CN1179724A - HCG Liquid formulations - Google Patents
HCG Liquid formulations Download PDFInfo
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- CN1179724A CN1179724A CN 95197791 CN95197791A CN1179724A CN 1179724 A CN1179724 A CN 1179724A CN 95197791 CN95197791 CN 95197791 CN 95197791 A CN95197791 A CN 95197791A CN 1179724 A CN1179724 A CN 1179724A
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Abstract
The invention refers to liquid pharmaceutical compositions containing hcG stabilised with a polyalcohol or a non-reducing sugar. Preferably, the compositions are stabilised with mannitol. In the preferred embodiments such compositions are aqueous solutions in a phosphate buffer at pH7. Such compositions are ready to be injected and, therefore, the step of reconstitution of the lyophilised powder is avoided, thus simplifying the way of use.
Description
The present invention relates to contain the liquid pharmaceutical formulation of promoting sexual gland hormone.Relate more specifically to polyhydric alcohol or stable hCG (human chorionic gonadotropin) liquid preparation of non-reducing sugar.
People know that high-purity protein is degraded easily, even owing to the material in the ingress of air causes.This characteristic is for the protein for preparing with recombinant DNA technology even more obvious.
Such protein is often stablized with polysaccharide such as lactose or with mannitol or with protein or aminoacid such as albumin and glycine.
Obtain dried powder with the method that generally includes the lyophilization step, obtain the Alasin of injectable stabilisation; The preparation of the stabilisation of making through such method is even store the activity that at room temperature also can keep longer cycle.
WO 93/11788 has described separately and has share the cryodesiccated pharmaceutical composition that contains promoting sexual gland hormone that carries out stabilisation with sucrose or with sucrose and other stabilizing agent.Show that in described patent application the stability that sucrose provides for the freeze-dried composition in the research is better than that lactose or mannitol provide.
The unmanned so far liquid stabilising chemical preparation of describing promoting sexual gland hormone.People's utmost point need obtain this liquid preparation, so that make compositions be easy to inject and avoid the reconstruction of freezing powder, thereby simplifies using method.
We find surprisingly, can obtain such liquid stabilising chemical preparation.
Main purpose of the present invention provides the composition of liquid medicine that contains hCG with polyhydric alcohol or non-reducing sugar stabilisation.Polyhydric alcohol is good with mannitol, and non-reducing sugar is good with sucrose.Liquid preparation of the present invention is stable then better with mannitol.
Solution is good with buffered aqueous solution, is selected from one group that phosphate, acetate or succinate are formed by buffer of the present invention.Preferable buffer is a phosphate, and pH is good with 7.00.
HCG is good with recombinant, for example can express in CHO (Chinese hamster ovary) by European patent 160699 described technology, transforms with corresponding D NA, is prepared.
Further purpose of the present invention provides the preparation method of described composition of liquid medicine, comprises with the buffer soln dilution hCG storing solution that contains excipient.
Another object of the present invention provides the described composition of liquid medicine of supply the market form, is included in this preparation in the container of sealed under aseptic conditions storage before be fit to using.
In order to make hCG stability of formulation of the present invention reach optimization, once carried out a series of trial tests with various pH, mistake ionic strength, the different buffer of dielectric constant and the reorganization hCG of variable concentrations.
In order to assess the effect of pH and buffer, with water for injection preparation 0.01M phosphate, succinate or acetate buffer solution.Is 6.0,7.0 or 8.0 with 1M NaOH with pH regulator.The storing solution of reorganization hCG is added in the buffer system, reaches 5, the solution of 000IU/ml.Then solution is filtered, in the impouring 3ml vial.The compositions of the preparation that makes like this is reported in table 1.These preparations have been carried out stable accelerated test research, so that by the higher temperature data extrapolation, the stability in the time of can predicting the preparation room temperature and be stored in the container.In this case, sample is stored in 40 ℃ and 50 ℃, investigates the stability of reorganization hCG by following standard conditions with its purity of HPSEC assay determination with inspection.
