CN1190897A - Stabilized pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calctum ions - Google Patents
Stabilized pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calctum ions Download PDFInfo
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- CN1190897A CN1190897A CN96195537A CN96195537A CN1190897A CN 1190897 A CN1190897 A CN 1190897A CN 96195537 A CN96195537 A CN 96195537A CN 96195537 A CN96195537 A CN 96195537A CN 1190897 A CN1190897 A CN 1190897A
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- Prior art keywords
- growth hormone
- zinc
- preparation
- optionally
- lysine
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K38/27—Growth hormone [GH] (Somatotropin)
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
A pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions shows a very high stability against deamidation, oxidation and cleavage of peptide bonds. The stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved formulation at ambient temperature.
Description
The present invention relates to contain the stabilizing pharmaceutical composition of growth hormone, prepare the method for said composition, use the compositions of zinc stable growth hormone, and treatment is because of the method for growth hormone caused by abnormal disease.
The growth hormone of people and barn-door fowl is for containing 191 amino acid whose protein approximately, and it is at the synthetic justacrine of antepituitary.The human growth hormone is made up of 191 aminoacid.
Growth hormone is a kind of important hormone, not only participates in the adjusting of body growth, but also participates in protein, carbohydrate and lipometabolic adjusting.The main effect of growth hormone is to promote growth.
The organ that influenced by growth hormone comprises skeleton, connective tissue, muscle, and internal organs such as liver, intestinal and kidney.
Because the development of recombinant technique and the successful clone of growth hormone gene, now put on the agenda to carrying out suitability for industrialized production as human growth hormone and Met-hGH, obtain the human growth hormone but can only from the hypophysis of people's corpse, extract before this.Though people advise using growth hormone therapy of short and small stature (because of growth hormone deficiency causes, normal of short and small stature and Turner syndrome), adult's growth hormone deficiency, infertility, burn, wound healing, malnutrition, union of fracture, osteoporosis, diffusivity gastrorrhagia and pseudarthrosis, but because the very limited supply of growth hormone has limited its application that promotes in short and small patient's child and adolescence longitudinal growth.
In addition, the somebody advises that the ratio of using the speed of growth of growth hormone increase poultry or reducing Animal fat consumes for the mankind.
The Pharmaceutical composition of growth hormone is not really stable.Especially the solution dosage of growth hormone can produce catabolite as going amidatioon or sulfur oxidation product and dimer or polymer form.
The main degradation reaction of hGH has 1) carry out desamidization or the not commensurability L-asp-hGH of last formation by direct hydrolysis by forming ring butanimide mediator, L-iso-asp-hGH, D-asp-hGH, and D-iso-asp-hGH (ref 1-3) and 2) the methionine oxidation (ref 4-9) on 14 and 125 sites.The main degradation products of hGH under solution even the lyophilised state is the hGH of deacylated tRNA amine.
Desamidization mainly occurs in the Asn on 149 sites, and a spot of deacylated tRNA amine reaction also takes place the Asn on other 152 sites.
HGH also is easy to take place oxidation reaction on its 14 and 125 site.
Oxidation takes place for hGH in the solution, and to form sulfoxide be owing to be dissolved in due to the oxygen in the dosage form.The dissolubility of oxygen in distilled water is about 200uM (9).The hGH that then is equivalent to 60nM when the hGH concentration that contains the 4IU/ml dosage form is 1.3mg/ml under normal condition of storage, calculates through stoichiometry, and the content of oxygen has surpassed 3000 times of oxidation hGH aequum.But wanting before the dosage form encapsulation gas in the buffer to be discharged not is an easy thing.
Though think that at present deacylated tRNA amine and the oxidised form of hGH do not have toxicity, the change of bioactive change or receptor-binding characteristic, the more natural hGH relatively configuration stability of its sulfoxide thing has reduced.
Exploitation contains the soluble dosage form of stable dawn of hGH, and deacylated tRNA amine reacts and the method for the speed of sulfoxide thing formation and searching control reaction is very important for understanding.
The kinetics of degraded depends on temperature, various additives or adjuvant in pH and the hGH dosage form.
Because unstability, growth hormone is to be stored under 4 ℃ the condition with freeze dried form at present, just prepares before using, and can making like this degrades reduces to minimum.
