CN101347614A - Growth hormone formulations - Google Patents
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- CN101347614A CN101347614A CNA2008101340518A CN200810134051A CN101347614A CN 101347614 A CN101347614 A CN 101347614A CN A2008101340518 A CNA2008101340518 A CN A2008101340518A CN 200810134051 A CN200810134051 A CN 200810134051A CN 101347614 A CN101347614 A CN 101347614A
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Abstract
Liquid growth hormone formulations are storage stable for more than six months at temperatures in the range 2-8 DEG C by simply formulating growth hormones in phosphate buffer with no other additives at around physiological pH. By ensuring a pH of about 6.2 or greater, growth hormone crystallisation during storage at refrigeration temperatures or above is inhibited or reduced. Low concentrations of non-ionic surfactant can help to reduce aggregation of growth hormone arising as a result of physical forces encountered during automated transfer of bulk formulation into dosage containers. Mannitol is included in order to provide an isotonic formulation. Preservatives are included to reduce bacterial contamination and thereby permit multiple dosage units which can be stored at 2-8 DEG C.
Description
The application is a number of patent application 00810174.4, the dividing an application of the application of the same name of on 07 11st, 2000 applying date.
The present invention relates to be fit to give the liquid formulations of the growth hormone (GH) of human body or animal body.More uniquely, the present invention relates to pharmaceutically more can accept, and can stand multiple manufacturing technology steps and do not have the human growth hormone's (hGH) of sizable activity or stability lost liquid formulations with preferred.
Natural hGH is the protein of the single polypeptide chain of 191 aminoacid compositions.This protein interior exists with monomeric form by two disulfide bond crosslinkings, and molecular weight is 22kDa.GH of animal and people's GH be the height homology on aminoacid sequence, so its feature is closely similar.
The main biological action of GH is the growth that promotes interior a series of organs of health and tissue.Organ and tissue that GH is responded comprise liver, intestinal, kidney, muscle, connective tissue and skeleton.
This disease of pituitary dwarf disease is easy to obtain medical treatment by giving this disease patient GH.By before the recombination method mass production hGH, can only prepare limited amount hGH by extracting pituitary gland from people's corpse effort.This practice can be brought the relevant danger of infectant, as with the relevant factor of Creutz Fil spy-jacob's syndrome (CJD), and these factors may pass to the patient who accepts GH.The separation of hGH gene and express the structure of the transformed host cell of hGH in cell culture has not only been developed the method for a kind of more reliable, safety and more economical effective treatment pituitary dwarf disease, and has been developed and used hGH to treat the probability of other disease.
A problem of being paid close attention to for a long time of the liquid formulations of medical protein (being not only hGH) is the unstability at lay up period.As everyone knows, the hGH aqueous solution can experience multiple degraded variation.For example deacylated tRNA amine of many chemical changes takes place, and this may be relevant with the pH of lay up period solution.The oxidation of methionine residues may take place.Because the shearing of peptide main chain also may take place in hydrolysis.Also exist and comprise and accumulative physical change for example cause forming insoluble matter.
For early stage suggestion how to handle above-mentioned instability problem is lyophilizing, but this freeze-drying prods that means generation certainly need be rebuild (reconstitution) at once before administration.Under the situation of self-administer, this often means that needs of patients reverts to aqueous solution with freeze-dried products among the conventional patient Yu Jia.This is inconvenient to the patient, and owing to lacking carefulness, lack the attention of details and explanation or only having the danger that medicine is rebuild because misread.
US 4 968 299 (Kabi Pharmacia) has described the patient and has been used for carrying out a kind of device that freeze-dried products is rebuild, thereby can reduce the probability of makeing mistakes when rebuilding.Even like this, needing reconstruction itself also is inconvenient for the patient, and the hGH that rebuilds can only stablize for 3 weeks when storing for 2-8 ℃.So make patient's effectively administration in some months, still need carefully to give careful note to details and illustrate, therefore still there is not grave danger according to therapeutic scheme.
In any case this manufacturing step of lyophilizing has expensive and shortcoming consuming time.
Therefore concentrate on the method that sufficiently stable instant hGH water preparation prescription is provided for simplifying the control oneself effort of administration of patient.The unstability of protein in aqueous solution is common phenomenon, is not the phenomenon relevant with hGH.