A phase 0.1M phosphate (pH6.7)+0.1M Na
2SO
4
Equivalent condition (Isocratic condition) 100%A phase
Post TSK G2000 SWXL
Flow velocity 0.5ml/ minute
UV-detector 214nm
Volume injected 20 μ l (10,000IU intensity)
40 μ l (5,000IU intensity)
Table 3 has been reported the percentage rate at the reorganization hCG monomer peak that records with HPSEC.The result shows, pH6.0 and 8.0 solution is than the less stable of the solution of pH7.0, and do not observe tangible stability difference between buffer.To reorganization hCG 5,000IU/ml solution has been assessed the effect of ionic strength, and this solution is adjusted to following osmotic pressure value with the preparation of 0.01M phosphate and succinate buffer (pH7.0) with NaCl: 150,300 and 400mOsm.The compositions of preparation is reported in table 2.Sample is stored in 4 ℃, 25 ℃, 40 ℃ and 50 ℃, measures the stability of reorganization hCG with HPSEC.The result that table 4 is reported shows that the increase of ionic strength has the negativity effect to the stability of reorganization hCG.
To with the preparation of 0.01M phosphate and succinate (pH7) contain 5 of 5,10 and 15% propylene glycol, 000IU/ml reorganization hCG solution has carried out the assessment of dielectric constant effect.The compositions of preparation is reported in table 2.Sample is stored in 4 ℃, 25 ℃, 40 ℃ and 50 ℃, measures the stability of reorganization hCG with HPSEC.The result that table 4 is reported shows that the percentage rate of increase propylene glycol has the negativity effect to the stability of reorganization hCG.
In order to assess the effect of reorganization hCG concentration, to containing 2,500,5,000,7,500 and 10 respectively, (0.01M, pH7.0) solution is 2 weeks of STABILITY MONITORING of 50 ℃ for the phosphate buffer of 000IU/ml reorganization hCG with HPSEC.The result that table 5 is reported shows that denseer stability of solution is higher.
For more various stabilizing agents and/or excipient effect to reorganization hCG stability, contain 10 with 0.01M phosphate buffer (pH7.0) preparation, recombinate six kinds of liquid preparations of hCG of 000IU/ml are as the first step.With sucrose, glycine, glucose, mannitol, lactose and NaCl as stabilizing agent/excipient.The compositions of preparation is reported in table 6.By sample being stored in 4 ℃, 25 ℃, 40 ℃ and 50 ℃ these preparations are carried out stability test, and test with bioassay and HPSEC.Then, on described first step result's basis, use sucrose and mannitol, prepare each 4 batches of two kinds of choice of formulation as stabilizing agent.Table 7 has been reported the compositions of these preparations.
Carry out bioassay according to the European Pharmacopoeia monograph.
Table 8 has been reported HPSEC stability data, and table 9 has been reported the biological activity value.The result shows below:
1. after storing in a week, the biological activity that contains the preparation of glucose and lactose reduces in the time of 50 ℃ significantly.It is measured that the monomer peak also is lower than other preparation.
2. in the presence of glycine and NaCl, compare with the preparation that contains sucrose and mannitol, the biological activity and the purity that record obviously reduce.In this case, the reorganization hCG percentile reduction in monomer peak is not the formation owing to state of aggregation, but because the increase of free subunit.
Table 10 and table 11 reported respectively with HPSEC record 5,000 and 10, the purity of 000IU intensity.Data show, even after 50 ℃ of 3 weeks of storage, the preparation purity that contains mannitol is higher than the preparation that contains sucrose.Table 12 and 13 reported 50 ℃ store 1 week back sucrose and the purity of the alpha subunit that records with reversed-phase HPLC of mannitol preparation.Data confirms to contain the preparation of mannitol than the better stability of preparation that contains sucrose.