The lyophilizing pharmaceutical dosage form that contains hGH is mixed with the solution form by patient at present during use, and 4 ℃ can store 14 days in this state, even but so still have some degradation reactions generations.
In addition, it also usually is inconvenient patient being prepared freeze dried growth hormone.
Therefore, prepare before advocating at present to use growth hormone as far as possible lately, and be under freeze dried form, to store and transportation dosage form.Producer make as far as possible in this transport chain of pharmacy dosage form under the cryogenic conditions of control as 4 ℃ carry out, like this can be with its extension of validity to 2 on the medicine frame year.
, along with the extensive use of the storage system of automedication and the expansion of the scope of application, last user obtains long enough time stable formulation under enough refrigerative conditions always not possible.
The preferred last used dosage form of user can keep stablizing one month under lyophilised state, thereby and kept in addition stablizing the service time that prolonged preparation in one month under the situation of preparation again in storing unit.
Therefore, need a kind of more stable growth hormone dosage form, the lyophilised state of this dosage form can keep the stable of long period under higher relatively temperature, and the solution state between the operating period also can keep the stability of long period under higher relatively temperature in addition.When the administration of growth hormone transfers to when being in administration and when not having above-mentioned suitable condition of storage, this stability is very important to this situation by clinical.
In addition, patient uses for convenience, makes the administering mode of growth hormone be suitable for location mode use, the dosage form that this stable meltable that just need contain growth hormone is separated.Can prepare the stable dissolve dosage form that contains growth hormone, needn't recombination preparation and use to be suitable for the patient with the cartridge case form of storing unit, thereby do not need the required suitable device of freeze-dried formulation, reorganization and be required technology and the sterile vessel of sterilization recombination preparation.
For the reason of safety, the lyophilized formulations of avoiding just recombinating before using preparation also needs.
In addition, it also is very useful avoiding step of freeze drying when the preparation growth hormone.The lyophilizing processing procedure is consuming time and expense is expensive, and because the restriction of lyophil apparatus capacity also usually is the bottleneck step in the production process.
Therefore, be necessary to reduce degraded speed so that dissolved hGH dosage form keep stablizing one month at the medicine frame with between the operating period.
Be not very successful for the trial of stablizing hGH, chief reason is effectively to prevent dimeric formation in the past.The problem that relevant dimer forms can be referring to Becker, document, biotechnology and the biochemical applications 9,478 (1987) of G.W. report.
International Patent Publication No. WO 89/09614 and Australian patent application number 30771/89 disclosed a kind of stable contain growth hormone, the pharmaceutical preparation of glycine and mannitol.Said preparation is in preparation back again between the operating period and all demonstrate the stability of improvement between the storage life at the course of processing and lyophilised state.
European patent application publication No. 3003746 has disclosed can use various stabilizing agents to stablize the growth hormone of animal, thereby reduce insoluble substance and keep the liquid activity of medicine down, this class stabilizing agent comprises some polyhydric alcohol, aminoacid, have the amino acid polymer of electric charge and choline salt at physiological condition pH condition downside chain.Polyhydric alcohol comprises unreduced saccharide, sugar alcohol, saccharic acid, tetramethylolmethane, lactose, water solublity dextran and Fick; Aminoacid comprises glycine, sarcosine, lysine or its salt, serine, arginine or its salt, betanin, N, N ,-dimethyl-glycine, aspartic acid or its salt, glutamic acid or its salt; The amino acid polymer that has electric charge at physiological pH condition downside chain can comprise poly-D-lysine, poly aspartic acid, polyglutamic acid, poly arginine, poly histidine, poly-ornithine or its salt; Choline derivative comprises choline chloride, choline dihydrogen citrate, two (2-Hydroxyethyl)trimethylammonium bitartrates, choline bicarbonate, citric acid three choline, choline ascorbate, choline borate, choline gluconate, phosphocholine, sulphuric acid two choline and mucopolysaccharide acid two choline.
US Patent specification book number is 4,917,685 to have disclosed a kind of embed-type doser it comprises, with the stable growth hormone of the stabilizing agent described in the EP303746.
