CN105412910A - Stable human growth hormone liquid preparation - Google Patents
Stable human growth hormone liquid preparation Download PDFInfo
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- CN105412910A CN105412910A CN201510788557.0A CN201510788557A CN105412910A CN 105412910 A CN105412910 A CN 105412910A CN 201510788557 A CN201510788557 A CN 201510788557A CN 105412910 A CN105412910 A CN 105412910A
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- growth hormone
- human growth
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/08—Solutions
Abstract
The invention discloses a stable liquid preparation, which consists of human growth hormone, and L-lysine, L-arginine or polyethylene glycol 300, as well as a poly (ethylene oxide)-poly (propylene oxide) copolymer, polyethylene glycol-15 poly-hydroxy stearate or polyethylene glycol-35 castor oil.
Description
The application is Chinese Patent Application No. 200680055699.5 (PCT/KR2006/002640), July 6 2006 applying date, and denomination of invention is the divisional application of " stable liquid formulation of human growth hormone ".
Technical field
The present invention relates to stable liquid preparation, it comprises human growth hormone; 1B, L-arginine or Liquid Macrogol; (propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini poly-with poly-(ethylene oxide).
Background technology
The human growth hormone produced in human pituitary is 191 amino acid whose single chain polypeptides, and the molecular weight had is about 22,000 dalton.Human growth hormone is mainly used in the growth hormone deficiency dwarfism (Endocrinol.Rev.4,155,1983) for the treatment of child.
Human growth hormone tends to as instability in pharmaceutical preparation.The growth hormone catabolite of product and dimer or the polymer form comprising desamidization or sulphoxylic acid can be generated in the solution.The predominant chemical degradation reaction of human growth hormone is Deamidation, and it especially carries out by direct hydrolysis or by the formation of cyclic succinimide intermediate L-asp-hGH, L-iso-asp-hGH, D-asp-hGH and D-iso-asp-hGH in the position of the asparagine residue of 149.At present, think that the product of these desamidizations of human growth hormone does not have virose or immovable biological activity or receptors bind performance, but compared with natural human growth hormone, the structural stability of sulfoxide decreases.
The human growth hormone of desamidization for being undesirable as medicine, because its experience quality deterioration, although biological activity does not change, and therefore its admissible content is provided by disclosed pureness specifications usually.In addition, the formation of growth hormone aggregation such as dimer or polymer causes undesirable immunogenicity, causes safety problem in vivo, and produces suspended solid, cause problem of appearance, thus causes patient to be unsatisfied with.
Protein stability and water closely related.Human growth hormone is commercially available mainly as the lyophilized formulations in order to increase its stability, and it must reconstruct before use.But carried out much research to the liquid preparation of human growth hormone, object is the convenience improved doctor and patient.Such as, the U.S. Patent number 6,448,225 relating to Genentech ' sNutropinAQ discloses the aqueous compositions of human growth hormone, it comprises human growth hormone, mannitol, buffer agent and nonionic surfactant, wherein describes citrate buffer agent as preferable examples.Korean Patent Application No. 10-1999-0001217 provides stable aqueous compositions, wherein human growth hormone being dissolved in comprises in the buffer solution of benzalkonium chloride, described buffer solution uses subacidity to prepare to the buffer agent of moderate acid, preferred maleate buffer.Korean Patent Application No. 10-1998-0052483 describes the liquid formulation of human growth hormone of pharmaceutically stable, wherein the preferred buffer solution be made up of sodium acetate and sodium glutamate.In addition, in Korean Patent Application No. 10-1994-0702139, NovoNordiskA/S describes a kind of pharmaceutical preparation, it comprises growth hormone, with the aminoacid being selected from Asp, Ile, Val, Leu and His, or the derivant of histidine, or comprise the peptide of at least one basic amino acid and at least one acidic amino acid, and non-ionic detergent such as Polysorbate or poloxamer.NovoNordiskA/S's NorditropinSimpleXx has at present gone on the market, and it comprises human growth hormone, histidine buffer, nonionic surfactant, sodium chloride and antiseptic.
But, as mentioned above, although carried out multiple trial to provide the liquid preparation of growth hormone, still need more stable growth hormone liquid preparation.
Summary of the invention
Technical problem
Therefore, the object of this invention is to provide stable liquid formulation of human growth hormone, it is by combining specific aminoacid such as 1B or L-arginine or Polyethylene Glycol and specific surfactant, to make the formation of deamidated products and gathering minimize, thus to enhance long-term storing stability and convenience relative to known liquid preparation.