Reversed-phase HPLC adopts following standard conditions to carry out:
A adds TFA 1ml in 1 liter of double distilled water
B adds TFA 0.79ml in 1 liter of acetonitrile
Gradient condition time A% B%
0??????????85???????15
20′???????60???????40
21′???????20???????80
22′???????85???????15
Post Aquapore RP300 25cm
40 ℃ of column temperatures
Flow velocity 1ml/ minute
UV-detector 214nm
Volume injected 10 μ l
Reported the result of biological activity determination in the table 14 and 15.The mannitol preparation is not observed perceptible biological activity and is reduced after 4 ℃ and 25 ℃ are placed 24 hours.
According to the present invention, composition of liquid medicine comprises hCG1,000-40, and 000IU/ml, with 10,000IU/ml is good, is included in the mannitol 10-180mg/l in the 0.01M buffer, is good with 54.6mg/ml.
Medication preparation embodiment
Material: phosphoric acid 85%RPEACD (Carlo Erba); Mannitol DAB, PhEurBP, FU, USP, FCC, E421 (Merck), NaOH 1M (Merck), water for injection.
Basic container as the preparation bottle comprises: 3ml vial (DIN 2R) (I type Pyrex), rubber closure (Pharmagummi W1816 V50), aluminum ring and upset medicated cap (flip off cap) (Pharma Metal GmbH).
Contain the preparation of the reorganization hCG solution of mannitol
Phosphoric acid (0.98g) is added in the water for injection (600ml).If desired, use 1M NaOH with pH regulator to 7.0.(54.6g) is added in the phosphoric acid solution with mannitol, proofreaies and correct pH again, if desired, is adjusted to 7.00 ± 0.2 with the phosphoric acid of 1M NaOH or 1: 5 dilution.To recombinate then, (10MIU or 20MIU if required final strength is respectively 5,000 or 10,000IU) are added in the excipient solution hCG storing solution, proofread and correct pH again, if desired, are adjusted to 7.00 ± 0.2 with the phosphoric acid of 1M NaOH or 1: 5 dilution.
Make solution become 1 liter with water for injection.Be not more than under laminar flow then this solution is filtered through the Millipak of 0.22 μ m, 20 filters, solution is collected in the flask, stir about is 1 minute lenitively.
Then with 0.5ml reorganization hCG solution filling bottle.
Table 1
The r-hCG liquid composite
| Acetate buffer solution | Amount/ml |
| Stock solution | ????5000IU |
| ???? Glacial acetic acid | ????0.6mg |
| ????NaOH?1M | In right amount to pH6.0,7.0,8.0 |
| Succinate buffer solution | |
| Stock solution | ????5000IU |
| ???? Succinic acid | ????1.18mg |
| ????NaOH?1M | In right amount to pH6.0,7.0,8.0 |
| Phosphate buffered solution | |
| Stock solution | ????5000IU |
| ???? Phosphoric acid 85% | ????0.98mg |
| ????NaOH?1M | In right amount to pH6.0,7.0,8.0 |
Table 2
The r-hCG liquid composite
Ionic strength/dielectric constant