EP-A-0 131 864 (Hoechst Aktiengesellschaft) has described by utilizing surfactant to prevent protein accumulative method in aqueous solution greater than 8.5kDa.
EP-A-0 211 601 (international mineral and chemical company limited) is though relate generally to lasting release formulation, but how also to have described by with non-ionic surface active agent some polyox-yethylene-polyoxypropylene block copolymer particularly, as PLURONIC (trade mark is BASF) or the preparation of GENAPOL (trade mark is Hoechst) block copolymer, and make liquid GH stable in solution.
WO 94/03198 (Genentech) discloses, and that follows that the front says utilizes the method for non-ionic surface active agent as hGH stabilizing agent in the liquid formulations.The non-ionic surface active agent of 0.1-5% (w/v) can make this prescription not cause the GH protein denaturation when being subjected to shearing force and surface tension in its prescription.The prescription that contains surfactant is considered to particularly useful to pulmonary drug and needle-free jet filling gun.
But surfactant is a toxicant, should avoid its use or the least possible usefulness.When prescription administration every day or especially true during administration very continually, particularly relate to child and chronic treatment.
About stablizing water preparation hGH prescription the whole bag of tricks has been proposed.WO89/09614 (Genentech) has described the hGH prescription that contains glycine, mannitol and a kind of buffer; HGH wherein: the mol ratio of glycine is 1: 50-1: 200.
EP-A-0 303 746 (international mineral and chemical company limited) described by with polyhydric alcohol such as non-reducing sugar, sugar alcohol, saccharic acid, lactose, penta erythritol, water-soluble glucan and Ficoll; Aminoacid is glycine, arginine and betanin for example; Have aminoacid polymer at the charged side-chain radical of physiological pH; And choline derivative such as choline chloride, choline dihydrogen citric acid or two choline glactaric acids prepare together, can make water preparation GH stable.Many macromolecular materials above-mentioned may bring some danger when the treatment patient.The medicine rules require must avoid using any nonessential additive, particularly synthetic additive (as penta erythritol), to reduce the danger to the patient.Many stabilizing agents of advising in this disclosure of the Invention are not suitable for clinical use, therefore can not be used for preparing suitable medicinal prescription.
WO 92/17200 (Genentech) relates to not only makes hGH stable in liquid, also makes it stable in freeze-dried products.Stable zinc is produced in suggestion: the hGH dimer.Zinc: the hGH dimer is by two zinc ioies and two hGH molecular compositions.
WO 93/12811 (Novo Nordisk) discloses a kind of liquid hGH prescription, uses agedoite as stabilizing agent and buffering material.
WO 93/19776 (Kani Pharmacia) has described a complete beat all discovery, and is more stable when preparing when promptly water preparation hGH product is prepared with citrate buffer solution than with phosphate buffer.
An object of the present invention is to provide sufficiently stable hGH prescription, can use immediately for the patient, and without any need for special preparation or reconstruction procedures.Another object of the present invention provides can preserve the prescription of some months at least in the domestic refrigerator.Another object of the present invention provides the large volume liquid formulations, and it can packing and fills with syringe and use for the patient, unacceptable GH activity or stability can not take place lose, and particularly unacceptable gathering can not take place.Further object of the present invention provides sufficiently stable liquid formulations, and it can avoid or use as few as possible being not suitable for medicinal composition, in other words just provides and is more suitable for medicinal prescription.
Further object of the present invention provides in the medium-term and long-term storage of refrigerator and for example reaches 6-18 month, or preserves a period of time and for example can avoid crystalline a kind of liquid formulations during a few days, a few weeks or months outside refrigerator.
Opposite fully with the existing knowledge in this area, the inventor is surprised to find the stabilizing agent that in fact needn't use various interpolations in above-mentioned solution, and simple hGH and phosphate buffer just can reach above purpose.In addition, the present invention proposes under the instruction of prior art: how surfactant is essential for stablizing the GH aqueous solution, and compares the stability why phosphate buffer can not produce with citrate buffer solution.
Therefore, one aspect of the present invention provides a kind of liquid growth hormone prescription of being made up of the growth hormone in the phosphate buffer basically.
Second aspect present invention provides a kind of liquid growth hormone prescription of being made up of growth hormone in the phosphate buffer and antiseptic basically.
Third aspect present invention provides a kind of liquid growth hormone prescription of being made up of growth hormone in the isotonic phosphate buffer liquid and antiseptic basically.