Accompanying drawing explanation
Fig. 1 be represent liquid preparation of the present invention 25 DEG C store three months time the remaining proportion of human growth hormone in Deamidation and gathering (%) figure.
Fig. 2 be represent liquid preparation of the present invention 2 DEG C to 8 DEG C store 1 year time the remaining proportion of human growth hormone in Deamidation and gathering (%) figure.
Preferred implementation
In an aspect, the present invention relates to stable liquid preparation, it comprises human growth hormone, 1B or L-arginine and poly-(ethylene oxide) poly-(propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini.
It can be naturally occurring for being intended to human growth hormone stabilized in liquid preparation of the present invention, or can derive from the prokaryote or eukaryote that use the recombinant DNA technology DNA of encoding human growth hormone to transform.Use described by escherichia coli or yeast have in the literature as the method that genetic recombinants host produces human growth hormone, such as Korean patent No. 25013, Korean patent No. 316347 or Korean Patent Publication No. 10-1997-0006498.Human growth hormone can be wild type or derivatives thereof.
Liquid preparation of the present invention comprises 1B or L-arginine as stabilizing agent.The preferably salt form of described stabilizing agent, such as L-lysine hydrochloride or L-arginine hydrochlorate.Compared with the amino acid stabilizers of other routine, described stabilizing agent shows the good effect not producing gathering in the liquid preparation of human growth hormone after storing predetermined time section.Above-mentioned stabilizing agent, as shown in table 8, do not assemble after 14 days, therefore show and better stability compared with the histidine in International Patent Publication No. WO1997/39768.When providing stable liquid formulation of human growth hormone, these results show and are only disclosing the good effect do not disclosed in the patent and other known references using aminoacid to quote as stabilizing agent above-mentioned.
Gathering (propylene oxide) copolymer (poloxamer), Solutol HS 15 (Solutol HS 15) or polyoxyl castor oil ELP (Polyethylene Glycol-35 Oleum Ricini) for poly-(ethylene oxide) in liquid preparation of the present invention is nonionic surfactant.In multiple nonionic surfactant, when the present inventor uses above-mentioned surfactant by them and specific combination of stabilizers, find that liquid preparation has the stability of enhancing.Compared with the Polysorbate such as polysorbas20 or Tween 80 of routine, the effect (table 5) that these surfactants show in the Deamidation and gathering of human growth hormone.Poloxamer is preferably PLURONICS F87 (poly-(ethylene oxide) poly-(propylene oxide) copolymer 1 88) or poloxamer188 (poly-(ethylene oxide) poly-(propylene oxide) copolymer 407), is more preferably PLURONICS F87 (poly-(ethylene oxide) poly-(propylene oxide) copolymer 1 88).
Liquid preparation of the present invention can comprise additive known in the art in addition, such as buffer agent, isotonic agent, antiseptic or analgesic.
Described buffer agent can be used for the pH value of regulates liquid preparation and does not affect human growth hormone, and example is acetate, glutamate, Glu, lactate, malate, citrate and phosphate.Optimization citric acid sodium or sodium acetate.Apparent from the result of embodiment 4, buffer agent does not affect the stability of liquid preparation of the present invention.Obtaining these results is because the good stability of liquid preparation of the present invention derives from the combination of specific stabilizing agent and specific surfactant.Buffer agent exists with the concentration of 5-100mM, preferably 5-50mM in liquid preparation of the present invention.
Isotonic agent used in the present invention can comprise sodium chloride, mannitol, sucrose, glucose, Sorbitol or its mixture.Preferred D-mannital.Isotonic agent preferably exists with the concentration of 20-50mg/ml in liquid preparation of the present invention.
Antiseptic used in the present invention can comprise benzyl alcohol, phenol and metacresol.Preferred benzyl alcohol.Benzyl alcohol plays the effect of analgesic and antiseptic.Antiseptic preferably exists to the amount of 9mg/ml scope with 1 in liquid preparation of the present invention.
In in detailed, the 1B that liquid preparation of the present invention comprises the human growth hormone of 2.5-7.5mg/ml, every mg human growth hormone be 0.01-1.0% (w/v) or poly-(ethylene oxide) of L-arginine and 0.01-1.0% (w/v) gather (propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini.In in more detailed, this liquid preparation comprises the human growth hormone of 2.5-5.5mg/ml; Every mg human growth hormone is 1B or the L-arginine of 0.02-0.5% (w/v); (propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini poly-with poly-(ethylene oxide) of 0.1-0.5% (w/v).
