CN1332635A - Controlled release formulation comprising GnRH-II - Google Patents
Controlled release formulation comprising GnRH-II Download PDFInfo
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- CN1332635A CN1332635A CN99815183A CN99815183A CN1332635A CN 1332635 A CN1332635 A CN 1332635A CN 99815183 A CN99815183 A CN 99815183A CN 99815183 A CN99815183 A CN 99815183A CN 1332635 A CN1332635 A CN 1332635A
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- xaa
- peptide
- gly
- trp
- tyr
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- 239000003862 glucocorticoid Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical formulation for the controlled release of a therapeutic peptide or a salt thereof, which peptide has the sequence pyroGlu-His-Trp-Ser-Xaa<1>-Gly-Xaa<2>-Xaa<3>-Pro-Gly-NH2 wherein Xaa<1> is His or Tyr, Xaa<2> is Trp or Leu, and Xaa<3> is Tyr or Arg, provided that when Xaa<1> is Tyr and Xaa<2> is Leu, then Xaa<3> is not Arg, and which formulation further comprises a pharmaceutically acceptable biodegradable polymer. The formulation can be used for treating bone and prostate disorders.
Description
Field that the present invention belongs to
The present invention relates to a kind of pharmaceutical preparation that can discharge therapeutic component for a long time.
Background of invention
Physiologic Studies to hypothalamic pituitary gonadal axis has had such conclusion: (GnRH can claim luteinizing hormone releasing hormone again to gonadotropin releasing hormone: the regulation and control hormone that LHRH) is a kind of key.This hormone is discharged by hypothalamus, acts on hypophysis, promotes the release of lutropin (LH) and follicule-stimulating hormone (FSH) (FSH).Recently, found a kind of and the homologous peptide matters of GnRH (White etc., Proc.Natl.Acad.Sci.USA 95 305-309,1998).This peptide is named as GnRH-II.The aminoacid sequence of these two kinds of peptides is compared as follows: GnRH pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 (SEQ I.D. No.5) GnRH-II pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (SEQ I.D. No.6)
The title of " GnRH-II " is said easily to a certain extent and is led to misunderstanding.This new peptide is a gene outcome independently, and can distinguish mutually with GnRH clearly on tissue distribution.GnRH-II seems not to be the release promotion thing of endogenic LH and FSH.Owing to there is not tangible proof to confirm the GnRH-II physiological role, therefore it does not obtain paying close attention to aspect medicine in application.
Summary of the invention
We have found the important function of GnRH-II to the part organ now.For example, it has certain influence to osteogenesis, and can regulate the propagation of prostate epithelial cell.Therefore, we have studied this material and the possible clinically application mode of analog thereof, and a theme of the present invention provides the suitable drugs preparation of reaching this purpose.Preparation of the present invention depends on and utilizes a kind of biodegradable polymer that peptide is rolled into bank, and this peptide enters the body circulation with controlled velocity.Said preparation comprises two key components: biologically active peptide and biodegradable polymer.Wherein biologically active peptide is a kind of decapeptide, and its sequence is as follows: pyroGlu-His-Trp-Ser-Xaa
1-Gly-Xaa
2-Xaa
3-Pro-Gly-NH
2(SEQ I.D.No.7) wherein, Xaa
1Be His or Tyr
Xaa
2Be Trp or Leu
Xaa
3Be that Tyr or Arg condition are: work as Xaa
1Be Tyr and Xaa
2When being Leu, Xaa
3Can not be Arg.
Polymer is any pharmaceutically useful biodegradable polymer, is preferably the copolymer of glycolic and lactic acid.The present invention also further relates to the application of said preparation aspect the treatment human diseases.The description of the drawings
Accompanying drawing 1 has provided the influence of the GnRH-II of ascending-dose to the ovariectomized rat serum calcium cancentration.
Detailed Description Of The Invention
Herein, amino acid abbreviations has its conventional sense, represents natural L-isomer (except the glycine of no chirality).
At first, the invention discloses a kind of pharmaceutical preparation, it can be long-time with controlled velocity (as minimum one day, preferred several days, more preferably week) discharge the treatment peptide, said preparation especially can be used for treating skeleton and prostatosis.Described treatment peptide is a decapeptide, and following sequence: pyroGlu-His-Trp-Ser-Xaa is arranged
1-Gly-Xaa
2-Xaa
3-Pro-Gly-NH
2(7) wherein, Xaa
1Be His or Tyr, Xaa
2Be Trp or Leu, Xaa
3Be Tyr or Arg, condition is to work as Xaa
1Be Tyr and Xaa
2When being Leu, Xaa
3Can not be Arg.Preferably, Xaa
1Be His, Xaa
2Be Trp, Xaa
3Be Tyr.Will be appreciated that described peptide can with sour salify (as acetic acid, trifluoroacetic acid, benzoic acid, hydrochloric acid, phosphoric acid etc.).So long as all contain within the scope of the invention with the salt of pharmaceutically acceptable acid formation.