Fourth aspect present invention provides a kind of liquid growth hormone prescription of being made up of the growth hormone in the isotonic phosphate buffer liquid basically.
Advantageously, the above-mentioned prescription of preservative free provides the method that makes things convenient for that gives single needle injection dosage when preserving in ampoule.For the spininess injected dose, preferably use antiseptic.
All above-mentioned prescriptions do not appreciated so far but certain wonderful advantage is, they the time are stable refrigerated storage temperature 2-8 ℃ of storage.The stability of available various test program assessment prescriptions.Provided various test programs among this paper embodiment 3 and the WO 94/03198 that is incorporated herein by reference, but these programs can be used to assess the detailed comprehensive method of testing of stability anything but.
Known with the growth hormone formulations that lacks any non-ionic surface active agent and use commercially available pad device to fill dosage container, the growth hormone that can produce unacceptable level is assembled.Yet if fluid pressure and shearing force in filling process (no matter whether using commercially available pad device) are reduced to minimum, the surfactant level can be reduced to minimum or be fully phased out so.Physics stuffing pressure that requirement reaches and the accurate balance between the surfactant concentration are determined by rule of thumb by persons skilled in the art.
According to physical pressure that in filling process, produces or shearing force level, when needing non-ionic surface active agent to avoid serious gathering, the concentration of non-ionic surface active agent can be low to moderate about 0.2% (w/v), be usually less than 0.05% (w/v), preferably be lower than 0.04% (w/v), more preferably less than 0.01% (w/v), even more preferably less than 0.001% (w/v).
Non-ionic surface active agent can comprise polysorbate, as polysorbate 20 or 80 etc., and poloxamer, as poloxamer 184 or 188,
Polyhydric alcohol and other ethylene/polypropylene block polymers.
The inventor finds that unexpectedly phosphate buffer can be used for GH prescription, and no matter is in the course of processing (as filling containers) or when storage, it is good astoundingly for the prescription of stable preparation.
Wonderful also have, and not using or only use very, the non-ionic surface active agent of low concentration does not have negative effect for the stability in the GH of refrigerated storage temperature (for example 2-8 ℃) storage prescription in container.Can preserve at least 3 months, or reach 6 months or 12 months, and can excessive influence GH the effectiveness or the pharmacy acceptability of prescription.
Fifth aspect present invention provides the growth hormone that contains in the phosphate buffer, randomly further contains the liquid growth hormone prescription of antiseptic.
Of the present invention above-mentioned aspect, phosphate buffer is preferably isoosmotic.When buffer etc. oozes, can be by neutral salt (as NaCl), or monosaccharide such as lactose, disaccharide such as sucrose or sugar alcohol such as mannitol provide isotonicity.
The inventor finds that also some chemical compound can advantageously substitute neutral salt and make the GH prescription for isoosmotic.
Therefore, sixth aspect present invention provides and has contained in the isotonic buffer solution, and randomly the liquid growth hormone prescription of the growth hormone in the phosphate buffer wherein provides the chemical compound of isotonicity to be selected from monosaccharide, for example lactose; Disaccharide, for example sucrose; Sugar alcohol, for example one or more in the mannitol.
As for pH, the pH that preferably fills a prescription is 5.0-7.0, and preferred pH is 5.6-6.5.
Be that for all prescriptions as mentioned herein, the inventor finds by guaranteeing that pH is about 6.2 or the higher crystallization or that it is reduced to is minimum of avoiding filling a prescription astoundingly.
For avoiding crystallization or make crystallization minimum, the pH that preferably fills a prescription is 6.15-7.4, more preferably 6.2-6.5.
Therefore detection is less than crystalline liquid formulations when the present invention includes storage described herein.Storage can be at least 1 month, and in preferred 6 weeks, more preferably time range is about 1-4 month, most preferably 3 months.Reserve temperature can be about 2 ℃ or higher, preferably approximately 4 ℃ or higher, preferred temperature range be about 2 ℃ to below 40 ℃, even preferred temperature range is about 2 ℃-25 ℃, most preferably 15 ℃.
The crystallization of crystallization preferred growth hormone.Any crystallization of liquid formulations is more preferably observed under 5 times of optical microscopes of amplification preferably by the naked eyes direct observation, even more preferably observes under 10 times of optical microscopes of amplification.Before observing under optical microscope, can filter fills a prescription and measure on the filter has or not crystallization.Observe under optical microscope, the filter aperture is approximately 5 first.