| ????Lot | ??r-hCG | ??NaCl | ??Prop. ??glyc. | Phosphate buffer 0.01 pH7.0 | Succinic acid buffer 0.01M pH7.0 |
| Fos/7.0/PG5 | ?5000IU/ml | ???- | ?50mg/ml | In right amount to 1ml | ???- |
| Fos/7.0/PG10 | ?5000IU/ml | ???- | ?100mg/ml | In right amount to 1ml | ???- |
| Fos/7.0/PG15 | ?5000IU/ml | ???- | ?150mg/ml | In right amount to 1ml | ???- |
| Suc/7.0/PG5 | ?5000IU/ml | ???- | ?50mg/ml | ???- | In right amount to 1ml |
| Suc/7.0/PG10 | ?5000IU/ml | ???- | ?100mg/ml | ???- | In right amount to 1ml |
| Suc/7.0/PG15 | ?5000IU/ml | ???- | ?150mg/ml | ???- | In right amount to 1ml |
| Fos/7.0/150 | ?5000IU/ml | ?4.4mg/ml | ????- | In right amount to 1ml | ???- |
| Fos/7.0/300 | ?5000IU/ml | ?8.8mg/ml | ????- | In right amount to 1ml | ???- |
| Fos/7.0/400 | ?5000IU/ml | ???11.7 ??mg/ml | ????- | In right amount to 1ml | ???- |
| Suc/7.0/150 | ?5000IU/ml | ?4.4mg/ml | ????- | ????- | In right amount to 1ml |
| Suc/7.0/300 | ?5000IU/ml | ?8.8mg/ml | ????- | ????- | In right amount to 1ml |
| Suc/7.0/400 | ?5000IU/ml | ???11.7 ??mg/ml | ????- | ????- | In right amount to 1ml |
Fill volume: 1ml
The FOS=phosphate buffer
SUC=succinate buffer
7.0＝pH7.0
PG5=propylene glycol 5%
PG10=propylene glycol 10%
PG15=propylene glycol 15%
150,300,400 osmolarities
Table 3
R-hCG purity (%)
HPSEC data pH/ buffering effect
| ???????????????????50℃ | ????????????40℃ | |||||
| ????LOT | ????T＝0 | ????1W | ????3W | ????5W | ????3W | ????5W |
| ??ACE/6 | ????100 | ????95.85 | ????92.70 | ????84.99 | ????97.51 | ????94.10 |
| ??ACE/7 | ????100 | ????96.62 | ????93.26 | ????88.02 | ????97.27 | ????94.05 |
| ??ACE/8 | ????100 | ????96.51 | ????92.70 | ????87.10 | ????97.45 | ????95.12 |
| ??SUC/6 | ????100 | ????94.56 | ????91.28 | ????82.11 | ????96.92 | ????93.11 |
| ??SUC/7 | ????100 | ????95.78 | ????94.0 | ????88.05 | ????96.91 | ????93.99 |
| ??SUC/8 | ????100 | ????95.36 | ????90.12 | ????83.00 | ????97.61 | ????94.02 |
| ??FOS/6 | ????100 | ????94.10 | ????90.76 | ????81.00 | ????97.50 | ????93.00 |
| ??FOS/7 | ????100 | ????96.90 | ????93.12 | ????86.93 | ????96.72 | ????93.74 |
| ??FOS/8 | ????100 | ????94.21 | ????82.52 | ????74.96 | ????96.77 | ????93.55 |
W=week
The ACE=acetate buffer
SUC=succinate buffer
The slow buffer of FOS=phosphoric acid association
6/7/8＝pH6.0，7.0，8.0
Table 4
R-hCG purity (%)
The HPSEC data
Ionic strength/dielectric constant
| ????LOT | ??????????????50℃ | ?????????40℃ | ???25℃ | ????4℃ | ||||
| ??T＝0 | ????1W | ????2W | ?????4W | ?????3W | ????6W | ????6W | ????4W | |
| ?Fos/7.0/PG5 | ??100 | ????91.9 | ????85.7 | ????80.8 | ????96.5 | ????94.3 | ????100 | ????100 |
| ?Fos/7.0/PG10 | ??100 | ????91.9 | ????81.0 | ????77.7 | ????93.9 | ????93.9 | ????100 | ????100 |