Another basis of preparation of the present invention is pharmaceutically useful biodegradable polymer.This polymer is well known in the prior art.They can be homopolymer (polymer of single monomer), also can be copolymer (different monomers by two or more form).Suitable monomer comprises the amino and the hydroxy derivatives of carboxylic acid.In a preferred embodiment of the invention, monomer is by hydroxy acyl monomeric unit, polymer that more preferably α-the hydroxy acyl unit is formed, most preferably is poly-(glycolic), the copolymer of poly-(lactic acid) or glycolic and lactic acid.This polymer has following chemical constitution:
Wherein R is a hydrogen in poly-(glycolic), is methyl in poly-(lactic acid), at random is hydrogen or methyl in copolymer.
The preparation of preparation of the present invention have two kinds can be complementary but diacritic method: peptide is introduced in the polymeric matrix, or more preferably with polymer with the peptide encapsulation.In a kind of method in back, encapsulated peptide can be that solid also can be solution, preferably solid.
Said preparation can be used for treating some human diseases, comprise that the osteogenesis disease is (as the age related osteoporosis, the relevant osteoporosis of hormone state behind the postmenopausal women, former and secondary hyperparathyroidism, the disposability osteoporosis, diabetes dependency osteoporosis and glucocorticoid dependency osteoporosis) and prostate growth disease (comprising benign prostatic hyperplasia and carcinoma of prostate).Secondly, the present invention includes a kind of method of individuality of suffering from bone or prostate growth disease or being considered to suffer from the danger of described disease for the treatment of.This Therapeutic Method comprises that give described individual treatment effective dose a kind of contain as the peptide of the following sequence of active component or its officinal salt with as the preparation of the pharmaceutically acceptable biodegradable polymers of second kind of composition:
PyroGlu-His-Trp-Ser-Xaa
1-Gly-Xaa
2-Xaa
3-Pro-Gly-NH
2(7) wherein, Xaa
1, Xaa
2, Xaa
3Definition the same, described preparation release peptide enters body circulation after polymer is etched.This Therapeutic Method can only comprise the single administration of said preparation, but comprises a series of multiple administrations probably.Administration frequency can from once a day to January once.The amount of bioactive peptide will be determined according to dosage regimen and route of administration in every dose.In general, this is measured at 1mg between the 1g.The doctor in charge can it has been generally acknowledged that relevant parameter determines dosage accurately according to this area.Said preparation can intramuscular injection or subcutaneous injection.
Active component peptide in the preparation of the present invention can make with the general known method in this area.For example, can prepare these peptides with solid phase synthesis process.This method comprises by following scheme and amino acid residue being added on the intermediate of resin-bonded in order.
1, the formation of the first resin-bonded intermediate
PG-Aaa-OH＋FG-Res-PG-Aaa-L-Res
Aaa=aminoacid
The PG=protecting group
The FG=functional group
The Res=fluoropolymer resin
The L=linking group (O-or-NH-)
2, deprotection
pG-Aaa-L-Res-H-Aaa-L-Res
3, chain elongation
PG-Bbb-OH＋H-Aaa-L-Res-PG-Bbb-Aaa-L-Res
4, repeating step 2 and 3 on demand
PG-Bbb-Aaa-L-Res-?-?-PG-Nnn-...-Bbb-Aaa-L-Res
5, separation/deprotection
PG-Nnn-...-Bbb-Aaa-L-Res-H-Nnn-...-Bbb-Aaa-OH(-NH
2)
In the step 1, the resin reaction of shielded aminoacid and functionalization.Protecting group (PG) is modal to be tertbutyloxycarbonyl (Boc) or 9-fluorenylmethyloxycarbonyl (Fmoc); Functional group on the resin (FG) generally is chloro alkyl, hydroxyl or amino.When FG was chloro alkyl or hydroxyl, linking group L was an oxygen atom; When FG was amino, L was-NH-.
In the step 2, protecting group PG is broken away from from the alpha-amido group.When PG was Boc, this can be with finishing such as acid such as trifluoroacetic acid or hydrochloric acid process resin in dichloromethane solvent; When PG is Fmoc, can finish deprotection with alkali treatment resin such as piperidines.
In the step 3, add amino acid residue and make peptide elongation.The aminoacid of a protection is attached on the amino group that step 2 discharges.A lot of reagent known in the state of the art can be finished this conversion reaction.A kind of agent combination is dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBt).Usually also need a kind of alkali.Suitable alkali comprises triethylamine and N, the N-diisopropyl ethyl amine.Solvent is used dichloromethane usually, dimethyl formamide or their mixture.