The crystalline method of particularly preferred test is that prescription is had or not crystallization in 15 ℃ of storages 3 months and perusal.
Though can use other antiseptic of debita spissitudo or antimicrobial compound to make prescription still acceptable, one or more in the preferred phenol of antiseptic, benzyl alcohol, metacresol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and the benzalkonium chloride as pharmacy.
In preferred embodiments, phosphate buffer is by the NaH that reaches the required an amount of suitable hydrated form of buffer expection concentration and pH
2PO
4And Na
2HPO
4Form, and be easy to persons skilled in the art and understand and grasp.
In preferred embodiments, growth hormone is behaved.
In particularly preferred prescription, the gathering of growth hormone is lower than 0.01%, preferably is lower than 0.1%, more preferably less than 1%, even more preferably less than 10%.This gathering can be tested by the normal volume exclusion HPLC that the back is mentioned in detail and measure, but can use the accumulative method of any suitable measurement.
The present invention also comprises the device that is used for liquid infusion is given the experimenter, and it has loaded above any liquid growth hormone prescription at least one dosage unit that uses.The example of this device is a pen injector device.The preferred people of experimenter.
The present invention also provides and comprises the injection device and the test kit of the independent container of any liquid growth hormone prescription above.This container preferably is fit to be complementary with injection device, thereby the liquid formulations in use in the container and the outlet of injection device are in the fluid connection state.
In particularly preferred embodiments, injection device is a pen injector device, and container is a cartridge case.
In addition, the invention provides the cartridge case that contains any liquid formulations of above describing, it uses with pen injector device.
Another surprised discovery of the inventor is if the container of GH is being full of back sealing, does not so just have the space or does not contact with air, so not only more can guarantee the aseptic of content in the container, and this factor also helps reducing or avoiding the gathering of GH.
Therefore, further aspect of the present invention comprises the container of the liquid GH prescription of sealing, does not have the space basically in the container of having filled.
When the subjects is a man-hour, so preferred growth hormone is the human growth hormone.Particularly preferred human growth hormone is by recombination method production, for example described in the EP-A-0 217 822 (SCIOS NOVA).Can be separately according to the present invention or the human growth hormone's that uses of combining with one another variant form and natural hormone comprise 191 amino acid whose growth hormone that are called somatropin and be called the growth hormone of 192 amino acid N ends of somatrem as methionine.The variant form that is called as hGH-V in addition, its natural being present in the conceived Placenta Hominis, known its gene has also prepared recombinant protein.
The content of hGH in the liquid formulations of the present invention depends on the volume of prescription and the hGH dosage number that this volume will provide.The preferred dosage volume is 0.4ml, but can use the volume range of 0.01ml-1.0ml.Other preferred dosage volume can be the scope of 0.1ml-0.6ml.
The content that gives hGH in preferred unit dosage every day is 1.3mg, though accurate dose can be because of concrete individual changing.But the scope of application is the dosage of 0.033mg-3.33mg, and preferred dosage is 0.33mg-2.0mg.When administration number of times reduces, should increase dosage.
According to the special suggestion that cures mainly the clinician, volume and/or dosage can become because of individual.
Usually, can contain the hGH of 0.5mg/ml-20mg/ml, preferred 1mg/ml-15mg/ml, more preferably 2mg/ml-10mg/ml, even more preferably 3mg/ml-5mg/ml according to prescription of the present invention.
The present invention also comprises the injection device that contains the aforesaid liquid growth hormone formulations and the test kit of container separately.When doser was a hypodermic syringe, this test kit can comprise bottle that contains hGH or the ampoule that syringe, syringe needle and this syringe use so.In a more preferred embodiment, injection device no longer is a simple hypodermic syringe, and container must mate with this injection device so separately, so in use the outlet fluid connection of liquid formulations in the container and injection device.
The example of doser includes but not limited to hypodermic syringe and pen injector device.
Particularly preferred injection device is a pen-type injector, and its container is a cartridge case, preferred disposable cartridge case.
The present invention provides on the other hand and has contained the aforesaid liquid growth hormone formulations, is used for the cartridge case that uses with pen injector device.This cartridge case can contain the growth hormone of single dose or multiple dose.