In in preferred, liquid formulation of human growth hormone of the present invention comprises the human growth hormone of 2.5-5.5mg/ml; Every mg human growth hormone is 1B or the L-arginine of 0.02-0.5% (w/v); Poly-(ethylene oxide) poly-(propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini of 0.1-0.5% (w/v); The sodium citrate of 5-20mM or sodium acetate; The D-mannital of 20-50mg/ml; With the benzyl alcohol of 1-9mg/ml.Liquid preparation be moderate acid or neutrality, the pH value preferably had is 5.8-7.0, be more preferably the pH value of 6.0-6.2.
In in other, the present invention relates to stable liquid preparation, it comprises human growth hormone, Liquid Macrogol; Poly-(ethylene oxide) poly-(propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini.
Be included in the human growth hormone in liquid preparation and gather (ethylene oxide) poly-(propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini same as described above.
Liquid preparation of the present invention can comprise Liquid Macrogol as stabilizing agent.Polyethylene Glycol is water miscible and is dissolved in the useful polymer of multiple organic solvent.Because Polyethylene Glycol is nontoxic and removes fast from health, so use it for stable pharmaceutical composition (International Patent Publication No. WO01/26692).Korean Patent Application No. 10-2003-0061434 discloses the liquid preparation of human growth hormone, and it comprises Polyethylene Glycol and replaces Polysorbate as nonionic surfactant, and does not comprise antibacterial such as benzyl alcohol or phenol.But in Polyethylene Glycol, described application describes the Polyethylene Glycol using the molecular weight of 0.001-20mg/ml to be greater than 3,000Da, and does not use surfactant.The Polyethylene Glycol (that is, Liquid Macrogol) that this and use molecular weight are 300Da and specific surfactant are so that the present invention improving liquid preparation stability forms contrast.As mentioned above, the present invention by combinationally using specific Polyethylene Glycol and specific surfactant minimizing gathering, thus makes liquid preparation to preserve for a long time.
Aforesaid liquid preparation of the present invention can comprise additive known in the art in addition, such as buffer agent, isotonic agent, antiseptic or analgesic.Described buffer agent, isotonic agent, antiseptic or analgesic are same as described above.
In in detailed, liquid preparation of the present invention comprises the human growth hormone of 2.5-7.5mg/ml, every mg human growth hormone be the Liquid Macrogol of 0.1-5.0% (v/v) and poly-(ethylene oxide) of 0.01-1.0% (w/v) gathers (propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini.In in more detailed, this liquid preparation comprises the human growth hormone of 2.5-5.5mg/ml; Every mg human growth hormone is the Liquid Macrogol of 0.2-1.0% (v/v); (propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini poly-with poly-(ethylene oxide) of 0.1-0.5% (w/v).
In in preferred, liquid formulation of human growth hormone of the present invention comprises the human growth hormone of 2.5-5.5mg/ml; Every mg human growth hormone is the Liquid Macrogol of 0.2-1.0% (v/v); Poly-(ethylene oxide) poly-(propylene oxide) copolymer, Solutol HS 15 or Polyethylene Glycol-35 Oleum Ricini of 0.1-0.5% (w/v); The sodium citrate of 5-20mM or sodium acetate; The D-mannital of 20-50mg/ml; With the benzyl alcohol of 1-9mg/ml.Liquid preparation be moderate acid or neutrality, the pH value preferably had is 5.8-7.0, be more preferably the pH value of 6.0-6.2.
Embodiment
In order to understand the present invention better, providing following examples to illustrate the present invention, should not be seen as restriction the present invention.
Embodiment 1: the preparation of liquid formulation of human growth hormone and analysis
Following preparation liquid preparation of the present invention.By the natural human growth hormone (Daewoong of 4.0mg/ml, Korea, it provided using bulk solution form before being lyophilized) with as buffer agent to regulate the 10mM aqueous solution of the sodium acetate (Sigma) of pH to 6.0-6.2 scope, sodium citrate (Sigma) or sodium dihydrogen phosphate (Sigma).After solution is adjusted to ultimate density, by itself and excipient (D-mannital, Sigma), surfactant { Solutol HS 15 (SolutolHS15, BASF), PLURONICS F87 (LutrolF68, BASF), poloxamer188 (LutrolF127, BASF), polyoxyl castor oil ELP (BASF), Tween20 (CRILLET1HP, or Tween80 (CRILLET4HP Croda), Croda) }, stabilizing agent (Liquid Macrogol (PEG300, BASF), PEG400 (PEG400, BASF), PVPK-12 (Kollidon12PF, BASF), PVPK-15 (Kollidon15PF, BASF), 1B (L-LysineHCl, or L-arginine (L-ArginineHCl Sigma), Sigma)), with the benzyl alcohol (Daejung as antiseptic, Korea) mix.