If the side chain of amino acid chain (Aaa-Nnn) comprises active group (for example amino, carboxyl, hydroxyl etc.), they need protection so.Normally those are sloughing group stable under the condition of PG to the Side chain protective group of selecting.If PG is Fmoc, Side chain protective group is the group based on tert-butyl group chemistry easily so; If PG is Boc, Side chain protective group is then based on fluorenyl methyl chemistry.Its blocking group known in the art can use equally.
In the step 4, repeat the circulation of deprotection and chain elongation, till needed peptide sequence occurs.
In the step 5, synthetic good peptide is separated from resin.Before separation or after separating, remove protecting group from side chain.When L be-during NH-, isolating peptide is a C-terminal amide form.When L be-during O-, the peptide that is discharged often is the C-terminal free acid, needs for second step form the C-terminal amide.
Peptide also can prepare by liquid phase synthesizing method.For mass production, the method is more convenient.
The polymer that relates among the present invention all is as known in the art usually.As mentioned before, preparation can be simple dispersion, and peptide mixes in the polymer as substrate, also can be that peptide is aggregated thing and is wrapped to form microcapsule.Peptide (solid) and polymer mixed is extremely even, make into dispersion, then mixture is compressed agglomerating.This process may add binding agent to obtain the suitable compositions of viscosity in mixture.The agglomerate of compression can be ground then, form suitable size suspension and be applicable to the granule of injection in (as water or wait ooze saline solution) in biocompatible liquid.
The solution of solid peptide (Powdered) or peptide all can be made the microencapsulation preparation, and especially the aqueous solution of peptide is preferably.Polymer at first is dissolved in the suitable organic solvent, subsequently peptide is added solution and strong agitation, and peptide is dispersed in the organic facies.Add another kind of organic solvent again, it has reduced the dissolubility of polymer in organic facies.Polymer is separated out from solution and is formed peplos (or forming peplos around liquid microdroplet) at solid-state peptide microparticle surfaces.Then remaining organic solvent is cleaned, made the microcapsule sclerosis of formation, they just can be used for being suspended in the suitable liquid being used for administration.
Above generality is described in following several embodiment and will obtains more detailed elaboration.These embodiment are used for illustrating of the present invention, and do not limit the present invention in any way.EXAMPLE Example 1 GnRH-II's is synthetic
The preparation of the protection peptide of 1A binding resin
pyroGlu-His(Bom)-Trp(CHO)-Ser(Bzl)-His(Bom)-Gly-Trp(CHO)-Tyr(Bzl)-Pro-Gly-
Ores
(60g, 1mol/g) initial solid phase method routinely prepares this peptide from the Merrifield resin of Boc-Gly-esterification.Synthesize in a manual synthesizer and carry out, the solvent of each operation and the cumulative volume of reagent are about 300ml.Deprotection/the washing of standard/coupling operation sees Table 1.
Table 1
In synthetic with the benzotriazole ester as active ester, they react with I-hydroxybenzotriazole (1 equivalent) and dicyclohexylcarbodiimide (1 equivalent) and relevant protection aminoacid and obtain.Used quantity (relevant with resin replacement capacity) sees Table 2.
| Step | Reagent | Time (branch) | Number of operations |
| The deprotection of Boc | ????HCl/DCM* | ????60 | ????1 |
| Washing | ??????DCM | ????2-4 | ????3 |
| Neutralization | ??10％DIPEA/DCM | ????4 | ????2 |
| Washing | ??????DCM | ????2-4 | ????1 |
| Coupling | Active ester | ???60-120** | ???1-2 |
| Washing | ??????DCM | ????2-4 | ????3 |
| * * * material in the DCM suspension of gas chlorination hydrogen blister feeding resin is determined the end of reaction by ninhydrin test | |||
Table 2
| The circulation sequence number | Amino acid derivativges | The molar excess number |
| ????1 | ?Boc-Pro-OH | ?????1.8 |
| ????2 | ?Boc-Tyr(Bzl)-OH | ?????1.8 |
| ????3 | ?Boc-Trp(CHO)-OH | ?????1.8 |
| ????4 | ?Boc-Gly-OH | ?????1.8 |
| ????5 | ?Boc-His(Bom)-OH | ?????1.8 |
| ????6 | ?Boc-Ser(Bzl)-OH | ?????2.0 |
| ????7 | ?Boc-Trp(CHO)-OH | ?????2.0 |
| ????8 | ?Boc-His(Bom)-OH | ?????2.0 |
| ????9 | ?pyroGlu-OH | ?????2.0 |
After the last coupling, (3 * 3L) washings are dried to constant weight 40 ℃ of reduced pressure to resin with dichloromethane.