The preferred embodiments of the invention will be described with reference to chart wherein by the following example:
Fig. 1 is that the hGH prescription of 5.6 phosphate buffer, sodium chloride and benzyl alcohol is at 2-8 ℃ stability data comparison diagram for additionally containing pH.What compare is these prescriptions that contain and do not contain the Pluronic surfactant.Time (week) maps to the purity (log%) of hGH, prescription A (pluronic is arranged, phosphate buffer, pH5.6), ◆ prescription B (no pluronic, phosphate buffer, pH5.6).
Fig. 2 is that the hGH prescription of 6.0 sodium chloride and benzyl alcohol is at 2-8 ℃ stability data comparison diagram for additionally containing pH.What compare is these prescriptions that contain citrate buffer solution or phosphate buffer.Time (week) maps to the purity (log%) of hGH, △ prescription A (pluronic is arranged, phosphate buffer, pH5.6), ◆ (pluronic and citrate buffer solution are arranged, and pH5.6), prescription C1 (has pluronic and citrate buffer solution, pH5.6) to prescription C2.
Fig. 3 is the stability data comparison diagram of hGH prescription at 2-8 ℃.Relatively be to contain to wait the hGH prescription that oozes citrate buffer solution and Pluronic surfactant to ooze citrate buffer solution with only containing etc., the hGH prescription that does not contain surfactant, ◆ prescription D (no pluronic and citrate buffer solution, pH6.0), △ prescription E2 (has pluronic and phosphate buffer, pH6.0), prescription E1 (pluronic is arranged, and citrate buffer solution, pH6.0), * prescription C2 (has pluronic and citrate buffer solution, pH6.0).
Embodiment 1-recombinate in a large number preparation and the purification of hGH
Reorganization hGH produces with the Chinese hamster ovary celI culture of expressing the hGH gene under condition of culture of hGH gene transformation.Being incorporated herein and describing cell among this paper EP-A-0 217 822 (SCIOS NOVA) as a reference in detail is how to prepare and grow.Persons skilled in the art just possess the ability that the culture grown cultures condition of industrialization or commercial scale is made amendment.
In case, need to extract hGH and purification and become to be fit to medicinal form by cultured cell production.This carries out according to the program that the AU 629177 (University of New South Wales and Garvan Institute for Medical Research) that is incorporated herein by reference describes.
Embodiment 2-prepares stable liquid formulations
The large volume prescription prepares by various compositions are mixed.The blended order of composition is not crucial.What accurate state of various compositions or form neither be crucial before mixing.In the method for optimizing of preparation prescription, for being convenient to most blended state, and blended order and mode are also selected most convenient to composition before mixing.
Provided particularly preferred formulation Example below:
Prescription 1
hGH 3.33mg/ml(10IU/ml)
NaCl 5.85mg/ml (being 0.59%w/v)
Benzyl alcohol 9.00mg/ml (being 0.9%w/v)
Water for injection q.s.
pH?6.0
Formula I I
hGH 3.33mg/ml(10IU/ml)
Water for injection q.s.
pH?6.0
Formula I II
hGH 3.33mg/ml(10IU/ml)
NaCl 5.85mg/ml (being 0.59%w/v)
Water for injection q.s.
pH?6.0
Formula I V
hGH 3.33mg/ml(10IU/ml)
Benzyl alcohol 9.00mg/ml (being 0.9%w/v)
Water for injection q.s.
pH?6.0
Prescription V
hGH 3.33mg/ml(10IU/ml)
Mannitol 35mg/ml (3.5%w/v)
Pluronic?F-68 2mg/ml (0.2％w/v)
Benzyl alcohol 9mg/ml (0.9%w/v)
Water for injection q.s.
pH?6.0
Prescription VI
hGH 3.33mg/ml(10IU/ml)
Mannitol 35mg/ml (3.5%w/v)
Pluronic?F-68 2mg/ml (0.2％w/v)
Benzyl alcohol 9mg/ml (0.9%w/v)
Water for injection q.s.
pH?6.2
Prescription in the foregoing description prepares in the following manner:
1. the preparation of dual intensity excipient solution is dissolved in water for injection by the excipient with all needs, and uses mole hydrochloride or sodium hydroxide solution to transfer to required pH.
2. raised growth hormone solution is put into container, and careful the stirring adds excipient.