By the liquid preparation that the obtains stored under strict conditions fortnight at 40 DEG C and 75%RH.Check the stability of the human growth hormone of preparation in Deamidation and polymerization in time.According to European Pharmacopoeia method (EP method), Deamidation uses reversed-phase HPLC (RP-HPLC) to measure, and the formation of dimer and polymer is measured by size-exclusion HPLC (SEC-HPLC).
Embodiment 2: evaluation table surface-active agent is on the impact of human growth hormone's stability
In order to study the acceptable surfactant of pharmacy to the impact of human growth hormone's stability, component listed in use table 1 prepares liquid formulation of human growth hormone, then analyzes according to the method identical with embodiment 1.
Table 1
Type according to surfactant is evaluated human growth hormone's Deamidation of the liquid preparation of so preparation and gathering, and result provides in table 2 below.
In table 2, according to the time at 40 DEG C, Deamidation (%) represents the calibration remaining proportion (%) of the active human growth hormone of non-desamidization, assembles the calibration remaining proportion (%) representing and do not form the active human growth hormone of dimer or polymer.
Table 2
Compared with the control, find that using surfactant to prepare preparation inhibits Deamidation and gathering.These results show, use surfactant to improve the stability of liquid formulation of human growth hormone.
Embodiment 3: evaluate stabilizing agent to the impact of human growth hormone's stability
In order to study difference with stabilizing agent to the impact of human growth hormone's stability, component listed in use table 3 prepares the liquid preparation of human growth hormone, then analyzes according to the method identical with embodiment 1.
Table 3
Type according to stabilizing agent is assessed the Deamidation of the liquid preparation of so preparation and gathering, and result provides in following table 4.
Table 4
As shown in table 4, in the stabilizing agent used, find that PEG300 (Liquid Macrogol) and two seed amino acids (L-LysHCl and L-ArgHCl) make human growth hormone's stabilisation.Especially, when using 1B and L-arginine, inhibit the gathering in preparation with higher degree.
Embodiment 4: evaluate buffer agent to the impact of human growth hormone's stability
For containing the liquid preparation of the PEG300 being proved to be the human growth hormone's stabilisation made in liquid preparation in embodiment 3 further according to the stability of the type research human growth hormone of buffer agent.
The component listed from table 5 according to method in the same manner as in Example 1 prepares the liquid preparation of human growth hormone.
Table 5
By the 40 DEG C of deamidated form of analyst's growth hormone and formation of dimer/polymer in time, measure the stability of the liquid preparation of so preparation according to the difference of Buffer types.The remaining proportion of active human growth hormone is described in in following table 6.
Table 6
Buffer agent is usually at above-mentioned patent and application (U.S. Patent number 6,448,225, Korean Patent Application No. 10-1999-0001217 and Korean Patent Application No. 10-1998-0052483) in be described as be in the liquid preparation of human growth hormone be important.But as shown in table 6, depend on the type of normally used buffer agent, liquid preparation of the present invention does not show the remarkable difference of stability aspect.
Embodiment 5: the contrast of the stability of liquid preparation
In order to compare the stability according to liquid preparation of the present invention, use and prepare two contrast liquid preparations (contrast 1 and contrast 2) with component listed in following table 7, and contrast with according to human growth hormone (hGH) liquid preparation prepared as embodiment 1 same procedure.
Table 7
The hGH liquid preparation so prepared is stored 14 days under 40 DEG C of conditions with 75%RH.Then, SEC-HPLC is used to measure the remaining proportion of growth hormone.In addition, by preparation at 2 DEG C to 8 DEG C under horizontal oscillations (amplitude is 20mm, vibration per minute 220 times) cultivate 24 hours, then check assemble and outward appearance.Result provides in following table 8.
Table 8
As shown in table 8, in the contrast 1 not containing any stabilizing agent, produce the aggregation of top level, in the contrast 2 using histidine to prepare as stabilizing agent, produce the second high level.By contrast, except DWF16, liquid preparation of the present invention does not produce aggregation.These results show, can by using specific aminoacid (1B or L-arginine) or PEG300 as stabilizing agent and the stable liquid formulation of human growth hormone of the incompatible preparation of specific group of surfactants.