Amino acid analysis: consistent with the sequence of anticipation.1B separates and deprotection
pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2????(6)
Peptide-resin-bonded thing that embodiment 1A is obtained is placed in the linen bag, and places pressure vessel.In this container, feed ammonia, reach 4 atmospheric end pressures, bleed off remaining ammonia after 72 hours, resin with acetic acid (3 * 100ml) and ethanol (3 * 100ml) extract respectively.Combining extraction liquid, the logical nitrogen degassing adds 10% charcoal and carries palladium, stirs the mixture in an atmospheric hydrogen.Reaction finishes back (HPLC monitoring), and filtering mixt evaporates filtrate.Residue reversed-phase HPLC purification obtains title compound.
The microencapsulation of embodiment 2 peptides
Use lactic acid and glycolic ratio are 50/50 copolymerization (D, L-lactic acid, glycolic).The solution of 3.7g copolymer in the 100ml dichloromethane in the reactor that agitator is housed adds the acetate (0.15g after the peptide that embodiment 1 is obtained is dissolved in acetic acid, obtains after the lyophilization) of GnRH-II.Mixture is stirred with 500 rev/mins speed, add in 10 minutes silicone oil (Dow-Corning 360Medical Fluid , 45g).Then with mixture by a thin nozzle import with 1000 rev/mins of sad-capric acid-triglyceride that continue stirrings (Miglyol 812,3.3L) in.After adding finishes, restir 1 hour.Filter then and collect, with washed with isopropyl alcohol twice, final drying obtains microcapsule.Embodiment 3 GnRH-II and analog are to osteoblast group's interaction in vitro analysis
(a) by standard method well known in the prior art, isolate human osteoblast cell (Nilsson etc., 1995) in the canceration bone from orthopaedic surgery.Bone is shifted out thing be ground into tiny osteocomma, then Eagle culture medium (DMEM)/F12 (1: 1 Gidco, Paisley U.K) thorough washing of improveing at Dulbecco.With these osteoblast-like cells, Mus osteoblast MC3T3-E1 and people's cloning osteosarcoma cell line MG-63 (non-mineralising) and SaOS-2 (mineralising osteosarcoma) all at DMEM: in 37 ℃, moist carbon dioxide incubator, cultivate among the F12 1: 1, be added with 10% hyclone (FCS in the described culture medium, Gibco), amphotericin B (500mg/L), gentamycin sulfate (50mg/L), L-glutaminate (2mM) and L-ascorbic acid (100mg/L).
(b) separating human marrow stromal cell from the GUSUIPIAN of using the phosphate buffer rinsing.Collect and centrifugal medullary cell by a Ficoll Hypaque post (Kimble etc., J.Clin.Invest.93 1959-1967,1994).With precipitation of the cell centrifugation on the interface and counting, be seeded in 75cm
2In the flask, cultivate in the CO2 gas incubator of 37 ℃ of humidities, culture medium is changed once weekly.After the cell growth converges, use trypsin EDTA collecting cell, inoculate be supplemented with 10% hyclone (FCS, Gibco), the α-MEM of penicillin (100U/ml), streptomycin (100mg/ml), amphotericin B and L-glutaminate (2mM) is (among the α-MEM).
(c) before adding GnRH-I and GnRH-II, all cells was all broken off the serum supply more than 48 hours.Cell is placed the DMEM of not adding of 12 well culture plates phenol red (avoiding phenol red estrogen-like effects), wherein be added with 10% carbon decoloring serum, placed 48 hours.Ultimate density scope 10 at adding peptide
-9To 10
-6Carry out the research of the dose-dependent effects of GnRH-I and GnRH-II and analog between the M.1mM succinyl cAMP is with comparing.Cell culture carried out respectively 24,48,96 hours, and peptide was changed once in per 24 hours.
(d) for estimating the influence of peptide on cell proliferation, after 24 hours in the general [
3H] thymidine adds with 1mCi/ml, and measure [
3H] the mixing of thymidine.Use scintillation counter to determine radioisotopic combination, come result of calculation with the cpm number of every milligram of total protein.
(e) expression (the Tintut Y etc. of osteoblast differentiation sign have also been measured.JBiol?Chem2737547-53，1998)。Several stages promptly adds behind the peptide and to separate total RNA in 24,48,72,96 hours before processing.The expression of I procollagen type, osteopontin and 28S RNA (as interior mark) is all measured by the Northern engram analysis.Alkali phosphatase, substrate GLA albumen, broken bone protein (osteoclastin) and GAPDH (as interior mark) use the specific primer of each gene design are measured by RT-PCR.
Peptide of the present invention has remarkable result during less than 100 μ M in concentration.