3. if desired, readjust pH, and solution is mended to final volume.In order to fill the cartridge case that uses with pen-type injector, solution filters and the mobilizable piston seal of an end of packing into by sterile filters, in the cartridge case of the other end with the aluminum strip of paper used for sealing sealing that contains rubber diaphragm separator.
Other test recipe is preparation in this way usually, and the particulars of these prescriptions provides in the following embodiments.
The stability of embodiment 3-test water preparation hGH prescription
Outturn sample is preserved under controlled condition 2-8 ℃, and analyzes at each time point.With the stability of two kinds of HPLC methods mensuration products, two kinds of methods are all according to the injection growth hormone part in the European Pharmacopoeia monograph that is incorporated herein by reference.First kind is reversed-phase HPLC 4 methods, is used to measure related protein, i.e. the catabolite that forms by desamidation and Oxidation.Second method is a volume-exclusion HPLC method, is used to measure dimer and high-molecular weight related substances.
The rpHPLC method is used for determining desamidation and the Oxidation of many different formulations when 2-8 ℃ of storage reached for 65 weeks.Data are face table 1-3 as follows, and Fig. 1-3 is seen in diagram.
Table 4 is results of stability that prescription V is carried out when preserving for 2-8 ℃.
Volume-exclusion HPLC above-mentioned (data not shown) is used for test and assembles.But there are not to find the dimer and the high-molecular weight related substances of detection limit under study for action.In all prescriptions, assemble and be less than 1% (in fact this is the fiducial limit of this test), promptly do not see gathering.
The result clearly illustrates that with regard to stabilized formulations, phosphate buffer is better than citrate buffer solution, shows that also lacking the Pluronic surfactant produces better stability.
Table 1
Stability study (2-8 ℃)
Prescription A (contain pluronic, phosphate buffer, pH5.6)
hGH 3.33mg/ml
Pluronic 0.8mg/ml
Phosphate buffer 10mM
Sodium chloride 5.9mg/ml
Benzyl alcohol 9mg/ml
Time (week) hGH% purity Log hGH% purity
0 98.90 1.9952
3 98.35 1.9928
9 97.84 1.9905
13 97.05 1.9870
30 96.26 1.9834
K days
-1* 10
4-1.253
Prescription B (do not contain pluronic, phosphate buffer, pH5.6)
hGH 3.33mg/ml
Phosphate buffer 10mM
Sodium chloride 5.9mg/ml
Benzyl alcohol 9mg/ml
Time (week) hGH% purity Log hGH% purity
0 96.28 1.9835
0 95.88 1.9817
4 95.45 1.9798
4 95.80 1.9814
15 95.67 1.9808
15 95.89 1.9818
26 94.46 1.9752
26 93.94 1.9729
39 94.15 1.9738
52 93.21 1.9695
K days
-1* 10
4-0.8272
Table 2
Stability study (2-8 ℃)
hGH 3.33mg/ml
Pluronic 0.8mg/ml
Citrate buffer solution 10mM
Sodium chloride 5.9mg/ml
Benzyl alcohol 9mg/ml
Prescription C1 and C2 (citrate buffer solution of pH5.6+pluronic)
Time (week) hGH+ log hGH+
0 97.89 1.9907
0 97.93 1.9909
4 97.12 1.9873
4 96.80 1.9859
13 95.44 1.9797
13 94.85 1.9770
26 93.19 1.9694
26 93.60 1.9713
52 91.32 1.9606
52 91.06 1.9593
0 97.48 1.9889
0 97.71 1.9899
4 96.93 1.9865
4 96.92 1.9864
13 94.89 1.9772
13 95.38 1.9795
26 92.59 1.9666
26 92.65 1.9668
52 90.69 1.9576
52 91.11 1.9596
K days
-1* 10
4-1.954
Table 3
Stability study (2-8 ℃)
Prescription D
hGH 3.33mg/ml
Phosphate buffer 10mM, pH6.0
Sodium chloride 5.9mg/ml
Benzyl alcohol 9mg/ml
Time (week) hGH% purity log hGH% purity
0 98.47 1.9933
4 97.82 1.9904
9 97.44 1.9887
K days
-1* 10
4-1.65
Stability study (2-8 ℃)
Prescription E1, E2 and E3 (citrate buffer solution pH6.0 contains pluronic)
hGH 3.33mg/ml
Pluronic 0.8mg/ml
Citrate buffer solution 10mM, pH6.0
Sodium chloride 5.9mg/ml
Benzyl alcohol 9mg/ml
Time (week) hGH% purity log hGH% purity
0 97.75 1.9901
0 97.56 1.9893
5 96.05 1.9825
5 96.95 1.9865
9 96.29 1.9836
9 96.12 1.9828
0 97.96 1.9910
0 97.93 1.9909
5 97.09 1.9872
9 96.52 1.9846