| ?Fos/7.0/PG15 | ??100 | ????89.2 | ????79.3 | ????76.2 | ????94.4 | ????93.8 | ????100 | ????100 |
| ?Suc/7.0/PG5 | ??100 | ????90.6 | ????84.3 | ?????- | ????91.7 | ?????- | ????- | ?????- |
| ?Suc/7.0/PG10 | ??100 | ????88.9 | ????81.4 | ?????- | ????94.1 | ?????- | ????- | ?????- |
| ?Suc/7.0/PG15 | ??100 | ????89.3 | ????79.9 | ?????- | ????93.5 | ?????- | ????- | ?????- |
| ?Fos/7.0/150 | ??100 | ????88.5 | ????79.2 | ????72.2 | ????93.0 | ????93.0 | ????100 | ????100 |
| ?Fos/7.0/300 | ??100 | ????80.5 | ????75.0 | ????67.9 | ????93.4 | ????92.1 | ????100 | ????100 |
| ?Fos/7.0/400 | ??100 | ????81.5 | ????74.8 | ????67.4 | ????94.6 | ????93.8 | ????100 | ????100 |
| ?Suc/7.0/150 | ??100 | ????83.1 | ????87.4 | ?????- | ????94.3 | ?????- | ????- | ?????- |
| ?Suc/7.0/300 | ??100 | ????82.4 | ????76.7 | ?????- | ????93.9 | ?????- | ????- | ?????- |
| ?Suc/7.0/400 | ??100 | ????81.8 | ????74.6 | ?????- | ????93.5 | ?????- | ????- | ?????- |
The test of-=not
The FOS=phosphate buffer
SUC=succinate buffer
7.0＝pH7.0
PG5=propylene glycol 5%
PG10=propylene glycol 10%
PG15=propylene glycol 15%
W=week
150,300, the 400=osmolarity
Table 5
R-hCG purity (%)
The HPSEC data
Concentration effect
| ????LOT | ?????????50℃ | ||
| ????T＝0 | ????1W | ????2W | |
| ????Fos/2500 | ????100 | ????87.3 | ????84.0 |
| ????Fos/5000 | ????100 | ????90.8 | ????89.1 |
| ????Fos/7500 | ????100 | ????92.9 | ????89.8 |
| ????Fos/10000 | ????100 | ????92.5 | ????90.9 |
Fos/2500：??2,500?IU/ml?r-hCG
Fos/5000：??5,000?IU/ml?r-hCG
Fos/7500：??7,500?IU/ml?r-hCG
Fos/10000：?1,0000?IU/ml?r-hCG
Table 6
Liquid preparation
The bottle compositions
| Composition/batch | ??r-hCG/SAC | r-hCG/MAN | ?r-hCG/GLY | ???r-hCG/GLU | ??r-hCG/LAT | ??r-hCG/NaCl |
| r-hCG?IU/ml | ????10,000 | 10,00010,000 | ???10,000 | ????10,000 | ????10,000 | ????10,000 |
| Sucrose mg/ml | ????102.6 | ?????- | ?????- | ??????- | ?????- | ?????- |
| Mannitol mg/ml | ?????- | ????54.6 | ?????- | ??????- | ?????- | ?????- |
| Glycine mg/ml | ?????- | ?????- | ????22.52 | ??????- | ?????- | ?????- |
| Glucose mg/ml | ?????- | ?????- | ?????- | ????54.6 | ?????- | ?????- |
| Lactose mg/ml | ?????- | ?????- | ?????- | ??????- | ????102.6 | ?????- |
| NaCl?mg/ml | ?????- | ?????- | ??????- | ?????- | ????9.0 |
Buffer: H
3PO
40.01M, pH7.0
Fill volume: 0.5ml
Table 7
Liquid preparation
The bottle compositions
| Composition | Unit | ??r-hCG/5000/S01 | ??r-hCG/10000/S01 |
| ????r-hCG | ????IU/ml | ????10,000 | ????20,000 |
| Sucrose | ????mg/ml | ????102.6 | ????102.6 |
| O. phosphoric acid | ????mg/ml | ????0.98 | ????0.98 |
| Sodium hydroxide | In right amount to pH7.0 | In right amount to pH7.0 |
| Composition | Unit | ??r-hCG/5000/S01 | ??r-hCG/10000/S01 |