Disclosed European Patent Application No. is 374,120 to disclose the stabilization formulations that contains hGH and have the polyhydric alcohol of three hydroxyls.Wherein mentioned glycerol and three (methylol) aminomethane.Also disclose in addition polyhydric alcohol with as the histidine monohydrochloride of buffer together.
International Patent Publication No. is that WO 92/00998 discloses the growth hormone crystallization that forms with zinc.
International Patent Publication No. is that WO 93/12811 discloses the stable somatotropin preparation that contains agedoite, and said preparation is freeze-dried powder form or aqueous solution form.
International Patent Publication No. is that WO 93/12812 discloses and contains the stable somatotropin preparation of organizing ammonia, and said preparation is freeze-dried powder form or aqueous solution form.Said preparation with contain phosphate buffer somatotropin preparation comparison deacylated tRNA amine reaction and reduced 25-30%.Disclose also in addition that the growth hormone with zinc can form crystallization under the condition that histidine exists.
It is a kind of with the growth hormone protein preparation of citrate as buffer substance that International Patent Publication No. is that WO 93/19776 discloses, and said preparation is more stable as the preparation of buffer with phosphate.Said preparation also can contain aminoacid such as glycine and alanine and/or mannitol or other sugar alcohol and/or glycerol and/or other carbohydrate, reaches optionally antiseptic such as benzylalcohol.
International Patent Publication No. is that WO 94/03198 discloses a kind of stable aqueous solution system type, and said preparation contains growth hormone, buffer, non-ionic surface active agent, optionally neutral salt, mannitol or antiseptic.
Disclosed European Patent Application No. is 177,478 to disclose a kind of slow releasing composition, and said composition is included in zinc and the growth hormone in the bio-compatible oil continuous phase.
Disclosed European Patent Application No. is 216,485 to disclose a kind of sustainable release composition, and said composition is included in zinc and the growth hormone in the carrier, this carrier contains vegetable oil and adjuvant, adjuvant is Cera Flava, aluminum monostearate, Brazil wax or liquid paraffin.
Disclosed European Patent Application No. number is 277,043 to have disclosed a kind of method, and this method reclaims growth hormone in the solution by adding a kind of transition metal salt and precipitating the complex of capacitive not.
International Patent Publication No. is that WO 93/13792 discloses a kind of sustained-release administration device that can be embedded, this device is equipped with growth hormone, zinc, a kind of selection contain the amino acid whose basic side chain of solving zinc-growth hormone group, and the aminoacid-arginine described in the above-mentioned example, alanine, histidine and glutamic acid.
The International Patent Publication No. number is the stable not growth hormone metallo-ion formulations of changeableness that WO 92/17200 discloses dimeric forms.Said preparation comprises glycine, can select the alanine that adds, glutamic acid, and aspartic acid, arginine or lysine, when freeze-dried formulation formed stable dry stick preparation to produce enough amounts, these aminoacid were very helpful.
Now made us finding uncannily before final formulation preparation, with zinc and optionally lysine or calcium ion handle growth hormone and can make it reaction has very high stability to deacylated tRNA amine in aqueous solution, and under the lyophilizing situation, be easy in aqueous solvent, dissolve.This stability of product makes it store and to transport with freeze dried state or dissolving or dissolved again dosage form.
Pharmaceutical preparation of the present invention can be any suitable way preparation administration, as non-intestinal or oral administration or mucosa delivery as passing through nasal mucosa medicine administration.This pharmaceutical preparation can be made the various forms of doses, as syringe or the pen device as being pre-charged with in it is packed into bottle or cartridge case or other container.
So preparation of the present invention can be made freeze dried Powdered, the carrier of later available routine such as distilled water or water for injection are recombinated, and also can be made into the solution form that contains growth hormone.Carrier comprises conventional stabilizing agent such as phenol, m-cresols and benzylalcohol.
The preferred embodiment of somatotropin preparation of the present invention is that the human growth hormone is reached optionally lysine or calcium ion processing with zinc in advance, and it also comprises the carrier of the aqueous buffer solution form of growth hormone.This preparation is a kind of backup form, and can store with the form of aqueous solution and transport and not significantly degraded.
Buffer as the pretreatment growth hormone solution can be as histidine, citrate, tartrate or phosphate buffer.But with the histidine buffering liquid is better.
