명과학 | The somatotropin formulation of improved syringeability |
| KR100423895B1 (en) * | 2001-02-19 | 2004-03-24 | 주식회사 엘지생명과학 | Compositions of suspensions of ceftiofur hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987002219A1 (en) * | 1985-10-15 | 1987-04-23 | The Liposome Company, Inc. | Alpha tocopherol-based vesicles |
| WO1987004592A1 (en) * | 1986-02-10 | 1987-08-13 | Liposome Technology, Inc. | Controlled-release liposome delivery system |
| WO1989005151A1 (en) * | 1987-12-04 | 1989-06-15 | The Liposome Company, Inc. | High integrity liposomes and method of preration and use |
-
1992
- 1992-11-27 KR KR1019920022551A patent/KR940011013A/en not_active Application Discontinuation
-
1993
- 1993-02-06 MY MYPI93000193A patent/MY134714A/en unknown
- 1993-02-24 CN CN93101680A patent/CN1103601C/en not_active Expired - Lifetime
- 1993-11-26 CZ CZ932552A patent/CZ280429B6/en not_active IP Right Cessation
- 1993-11-26 SK SK1328-93A patent/SK279352B6/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987002219A1 (en) * | 1985-10-15 | 1987-04-23 | The Liposome Company, Inc. | Alpha tocopherol-based vesicles |
| WO1987004592A1 (en) * | 1986-02-10 | 1987-08-13 | Liposome Technology, Inc. | Controlled-release liposome delivery system |
| WO1989005151A1 (en) * | 1987-12-04 | 1989-06-15 | The Liposome Company, Inc. | High integrity liposomes and method of preration and use |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103751769A (en) * | 2013-12-25 | 2014-04-30 | 楼秀余 | Lyophilized recombinant human growth hormone capsule and preparation method thereof |
| CN103751769B (en) * | 2013-12-25 | 2015-08-19 | 楼秀余 | A kind of lyophilizing recombinant human somatropin capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR940011013A (en) | 1994-06-20 |
| CN1087277A (en) | 1994-06-01 |
| SK279352B6 (en) | 1998-10-07 |
| CZ255293A3 (en) | 1994-06-15 |
| CZ280429B6 (en) | 1996-01-17 |
| SK132893A3 (en) | 1994-07-06 |
| MY134714A (en) | 2007-12-31 |
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Expiration termination date: 20130224 Granted publication date: 20030326 |