9 96.51 1.9846
0 98.54 1.9936
0 98.47 1.9933
5 97.68 1.9898
5 97.43 1.9887
9 96.67 1.9853
9 96.77 1.9857
K days
-1* 10
4-2.55
Table 4
Stability study; Prescription V, 2-8 ℃
Time (week) hGH% purity log hGH% purity
0 97.21 1.988
0 97.23 1.988
4.5 96.50 1.985
4.5 96.65 1.985
9 95.18 1.979
9 95.19 1.979
13 95.23 1.979
13 95.32 1.979
26 94.64 1.976
26 94.41 1.975
K days
-1* 10
4-2.489
Embodiment 4-avoids crystallization by the pH that regulates liquid formulations
By regulating a series of pH versions (increment of 0.1 unit) of the amount preparation prescription VI of phosphate buffer composition separately.Prescription is filled into each capsule that is used for pen-type injector by the packing of 1.5ml equal portions.Capsule was 15 ℃ of storages 3 months.Observe with the naked eye at duration of storage whether crystallization is arranged in the capsule.
Be lower than 6.2 at pH, promptly in the prescription of pH6.1, observed crystallization.PH be 6.2 and higher prescription in do not have crystallization.
Through comparing, prescription V (pH6.0) shows crystallization when preserving for 6 weeks for 15 ℃ or 25 ℃.Prescription V (pH6.0) shows crystallization 2-8 ℃ of storage in the time of 2-3 month.
Claims (34)
1. liquid growth hormone prescription that contains the growth hormone in the isotonic buffer solution wherein provides the chemical compound of isotonicity to be selected from monosaccharide, disaccharide and the sugar alcohol one or more.
2. according to the liquid formulations of claim 1, wherein buffer is a phosphate buffer.
3. according to the liquid formulations of claim 1 or 2, wherein isotonicity is by mannitol and/or sucrose, and preferred lactose provides.
4. according to the liquid formulations of each requirement of claim 1-3, its pH scope is 5.6-6.5.
5. according to the liquid formulations of each requirement of claim 1-3, its pH scope is 6.2 or about more than 6.2.
6. according to the liquid formulations of each requirement of claim 1-4, its pH scope is 6.15-7.4, and preferred pH scope is 6.2-6.5.
7. according to the liquid formulations of aforementioned each claim, it also contains antiseptic.
8. according to the liquid formulations of claim 7, wherein antiseptic is selected from one or more in phenol, benzyl alcohol, metacresol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and benzalkonium chloride, the benzethonium chloride.
9. according to the liquid formulations of aforementioned each claim, it further contains non-ionic surface active agent.
10. according to the liquid formulations of claim 9, wherein the concentration range of non-ionic surface active agent is 0.05%-5% (w/v), preferred 0.1%-1.0% (w/v).
11. liquid growth hormone prescription of mainly forming by the growth hormone in the phosphate buffer.
12. liquid growth hormone prescription of mainly forming by growth hormone in the phosphate buffer and antiseptic.
13. liquid growth hormone prescription of mainly forming by growth hormone in the acid buffer such as phosphatizing such as grade and antiseptic.
14. liquid growth hormone prescription of mainly forming by the growth hormone that waits in the phosphatizing acid buffer.
15. liquid growth hormone prescription that contains the growth hormone in the phosphate buffer.
16. according to the liquid formulations of claim 15, it further contains concentration less than 0.05%, preferably less than 0.04%, is more preferably less than 0.01%, even is more preferably less than the non-ionic surface active agent of 0.001% (w/v).
17. according to the liquid formulations of claim 15 or 16, wherein phosphate buffer is isoosmotic, randomly, the pH scope preferably further contains antiseptic at 5.6-6.5.
18. according to the liquid formulations of claim 17, wherein antiseptic is selected from one or more in phenol, benzyl alcohol, metacresol, methyl parahydroxybenzoate, propyl p-hydroxybenzoate and benzalkonium chloride, the benzethonium chloride.