The pH value of anticipating solution should be between about 2 to 9, but serve as that better 7-7.3 is best with 6 to 8.
In order to make preparation stabilization, the pH value of the pretreated last preparation of growth hormone should be between 2 to 9, but are that better 6.0 to 6.8 is best with 6-8.
In order to obtain stable effect, zinc and optionally the amount of lysine or calcium ion zinc preferably add to 2mM, but with every mole of growth hormone 1 GH1 to 4 mole zinc serves as better, better with every mole of growth hormone 1 GH1 to 2 mole zinc, preferably every mole of growth hormone 1 GH1 mole zinc.
The zinc that adds serves as better with the form such as the zinc chloride of the compatible soluble-salt of physiology.
If using calcium serves as better with form such as the calcium chloride that adds the compatible soluble-salt of physiology.
Pharmaceutical preparation of the present invention also can comprise for salt or the sugar alcohol of regulating intensity, and for the ease of processing as lyophilizing and the selectivity excipient that also dissolves freeze dried preparation before use fast fully.
Excipient can have to be selected from: disaccharide such as lactose, and trehalose and sucrose, sugar alcohol such as sorbitol or mannitol, polysaccharide is as commercial glucosan (Dextran) polymer such as Dextran
40, Dextran
70, perhaps Dextran
75, Fick (Ficoll), polyhydric alcohol such as Polyethylene Glycol or polyvinyl alcohol, perhaps above-mentioned two kinds or more of mixture.
The present invention relates to the method for useful in preparing drug formulations on the other hand, said preparation comprises with zinc and optionally lysine or calcium ion carry out pretreated growth hormone, wherein growth hormone is dissolved in and contains the zinc and the solution of lysine or calcium ion optionally, concrete step is earlier zinc chloride to be dissolved in the deionized water that contains selective lysine or calcium ion, with this solution left standstill for a moment, add growth hormone then and regulate pH to 2 to 9.
Regulate pH value by adding the acid that growth hormone is had no side effect, preferred acceptable acid of physiology such as mineral acid example hydrochloric acid, sulphuric acid or nitric acid or organic acid such as acetic acid.
In an embodiment of the inventive method, optionally add salt and a kind of excipient, in the container of then solution being packed into and carry out lyophilizing.
The invention still further relates to use zinc and optionally lysine or calcium ion come the pretreatment growth hormone, thereby obtain stable somatotropin preparation.
The invention still further relates to the method for the disease that treatment causes unusually because of growth hormone, this method comprises the preparation that gives a kind of growth hormone of handling through zinc and selectivity lysine or calcium ion in advance.
Described herein " growth hormone " can derive from following animal organ such as bird, cattle, and horse, the people, sheep, pig, Oncorhynchi, Squaliobarbus ourriculus or tuna, but with the people, the growth hormone of cattle or pig are better, are best with people's growth hormone.Employed growth hormone can be the spontaneous growth hormone that extracts from natural goods among the present invention, as use conventional method to extract from pituitary gland, or with the growth hormone of recombinant technique preparation,, reported in 1-11 (1990) magazine at biotechnology and biological engineering .36 as E.B.Jensen and S.Carlsen." growth hormone " can be to have cut away one or more amino acid whose growth hormone; It can be the analog that one or more aminoacid has been replaced by other aminoacid in the spontaneous growth hormone, wherein aminoacid is better with the natural amino acid, but above-mentioned replacement should not cause that bad influence is as having increased antigenicity or having reduced pharmaceutically active; Also can be its derivant that has N-or C-end, as Met-hGH.With this growth hormone of hGH serves as better.
This speech of growth hormone " dosage " is meant the amount that can play therapeutic effect in the scheme of administration.The amount that prepared preparation contains hGH is at least 0.1mg/ml, serves as better to reach 10mg/ml, is generally 1mg/ml to 40mg/ml, serves as better with 1mg/ml to 25mg/ml, and to 5mg/ml, dosage calculates according to standby preparation as 1mg/ml.As taking said composition for the low dwarfism patient of trouble pituitary function, said preparation should contain hGH 0.1mg/ml to 10mg/ml, and this is corresponding with the dosage that will treat disease.It is very important that concentration range of the present invention is not, and can change according to the doctor who carries out treatment.