In addition, for storing three months at 25 DEG C and storing at 2 DEG C-8 DEG C until 1 year time the remaining proportion of growth hormone check liquid preparation.Result provides in following table 9 and Fig. 1 and 2.
Table 9
As shown in table 9 and Fig. 1 and 2, in the storage process of at least one year section, liquid preparation is stable.
Industrial applicibility
As mentioned above, the present invention adopts specific stabilizing agent and specific surfactant to combine, overcome the problem that liquid formulation of human growth hormone stability is low, thus inhibit the formation of the deamidated products of human growth hormone, and prevent gathering to become dimer or polymer especially, stability is significantly strengthened.Therefore, liquid preparation of the present invention is quite tolerant for extraneous stress in transport and storage process.
Claims (4)
1. liquid preparation, comprises human growth hormone, 1B or L-arginine and PLURONICS F87, and wherein human growth hormone exists with the amount of 2.5-5.5mg/ml scope; 1B or L-arginine exist with the amount that every mg human growth hormone is 0.02-0.5w/v% scope; And PLURONICS F87 exists with the amount of 0.1-0.5w/v% scope.
2. the liquid preparation of claim 1, wherein said 1B or L-arginine are hydrochlorates.
3. the liquid preparation of claim 1, comprises at least one be selected from buffer agent, isotonic agent, antiseptic and analgesic in addition.
4. the liquid preparation of claim 3, wherein human growth hormone exists with the amount of 2.5-5.5mg/ml scope; 1B or L-arginine exist with the amount that every mg human growth hormone is 0.02-0.5w/v% scope; PLURONICS F87 exists with the amount of 0.1-0.5w/v% scope; Sodium citrate or sodium acetate exist with the amount of 5-20mM scope; D-mannital exists with the amount of 20-50mg/ml scope; Exist with the amount of 1-9mg/ml scope with benzyl alcohol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006800556995A CN101505789A (en) | 2006-07-06 | 2006-07-06 | A stable liquid formulation of human growth hormone |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2006800556995A Division CN101505789A (en) | 2006-07-06 | 2006-07-06 | A stable liquid formulation of human growth hormone |
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| CN105412910A true CN105412910A (en) | 2016-03-23 |
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| CN201510786949.3A Pending CN105363022A (en) | 2006-07-06 | 2006-07-06 | Stable human growth hormone liquid preparation |
| CN201510788557.0A Pending CN105412910A (en) | 2006-07-06 | 2006-07-06 | Stable human growth hormone liquid preparation |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510786949.3A Pending CN105363022A (en) | 2006-07-06 | 2006-07-06 | Stable human growth hormone liquid preparation |
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| HK (1) | HK1215930A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001024814A1 (en) * | 1999-10-04 | 2001-04-12 | Chiron Corporation | Stabilized liquid polypeptide-containing pharmaceutical compositions |
| WO2005027960A1 (en) * | 2003-09-25 | 2005-03-31 | Cangene Corporation | Liquid human growth hormone formulation containing polyethylene glycol |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AUPN801296A0 (en) * | 1996-02-12 | 1996-03-07 | Csl Limited | Stabilised growth hormone formulation and method of preparation thereof |
| JP3723857B2 (en) * | 1998-02-04 | 2005-12-07 | 日本ケミカルリサーチ株式会社 | Aqueous pharmaceutical composition containing human growth hormone |
-
2006
- 2006-07-06 CN CN201510786949.3A patent/CN105363022A/en active Pending
- 2006-07-06 CN CN201510788557.0A patent/CN105412910A/en active Pending
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2016
- 2016-04-06 HK HK16103885.4A patent/HK1215930A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001024814A1 (en) * | 1999-10-04 | 2001-04-12 | Chiron Corporation | Stabilized liquid polypeptide-containing pharmaceutical compositions |
| WO2005027960A1 (en) * | 2003-09-25 | 2005-03-31 | Cangene Corporation | Liquid human growth hormone formulation containing polyethylene glycol |
Non-Patent Citations (1)
| Title |
|---|
| KOUHEI TSUMOTO等: "role of arginine in protein refolding, solubilization, and purification", 《BIOTECHNOL PROG》 * |
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| HK1215930A1 (en) | 2016-09-30 |
| CN105363022A (en) | 2016-03-02 |
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