19. according to claim 13,14 or 17 liquid formulations, wherein the isotonicity of phosphate buffer is by neutral salt such as NaCl; Or by being selected from monosaccharide such as lactose; Disaccharide such as sucrose; Or the chemical compound in sugar alcohol such as the mannitol provides.
20. according to the liquid formulations of aforementioned each claim, wherein growth hormone is behaved.
21. according to the liquid formulations of aforementioned each claim, wherein growth hormone shows and to be lower than 0.01% gathering, preferably is lower than 0.1%, more preferably less than 1%, even more preferably less than 10% gathering.
22. liquid growth hormone prescription that contains following composition:
hGH 3.33mg/ml(10?IU/ml)
NaH
2PO
4.2H
2O 0.85mg/ml
Na
2HPO
4.7H
2O 0.31mg/ml
Mannitol 35mg/ml (3.5%w/v)
Pluronic?F-68 2mg/ml(0.2％w/v)
Benzyl alcohol 9mg/ml (0.9%w/v)
Water for injection q.s.
pH?6.2
23. according to the liquid formulations of aforementioned each claim, it does not have detectable crystallization when storage.
24. according to the liquid formulations of claim 23, wherein storage is at least 1 month, in preferred 6 weeks, preferred time range is about 1 month-4 months, most preferably 3 months.
25. liquid formulations according to claim 23 or 24, wherein reserve temperature is about 2 ℃ or higher, preferably approximately 4 ℃ or higher, preferred temperature range be about 2 ℃ to below 40 ℃, even preferred temperature range is about 2 ℃-25 ℃, most preferably 15 ℃.
26. according to the liquid formulations of claim 23-25, wherein crystallization is the crystallization of growth hormone.
27. according to the liquid formulations of each requirement of claim 23-26, wherein crystallization detects by an unaided eye, preferably amplifying 5 * optical microscope observe down, more preferably amplifying 10 * optical microscope under observation.
28. one kind is used for giving the experimenter with liquid and having loaded the device of filling a prescription for the liquid growth hormone according to claim 1-27 of at least one dosage unit that uses by injection.
29. according to the device of claim 28, it is a pen-type injector.
30. according to the device of claim 28 or 29, wherein the experimenter behaves.
31. one kind contains an injection device and according to the test kit of the independent container of the liquid growth hormone prescription of each requirement of claim 1-27.
32. according to the test kit of claim 31, wherein container is fit to be complementary with injection device, makes when using the liquid formulations in the container and the outlet fluid connection of injection device.
33. according to the test kit of claim 32, wherein injection device is a pen-type injector, container is a cartridge case.
34. the cartridge case of the liquid formulations of each requirement that contains with good grounds claim 1-27, it is used for using with pen injector device.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9916252.1A GB9916252D0 (en) | 1999-07-12 | 1999-07-12 | Growth hormone formulation |
| GB9916252.1 | 1999-07-12 | ||
| GB9918902.9 | 1999-08-12 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00810174A Division CN1360506A (en) | 1999-07-12 | 2000-07-11 | Growth hormone formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101347614A true CN101347614A (en) | 2009-01-21 |
Family
ID=10857052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101340518A Pending CN101347614A (en) | 1999-07-12 | 2000-07-11 | Growth hormone formulations |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101347614A (en) |
| GB (1) | GB9916252D0 (en) |
| ZA (1) | ZA200200176B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112494638A (en) * | 2020-12-22 | 2021-03-16 | 深圳科兴药业有限公司 | Human growth hormone injection composition and preparation method thereof |
-
1999
- 1999-07-12 GB GBGB9916252.1A patent/GB9916252D0/en not_active Ceased
-
2000
- 2000-07-11 CN CNA2008101340518A patent/CN101347614A/en active Pending
-
2002
- 2002-01-09 ZA ZA200200176A patent/ZA200200176B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112494638A (en) * | 2020-12-22 | 2021-03-16 | 深圳科兴药业有限公司 | Human growth hormone injection composition and preparation method thereof |
| CN112494638B (en) * | 2020-12-22 | 2023-12-19 | 深圳科兴药业有限公司 | Human growth hormone injection composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9916252D0 (en) | 1999-09-15 |
| ZA200200176B (en) | 2003-08-27 |
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Application publication date: 20090121 |