Lysine used in the present invention serves as better with natural alpha amino acid.Lysine can be 1 or d lysine or both mixture.
More stable and preferred the same with the preparation that contains the histidine used as stabilizers accordingly stable as the conventional dosage form that contains phosphate buffer of preparation, then obtained " high stability " dosage form described in the present invention, wherein with WO 93/12812 in the preparation of phosphate buffer relatively, react as the deacylated tRNA amine of its hGH of corresponding preparations of stabilizing agent with histidine and to have reduced 20%.
Solvent used in the inventive method can be water, alcohols such as ethanol, n-propanol or isopropyl alcohol, butanols or their mixture.Can contain stabilizing agent such as phenol in the solvent, m-cresols or benzylalcohol.
Relevant with somatotropin preparation herein " pretreatment " speech was meant before somatotropin preparation adds other composition for preparation, used zinc and optionally lysine or calcium ion are handled growth hormone.
The present invention will set forth the present invention in more detail by following embodiment.But these embodiment are used for limiting the scope of the present invention that additional claim limits.
Experimental section
Embodiment
Reduce the reaction of deacylated tRNA amine
For containing 4mg/ml hGH, 0.18mM ZnCl
2, 3mM histidine, 1.5% benzylalcohol, the hGH preparation of pH6.8 are to measure after the different pretreatment of 37 ℃ of processes the speed of deacylated tRNA amine, and relatively pH is the difference of preparation on deacylated tRNA amine speed of 6.8 o'clock histidine and phosphate buffer.
The hGH preparation is to prepare by the solution that 24mg hGH is dissolved in below the 2.5ml
a)2mM?CaCl
2+0.36mM?ZnCl
2，pH7-7.3
B) 2mM lysine+0.36mM ZnCl
2, pH7-7.3
c)0.36mM?ZnCl
2，pH7-7.3。
After leaving standstill 1h under 4 ℃ (make zinc and hGH compound), use PD10 to desalt pillar (Pharmacia) reprovision preparation a)-c), make it become 3ml 6mM histidine, 0.36mM ZnCl
2, the preparation of 8mg/mlhGH.The benzylalcohol that adds 3ml 3% then makes last preparation contain 4mg/ml hGH, 3mM histidine, 0.18 ZnCl
2MM, 1.5% benzylalcohol, (by adding HCl/NaOH) with pH regulator to 6.8.
Used control formulation is a) 4mg/ml hGH, 3mM histidine, 0.18mM ZnCl
2, 1.5% benzylalcohol, pH6.8; B) 4mg/ml hGH, 3mM histidine, 1.5% benzylalcohol, pH6.8; And c) 4mg/ml hGH, 3mM histidine, 3mM Na
2HPO
4, 1.5% benzylalcohol, pH6.8.Control dosage forms is in advance without Zn
++Handle.
HGH preparation described in the table stores 7 days under 37 ℃ condition below, analyzes the content of the hGH of deacylated tRNA amine then with IE-HPLC.The results are shown in following table.
| Preparation | PH begins/and pH is last | Content (%) # of deacylated tRNA amine hGH | With comparison deacylated tRNA amine content (%) with histidine |
| The 3mM histidine, 0.18mM ZnCl 2, 1.5% benzylalcohol, pH6.8.A) pretreatment set by step | 6.78/6.84 | 10.0 | 84 |
| The 3mM histidine, 0.18mM ZnCl 2, 1.5% benzylalcohol, pH6.8.B set by step) pretreatment | 6.75/6.83 | 11.3 | 88 |
| The 3mM histidine, 0.18mM ZnCl 2, 1.5% benzylalcohol, pH6.8.C set by step) pretreatment | 6.79/6.87 | 11.5 | 89 |
| The 3mM histidine, 0.18mM ZnCl 2, 1.5% benzylalcohol, pH6.8.Not pretreatment | 6.84/6.92 | 12.8 | 99 |
| The 3mM histidine, 1.5% benzylalcohol, pH6.8. | 6.84/6.92 | 12.9 | 100 |
| 3mM Na 2HPO 4, 1.5 % benzylalcohols, pH6.8 | 6.83/6.86 | 15.9 | 123 |
The amount of # deacylated tRNA amine is 1% gauged by every 0.1pH unit deviation of pH value 6.8.