Embodiment 4 GnRH-II and analog thereof are to osteoclast group's interaction in vitro analysis
(a) people's cloning osteoclast precursor cell line (FLG29.1) is as the external model (Gattei V etc., Cell Growth Differ 7 753-63 1996) of osteoclast differentiation.In addition, the co-cultivation thing of FLG29.1 and osteoblast Saos-2 is estimated the variation of animal migration, cohesiveness, cytochemistry, morphology and the biochemistry aspect of cell.Adding 10 to FLG29.1 and coculture
-9To 10
-6Behind the peptide of M final concentration, the dose-dependent effects of research GnRH-I and GnRH-II and analog thereof.Adding parathyroid hormone compares.Mensuration is broken up the enhancing of (being fused into big multinuclear unit) to preceding osteoclast or is suppressed and some other factorses (Orlandini etc., Cell Tissue Res.281 33-42,1995).These comprise: 1, the positive staining of tartrate resistant phosphatase in the FLG29.1 cell; 2, by the reduction of the alkaline phosphatase activities of Saos-2 cellular expression; 3, the appearance of the typical superstructure feature of mature osteoclast in the FLG29.1 cell; 4, granulocyte-macrophage colony stimutaing factor is released into culture medium; 5, for estimating the influence of peptide on cell proliferation, in afterwards 24 hours with 1mCi/ml add [
3H] thymidine, and by said method measured [
3H] combination of thymidine.
(b) from people's GUSUIPIAN isolating medullary cell at 10nM 1,25-(OH)
2Vitamin D
3Exist down and cultivated 7 days, form multinucleated osteoclast, used herein is standard technique known in the art (Takahashi etc., Endocrinol 122 1473-1482,1988).Take out culture medium (α-MEM) and with the no phenol red of new preparation and be supplemented with antibiotic, the heat-inactivated FCS of 10% carbon decoloring, the culture medium that includes GnRH-I, GnRH-II or its analog replaces, cultivated again 24 hours.Collect buoyant cell, osteoclast is expressed dyeing with tartrate resistant phosphatase (TRAP), and this is a sign (Hughes etc., Nat.Med.2.1132-1135,1996) of osteoclast differentiation.
1, cell pH be in the 0.2M acetate buffer that includes tartaric acid and 2% naphthols AS-BI phosphate (being dissolved in the glycol monoethyl ether) of 4.7-5.0 with 20mg/ml 37 ℃ cultivated 15 minutes.Then, cell transfer was kept 10 minutes to another solution and in 37 ℃, described solution is made up of above-mentioned same buffer, and same tartaric acid concentration is arranged, and contains 0.1% paramagenta (with mixing 5 minutes by six nitrogenize under the equal-volume 4% sodium nitrite solution room temperature).Cause cytoplasmic red staining in the cell of expressing TRAP like this, nuclear is redyed with the Harris hematoxylin.
2, the multinucleated osteoclast of apoptosis is confirmed greatly by the strongly expressed of TRAP and than the TRAP positive cell volume of similar work.Confirm the apoptosis of cell with acridine orange dyeing.The osteoclast of living is fixing and through counting behind the TRAP brazilwood extract dyeing in 95% ethanol, and the osteoclast of apoptosis is represented with the percentage ratio that accounts for multinucleated osteoclast sum in each culture hole (live with apoptosis).
Peptide of the present invention has remarkable effect during less than 100 μ M in concentration.The analysis of expressing among embodiment 5 GnRH mRNA osteoblast and the osteoclast group
From cultured cells as mentioned above, extract total RNA:
1, isolating osteoblast-like cells from the canceration bone
2, Mus osteoblast MC3T3-E1
3, MG-63 (non-mineralization)
4, SaOS-2 (mineralising osteosarcoma)
5, human bone marrow substrate cell
6, people FLG29.1 osteoclast precursor cell
7, the multinucleated osteoclast of bone marrow generation
The expression of GnRH-I and GnRH-II uses the described PCR primer of SEQ I.D.No1-4 to measure by RT-PCR.The integrity of the cDNA that generates is estimated by the level relatively of measuring the actin amplification.Embodiment 6 GnRH-II are to the influence of the bmd of ovariectomized rat
(a) grow up to female that (in 8 weeks, 200-215g) Sprague Dawley rat makes bilateral oophorectomy (OVX).Animal arrives and begins to handle after the back keeps all around again.Allow animal freely absorb Purino rat foodstuff (1.00% calcium, 0.61% phosphorous acid) and water.Each research should comprise the group (8 every group) of 6 individual weights coupling.
(b) begin experiment around behind the OVX.All around, the basis is contrasted the OVX group put to death (A group).All the other respectively organize injection every day once: carrier (B group), GnRH-II1 μ g/kg body weight (C group), 10 μ g/kg body weight (D group), 100 μ g/kg body weight (E group), and the hPTH (1-34) (F group) of 80 μ g/kg.