| ????r-hCG | ????IU/ml | ????10,000 | ????20,000 |
| Mannitol | ????mg/ml | ????54.6 | ????54.6 |
| O. phosphoric acid | ????mg/ml | ????0.98 | ????0.98 |
| Sodium hydroxide | In right amount to pH7.0 | In right amount to pH7.0 |
Fill volume: 0.5ml
The compatibility of table 8 and different excipient
HPSEC stability data: purity (%)
| Lot number | ????????????50℃ | ?????????????????40℃ | ?????????????25℃ | ??????4℃ | ||||||||||
| ?T＝0 | ?1W | ?2W | ?6W | ?2W | ?4W | ?6W | 11W | ?4W | ?6W | ?8W | ?11W | ?8W | 12W | |
| ?FOS/SAC | ?100 | 94.1 | 90.3 | 83.0 | 98.0 | 95.5 | 96.1 | 94.8 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 |
| ?FOS/GLY | ?100 | 94.2 | 90.4 | 81.5 | 97.5 | 96.3 | 95.5 | 95.5 | ?100 | ?100 | ?100 | ?100 | ?100 | ?100 |
| ?FOS/GLU | ?100 | 85.0 | 74.9 | N.T | 88.0 | N.T | N.T | N.T | ?N.T | ?N.T | ?N.T | ?N.T | ?N.T | ?N.T |
| ?FOS/MAN | ?100 | 94.0 | 91.7 | 83.5 | 97.9 | 97.1 | 95.8 | 95.4 | ?N.T | ?100 | ?100 | ?100 | ?100 | ?100 |
| ?FOS/LAT | ?100 | 88.3 | 71.6 | N.T | 89.0 | N.T | N.T | N.T | ?N.T | ?N.T | ?N.T | ?N.T | ?N.T | ?N.T |
| ?FOS/NaCl | ?100 | 89.7 | 85.6 | 71.7 | 97.2 | 95.2 | 94.2 | 94.1 | ?N.T | ?100 | ?100 | 98.5 | ?100 | ?100 |
W=week
Fill volume=0.5ml
The FOS=phosphate buffer
SAC=sucrose, the GLY=glycine, the GLU=glucose, the MAN=mannitol, the LAT=breast is half congealed
N.T.=does not test
The compatibility of table 9 and different excipient
Biometric data (IU/ml)
| Lot number | ?????????????50℃ | ??????????????????40℃ | ???????25℃ | ??????4℃ | ||||||||
| ??T＝0 | ?1W | ??2W | ??7W | ??2W | ??4W | ??7W | ??10W | ??8W | ?11W | ??8W | ??12W | |
| FOS/SAC | ?9473 | 7854 | ?8245 * | ??N.V. | ?8090 | 10368 | ?9126 | ?8269 | ?8809 * | 11222 | ?9588 | ?8489 |
| FOS/GLY | ?7850 * | 5642 | ?4913 | ???- | ?6421 | ?8112 | ?6780 | ?6635 * | ??- | 7159 | ??- | ?6821 * |
| FOS/GLU | ?8370 | N.V. | ??- | ???- | ??- | ??- | ??- | ??- | ??- | ?- | ??- | ??- |
| FOS/MAN | ?9498 | 7031 | ?7224 | ?6321 * | 10605 | 13216 | ?9374 * | ?6904 | ?7285 | 7941 | 10079 | ?8762 |
| FOS/LAT | ?7976 | N.V. | ??- | ???- | ??- | ??- | ??- | ??- | ??- | ?- | ??- | ??- |
| FOS/NaCl | ?8486 | 8394 | ?6433 | ???- | ?9262 | 10576 | ??- | ?7578 | ?9151 * | 9353 * | 8804 | ?8377 |
W=week
Fill volume=0.5ml
*=Validity Test
N.v.=does not have Validity Test
The test of-=not
The FOS=phosphate buffer
SAC=sucrose, the GLY=glycine, the GLU=glucose, the MAN=mannitol, the LAT=breast is half congealed
N.T.=does not test
Table 10 liquid preparation: concentration 5,000IU/ bottle
HPSEC stability data: purity (%)
Formulation development
| Lot number | ?????????50℃ | ????40℃ | ||
| ????T＝0 | ????1W | ????3W | ????3W | |
| ?HCG/5000/S01 | ????100 | ????90.0 | ????86.3 | ????97.2 |