Top table is presented at reuse salt and handles before the final histidine preparation, and under the condition of calcium ion or lysine existence, after zinc ion was handled hGH solution, for histidine, hGH deacylated tRNA amine speed reduced to 84% (the phosphate preparation is 68%).
List of references
1) parenteral formulation of Y.-C.J.Wang and M.A.Hanson. albumen and polypeptide class: stability and stabilizing agent.Non-intestinal Science and Technology magazine 42 (Suppl.) (1988) 53-525.
2) M.C.Manning, K.Patel, the stability of R.T.Borchardt. protein drug.Drug research 6 (11) (1989) 903-918.
3) .B.A.Johnson, J.M.Shirokawa, W.S.Hancock, M.W.Spellman, L.J.Basa and D.W.Asward. journal of biological chemistry 264,1462-71 (1989).
4) L.C.Teh et al., journal of biological chemistry, 262,785-794 (1987).
5) G.W.Becker et al., biotechnology, biochemistry are used, and 10,326-337 (1988).
6) R.A.Houghten et al., biochemistry, biophysics, 178,350-355 (1977)
7) R.M.Riggin et al., bioanalysis, 167,199-209 (1987).
8)P.Gellerfors?et?al.，Acta?Paediatr.Scand(suppl)，370，93-100(1990).
9) M.J.Kaufman, drug research, 7 (3) 289-292 (1990).
Claims (10)
1. pharmaceutical preparation, it comprises in advance with zinc and the growth hormone handled of lysine or calcium ion optionally.
2. desired pharmaceutical preparation also comprises carrier in the claim 1, and its form is through zinc and the growth hormone buffer solution handled of lysine or calcium ion optionally.
3. desired pharmaceutical preparation in the claim 1 or 2 wherein is adjusted to pH value between 2 to 9.
4. the preparation of any desired medicine, the wherein about 2mM of zinc ion concentration as many as during aforesaid right requires.
5. any desired pharmaceutical preparation during aforesaid right requires, it also comprises salt and/or saccharide and/or sugar alcohols.
6. aforesaid right requires any desired pharmaceutical preparation among the 1-5, and wherein growth hormone is hGH.
7. the method for useful in preparing drug formulations, said preparation comprises with zinc and optionally lysine or the pretreated growth hormone of calcium ion, wherein growth hormone is dissolved in and comprises zinc and the acid of selectivity speed or bore ion solution, this method comprises zinc chloride is dissolved in the deionized water that optionally contains lysine or calcium ion, make this solution left standstill for a moment, add growth hormone, and optionally add antiseptic, optionally pH value is adjusted to about 2 to 9.
8. desired method in the claim 7 wherein optionally adds salt and/or sugar alcohols and excipient, in the container of then solution being packed into and lyophilizing handle.
9. use zinc and optionally thereby lysine or calcium ion are anticipated growth hormone and obtained stable somatotropin preparation.