(c) all rats were weighed once in per four days, surpassed the adjustment dosage of the heavy 50g of average group.Rat is replaced calcein (30mg/kg) or tetracycline (30mg/kg) solution in subcutaneous injection 2% sodium bicarbonate-saline, after drug treating, the mineralising surface carried out labelling in the 10th, 19 and 26 day respectively.Measure bone density with dual intensity X line absorption spectrum DEXA.In the time of 28 days, measure serum calcium level with the colorimetric reagent box.
(d) postmortem is observed the obvious atrophy of orifice of uterus and is not seen that ovary tissue can affirm the success of rat OVX.Separate the bilateral thigh bone from femoral joint.Remove muscle and soft tissue from left side tibia and femur, in 70% ethanol, preserve; Right lower limb tibia front end projection is used the razor scraping, until almost exposing bone marrow.Right side tibia and femur steep after 24 hours in the formalin of 10% phosphoric acid buffer, move in 70% ethanol.
The GnRH-II of the daily 10-100 μ of OO animal per g/kg and the hPTH of 80 μ g/kg handled 28 days, caused significant hypercalcemia.The results are shown in accompanying drawing 1.The celluar localization of embodiment 7 GnRH-II in the paraffin section of normal person and rat bone
(a) with the section of freezing and/or paraffin-embedded people and rat bone fixedly 3-36 hour (size that depends on section) (room temperature 3-5 hour, descended about 24 hours at 4 ℃ then), be immersed in then among 0.1MTris+5%EDTA (12.11g+50gEDTA) pH7.3 up to decalcification.
(b) bone slice is handled (the anti-GnRH-II antibody of the polyclone of rabbit) by standard technique with antibody staining then.
In the platelet of grown cultures plate, megalokaryocyte, all observed GnRH-II dyeing (especially in the chondrocyte of propagation).In particularly active osteoblast of bone formation cell and new osteoid, some dyeing have also been observed.
Embodiment 1 has illustrated the synthetic of peptide of the present invention, 2 preparations of describing this peptide formulations of embodiment, and embodiment 3-7 has confirmed the biological activity of this peptide.Scope of the present invention is not subjected to any restriction of these embodiment.Especially can recognize: the multiple controlled release preparation that can prepare these peptides by the physical property that changes polymer and/or peptide and combination of polymers.But these versions have equal biological nature, and drop among the indicated scope of the invention of following claim.
The SEQ ID NO 1-4 that relates among the embodiment 5 is:
CTG?CAG?CTG?CCT?GAA?GGA??C????(1)
GGG?CGG?GGC?GGG?GCT?CTC??G????(2)
ATT?CTA?CTG?ACT?TGG?TGC?GTG???(3)
GGA?ATA?TGT?GCA?ACT?TGG?TGT???(4)
Sequence table (1) general information (i) applicant:(A) title:FERRING BV (B) street name:MARSSTRAAT 9; PO BOX 3129 (C) city: HOOFDDORP (D) state: nothing (E) name of the country: Holland (F) postcode (ZIP) 2130 KC (ii) denomination of invention: controlled release preparation (iii) sequence number: 7 (iii) computer-reader form: (A) media type: floppy disk (B) computer: IBM PC compatible (C) operating system: PC-DOS/NS-DOS (D) software: PatentIn Release#1.0, information (i) sequence signature of Version#1.30 (EPO) (2) (2) SEQ ID NO 1: (A) chain length: 19 base-pairs (B) type: nucleic acid (C) chain number: strand (D) morphology: line style (ii) molecule type: cDNA (iii) sequence description: SEQ ID NO 1:
Information (i) sequence signature of CTGCAGCTGC CTGAAGGAG 19 (2) SEQ ID NO 2: (A) chain length: 19 base pairs (B) type: nucleic acid (C) chain number: strand (D) morphology: line style is molecule type (ii): cDNA is sequence description (iii): SEQ ID NO 2:
The information of GGGCGGGGCG GGGCTCTCG 19 (2) SEQ ID NO 3: (i) sequence signature: (A) chain length: 21 base pairs (B) type: nucleic acid (C) chain number: strand (D) morphology: line style is molecule type (ii): cDNA is sequence description (iii): SEQ ID NO 3:
The information of ATTCTACTGA CTTGGTGCGT G 21 (2) SEQ ID NO 4: (i) sequence signature: (A) chain length: 21 base pairs (B) type: nucleic acid (C) chain number: strand (D) morphology: line style is molecule type (ii): cDNA is sequence description (iii): SEQ ID NO 4:
GGAATATGTG CAACTTGGTG T 21, (2) information of SEQ ID NO 5:, (i) sequence signature:, (A) chain length: 10 aminoacid, (B) type: aminoacid, (C) chain number: strand, (D) topology: line style, (ii) molecule type: peptide, (ii) feature description:, (ix) feature:, (A) title/key word: decorating site, (B) position: 1, (C) out of Memory :/product=" primary Glu is pyroGLU ", (xi) sequence description: SEQ ID NO 5:
Glu?His?Trp?Ser?Tyr?Gly?Leu?Arg?Pro?Gly
15 10, (2) information of SEQ ID NO 6:, (i) sequence signature:, (A) chain length: 10 aminoacid, (B) type: aminoacid, (C) chain number: strand, (D) topology: line style, (ii) molecule type: peptide, (iii) feature description:, (ix) feature:, (A) title/key word: decorating site, (B) position: 1, (C) out of Memory :/product=" primary Glu is pyroGLU ", (xi) sequence description: SEQ ID NO 6:
Glu?His?Trp?Ser?His?Gly?Trp?Tyr?Pro?Gly
1 5 10 ( 2 ) SEQ ID NO 5： ( i ) ： ( A ) ：10 ( B ) ： ( C ) ： ( D ) ： ( ii ) ： ( iii ) ： ( ix ) ： ( A ) /： ( B ) ：1 ( D ) ：/＝“GlupyroGLU“ ( ix ) ： ( A ) /： ( B ) ：5 ( D ) ：/＝“XaaHisTyr” ( ix ) ： ( A ) /： ( B ) ：7 ( D ) ：/＝“XaaTrpLeu” ( ix ) ： ( A ) /： ( B ) ：8 ( D ) ：/＝“XaaTyrArg” ( xi ) ：SEQ ID NO 7：
Glu?His?Ter?Ser?Xaa?Gly?Xaa?Xaa?Pro?Gly
1??????????5?????????????10
Claims (6)
1. the pharmaceutical preparation of a sustained release treatment peptide or its salt, described peptide has following sequence:
pyroGlu-His-Trp-Ser-Xaa
1-Gly-Xaa
2-Xaa
3-Pro-Gly-NH
2
Wherein, Xaa
1Be His or Tyr,
Xaa
2Be Trp or Leu,
Xaa
3Be Tyr or Arg,
Condition is to work as Xaa
1Be Tyr and Xaa
2When being Leu, Xaa
3Can not be Arg,
Said preparation also comprises a kind of pharmaceutically useful biodegradable polymer.
2. pharmaceutical preparation according to claim 1 is characterized in that described peptide is
pyroGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH
2
3. pharmaceutical preparation according to claim 1 is characterized in that described polymer is the polymer of the hydroxy derivatives of carboxylic acid, or the copolymer of this derivant.
4. pharmaceutical preparation according to claim 3 is characterized in that described polymer is a glycolic acid polymer, lactic acid polymer, or the copolymer of lactic acid and glycolic.
5. pharmaceutical preparation according to claim 1 is characterized in that peptide is aggregated the thing microencapsulation.
6. method for the treatment of human body diseases comprises the individual treatment of this treatment of needs is imitated the controlled release preparation that the above claim of dosage is mentioned in each.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9826662.0 | 1998-12-03 | ||
| GB9826662A GB2344287A (en) | 1998-12-03 | 1998-12-03 | Controlled release pharmaceutical formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1332635A true CN1332635A (en) | 2002-01-23 |
Family
ID=10843631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99815183A Pending CN1332635A (en) | 1998-12-03 | 1999-12-02 | Controlled release formulation comprising GnRH-II |
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|---|---|
| EP (1) | EP1140133A1 (en) |
| JP (1) | JP2002531411A (en) |
| KR (1) | KR20010089538A (en) |
| CN (1) | CN1332635A (en) |
| AU (1) | AU770676B2 (en) |
| BR (1) | BR9915943A (en) |
| CA (1) | CA2353798A1 (en) |
| CZ (1) | CZ20011893A3 (en) |
| EE (1) | EE200100293A (en) |
| GB (1) | GB2344287A (en) |
| HR (1) | HRP20010421A2 (en) |
| HU (1) | HUP0104943A3 (en) |
| IL (1) | IL143496A0 (en) |
| MX (1) | MXPA01005543A (en) |
| NO (1) | NO20012636L (en) |
| NZ (1) | NZ511984A (en) |
| PL (1) | PL348575A1 (en) |
| RU (1) | RU2233170C2 (en) |
| SK (1) | SK7552001A3 (en) |
| TR (1) | TR200102273T2 (en) |
| WO (1) | WO2000032218A1 (en) |
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| CH661206A5 (en) * | 1983-09-23 | 1987-07-15 | Debiopharm Sa | PROCESS FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF HORMONDEPENDENT DISEASES. |
| DE3414595A1 (en) * | 1984-04-18 | 1985-10-31 | Hoechst Ag, 6230 Frankfurt | USE OF GONADOLIBERIN AND GONADOLIBERINAGONISTS FOR TREATING CLIMATE COMPLAINTS |
| US4540513A (en) * | 1984-09-25 | 1985-09-10 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Decapeptide having gonadotropin releasing activity |
| US4721775A (en) * | 1985-08-26 | 1988-01-26 | Board Of Regents, The University Of Texas System | Effective peptides related to the luteinizing hormone releasing hormone from L-amino acids |
| NZ240214A (en) * | 1990-10-16 | 1993-02-25 | Takeda Chemical Industries Ltd | Polymer compositions comprising a polylactic acid and a copolymer of glycolic acid and a hydroxycarboxylic acid; use as carrier for prolonged release pharmaceutical compositions of water soluble drugs |
| IT1243390B (en) * | 1990-11-22 | 1994-06-10 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF PARTICLES SUITABLE FOR THE CONTROLLED RELEASE OF PHARMACOLOGICALLY ACTIVE SUBSTANCES AND PROCEDURE FOR THEIR PREPARATION. |
| CA2192773C (en) * | 1995-12-15 | 2008-09-23 | Hiroaki Okada | Production of sustained-release preparation for injection |
| AU3388597A (en) * | 1996-06-13 | 1998-01-07 | University Of Cape Town | Human type ii gonadotropin-releasing hormone receptor |
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1998
- 1998-12-03 GB GB9826662A patent/GB2344287A/en not_active Withdrawn
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1999
- 1999-12-02 CA CA002353798A patent/CA2353798A1/en not_active Abandoned
- 1999-12-02 JP JP2000584909A patent/JP2002531411A/en active Pending
- 1999-12-02 TR TR2001/02273T patent/TR200102273T2/en unknown
- 1999-12-02 IL IL14349699A patent/IL143496A0/en unknown
- 1999-12-02 MX MXPA01005543A patent/MXPA01005543A/en unknown
- 1999-12-02 SK SK755-2001A patent/SK7552001A3/en unknown
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- 1999-12-02 AU AU15732/00A patent/AU770676B2/en not_active Ceased
- 1999-12-02 EP EP99958357A patent/EP1140133A1/en not_active Withdrawn
- 1999-12-02 BR BR9915943-0A patent/BR9915943A/en not_active IP Right Cessation
- 1999-12-02 RU RU2001118040/15A patent/RU2233170C2/en not_active IP Right Cessation
- 1999-12-02 EE EEP200100293A patent/EE200100293A/en unknown
- 1999-12-02 PL PL99348575A patent/PL348575A1/en not_active Application Discontinuation
- 1999-12-02 CZ CZ20011893A patent/CZ20011893A3/en unknown
- 1999-12-02 WO PCT/GB1999/004045 patent/WO2000032218A1/en not_active Application Discontinuation
- 1999-12-02 HU HU0104943A patent/HUP0104943A3/en unknown
- 1999-12-02 NZ NZ511984A patent/NZ511984A/en unknown
- 1999-12-02 CN CN99815183A patent/CN1332635A/en active Pending
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2001
- 2001-05-29 NO NO20012636A patent/NO20012636L/en not_active Application Discontinuation
- 2001-06-01 HR HR20010421A patent/HRP20010421A2/en not_active Application Discontinuation
- 2001-06-01 ZA ZA200104530A patent/ZA200104530B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104789524A (en) * | 2015-04-30 | 2015-07-22 | 四川大学 | Osteoporotic rat primary osteoblasts isolated culture method and application thereof |
| CN110418799A (en) * | 2017-01-20 | 2019-11-05 | 免疫系统调节控股有限公司 | New compound (immunostimulatory peptides) |
Also Published As
| Publication number | Publication date |
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| WO2000032218A1 (en) | 2000-06-08 |
| NO20012636D0 (en) | 2001-05-29 |
| RU2233170C2 (en) | 2004-07-27 |
| TR200102273T2 (en) | 2001-12-21 |
| NZ511984A (en) | 2002-11-26 |
| HUP0104943A2 (en) | 2002-06-29 |
| HRP20010421A2 (en) | 2002-06-30 |
| SK7552001A3 (en) | 2002-02-05 |
| EP1140133A1 (en) | 2001-10-10 |
| MXPA01005543A (en) | 2003-07-14 |
| AU1573200A (en) | 2000-06-19 |
| NO20012636L (en) | 2001-07-12 |
| BR9915943A (en) | 2001-08-21 |
| GB9826662D0 (en) | 1999-01-27 |
| HUP0104943A3 (en) | 2002-08-28 |
| IL143496A0 (en) | 2002-04-21 |
| PL348575A1 (en) | 2002-06-03 |
| ZA200104530B (en) | 2002-06-04 |
| JP2002531411A (en) | 2002-09-24 |
| CA2353798A1 (en) | 2000-06-08 |
| AU770676B2 (en) | 2004-02-26 |
| KR20010089538A (en) | 2001-10-06 |
| GB2344287A (en) | 2000-06-07 |
| EE200100293A (en) | 2002-08-15 |
| CZ20011893A3 (en) | 2002-05-15 |
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