10. a treatment is because of the method for growth hormone deficiency associated diseases, and it comprises and gives the preparation described in the claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US119395P | 1995-07-14 | 1995-07-14 | |
| US60/001,193 | 1995-07-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1190897A true CN1190897A (en) | 1998-08-19 |
Family
ID=21694837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195537A Pending CN1190897A (en) | 1995-07-14 | 1996-06-28 | Stabilized pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calctum ions |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0839049A1 (en) |
| JP (1) | JPH11509212A (en) |
| KR (1) | KR19990028981A (en) |
| CN (1) | CN1190897A (en) |
| AU (1) | AU715997B2 (en) |
| BR (1) | BR9609741A (en) |
| CA (1) | CA2226523A1 (en) |
| CZ (1) | CZ9498A3 (en) |
| HU (1) | HUP9802287A3 (en) |
| IL (1) | IL122583A0 (en) |
| NO (1) | NO980155L (en) |
| PL (1) | PL324379A1 (en) |
| WO (1) | WO1997003692A1 (en) |
| ZA (1) | ZA965368B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109010254A (en) * | 2008-08-15 | 2018-12-18 | 硬木药品公司 | It is suitble to the stable solid pharmaceutical preparation of the guanylate cyclase-C receptor agonist polypeptide of oral administration |
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| US6191107B1 (en) | 1997-09-26 | 2001-02-20 | Takeda Chemical Industries, Ltd. | Complex of human growth hormone and zinc |
| NZ525914A (en) | 1998-03-10 | 2004-03-26 | Genentech Inc | Novel polypeptides and nucleic acids encoding the same |
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| CA2328496C (en) | 1998-05-15 | 2016-01-05 | Genentech, Inc. | Il-17 homologous polypeptides and therapeutic uses thereof |
| US20020172678A1 (en) | 2000-06-23 | 2002-11-21 | Napoleone Ferrara | EG-VEGF nucleic acids and polypeptides and methods of use |
| EP1978029A3 (en) | 1999-06-15 | 2008-10-15 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids endoding the same |
| CA2494705A1 (en) | 1999-12-01 | 2001-06-07 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
| EP1897946B1 (en) | 1999-12-23 | 2012-07-11 | Genentech, Inc. | IL-17 homologous polypeptides and therapeutic uses thereof |
| ATE424457T1 (en) | 2000-01-13 | 2009-03-15 | Genentech Inc | HUMAN STRA6 POLYPEPTIDES |
| KR20090007504A (en) | 2000-02-24 | 2009-01-16 | 몬산토 테크놀로지 엘엘씨 | Non-aqueous injectable formulations for extended release of somatotropin |
| US6740520B2 (en) | 2000-03-21 | 2004-05-25 | Genentech, Inc. | Cytokine receptor and nucleic acids encoding the same |
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| AU1757092A (en) * | 1991-03-28 | 1992-11-02 | Genentech Inc. | Stable growth hormone metal ion formulations |
-
1996
- 1996-06-25 ZA ZA965368A patent/ZA965368B/en unknown
- 1996-06-28 EP EP96922775A patent/EP0839049A1/en not_active Withdrawn
- 1996-06-28 BR BR9609741A patent/BR9609741A/en not_active Application Discontinuation
- 1996-06-28 AU AU63534/96A patent/AU715997B2/en not_active Ceased
- 1996-06-28 CA CA002226523A patent/CA2226523A1/en not_active Abandoned
- 1996-06-28 KR KR1019980700283A patent/KR19990028981A/en not_active Application Discontinuation
- 1996-06-28 PL PL96324379A patent/PL324379A1/en unknown
- 1996-06-28 IL IL12258396A patent/IL122583A0/en unknown
- 1996-06-28 CN CN96195537A patent/CN1190897A/en active Pending
- 1996-06-28 CZ CZ9894A patent/CZ9498A3/en unknown
- 1996-06-28 HU HU9802287A patent/HUP9802287A3/en unknown
- 1996-06-28 JP JP9506179A patent/JPH11509212A/en active Pending
- 1996-06-28 WO PCT/DK1996/000293 patent/WO1997003692A1/en not_active Application Discontinuation
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1998
- 1998-01-13 NO NO980155A patent/NO980155L/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109010254A (en) * | 2008-08-15 | 2018-12-18 | 硬木药品公司 | It is suitble to the stable solid pharmaceutical preparation of the guanylate cyclase-C receptor agonist polypeptide of oral administration |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA965368B (en) | 1997-01-14 |
| PL324379A1 (en) | 1998-05-25 |
| NO980155D0 (en) | 1998-01-13 |
| HUP9802287A3 (en) | 2000-10-30 |
| KR19990028981A (en) | 1999-04-15 |
| WO1997003692A1 (en) | 1997-02-06 |
| BR9609741A (en) | 1999-03-16 |
| HUP9802287A2 (en) | 1999-02-01 |
| MX9800358A (en) | 1998-07-31 |
| NO980155L (en) | 1998-01-13 |
| CA2226523A1 (en) | 1997-02-06 |
| AU715997B2 (en) | 2000-02-17 |
| JPH11509212A (en) | 1999-08-17 |
| CZ9498A3 (en) | 1998-06-17 |
| AU6353496A (en) | 1997-02-18 |
| IL122583A0 (en) | 1998-06-15 |
| EP0839049A1 (en) | 1998-05-06 |
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