| ?HCG/5000/M01 | ????100 | ????89.5 | ????88.3 | ????97.6 |
W=week
S01=sucrose
The M01=mannitol
Table 11 liquid preparation: concentration 10,000IU/ bottle
HPSEC stability data: purity (%)
Formulation development
| Lot number | ??????????50℃ | ??40℃ | ||
| ???T＝0 | ?????1W | ?????3W | ?????3W | |
| ?HCG/10000/S01 | ????100 | ????91.8 | ????88.9 | ????97.9 |
| ?HCG/10000/M01 | ????100 | ????93.4 | ????92.1 | ????97.2 |
W=week
S01=sucrose
The M01=mannitol
Table 12 liquid preparation:
Record alpha subunit purity with RP-HPLC
| Lot number | ????50℃ | |
| ????T＝0 | ????1W | |
| HCG/5000/S01α(％) | ????100 | ????90.2 |
| HCG/5000/M01α(％) | ????100 | ????94.7 |
W=week
S01=sucrose
The M01=mannitol
Table 13 liquid preparation:
Record alpha subunit purity with RP-HPLC
| Lot number | ????50℃ | |
| ????T＝0 | ????1W | |
| HCG/5000/S01α(％) | ????100 | ????92.4 |
| HCG/5000/M01α(％) | ????100 | ????95.2 |
W=week
S01=sucrose
The M01=mannitol
Table 14 liquid preparation
Biometric data (IU/ml)
| Lot number | ??????????????????????????????50℃ | ||||
| ????T＝0 | ????1W | ????3W | ????4W | ????5W | |
| ?HCG/5000/S01 | ????09194 (7484-11298) | ????6427 ??(4770-8660) | ????6757 ??(5454-8371) | ?????- | ????NV |
| ?HCG/5000/M01 | ????8548 (6376-11459) | ????9249 (7495-11414) | ????6977 ??(5649-8618) | ????6207 (4767-8082) | ????3219 *(1436-5150) |
| Lot number | ??????????????????????????????40℃ | |||
| ????4W | ????6W | ????10W | ????13W | |
| ?HCG/5000/S01 | ????8682 *(6092-12393) | ????10102 (7733-13195) | ?????- | ?????- |
| ?HCG/5000/M01 | ????10203 (7813-13325) | ????7959 (6118-10356) | ????8192 (6276-10692) | ????7309 (5932-9005) |
W=week
NV=does not have Validity Test
S01=sucrose
The M01=mannitol
*A Validity Test
Table 14 (continuing)
| Lot number | ?????????????????????25℃ | |||
| ????T＝0 | ????5W | ????13W | ????24W | |
| ?HCG/5000/S01 | ????9194 (7484-11298) | ????- | ?????- | ?????- |
| ?HCG/5000/M01 | ????8548 (6376-11459) | ????6660 *(3855-10118) | ????8969 ?(7007-11479) | ????8232 *(5787-11712) |
| Lot number | ????????????????????????4℃ | ||
| ????5W | ????13W | ????240W | |
| ?HCG/5000/S01 | ????7555 (5904-9667) | ?????- | ?????- |
| ?HCG/5000/M01 | ????8869 *(5968-12826) | ????10330 (8167-13065) | ????9799 (7714-12447) |
W=week
NV=does not have Validity Test
S01=sucrose
The M01=mannitol
*A Validity Test
Table 15 liquid preparation: 10,000 IU bottles
Biometric data (IU/ml)
| Lot number | ??????????????????????50℃ | |||
| ????T＝0 | ????1W | ????2W | ????4W | |
| ?HCG/10000/S01 | ????20273 (15170-27091) | ????15531 (11842-20368) | ????14971 ?(11307-19824) | ????- |
| ?HCG/10000/M01 | ????18919 (14150-25295) | ????15880 (12605-20006) | ????13495 ??(9994-18222) | ????14855 (11579-19058) |
| Lot number | ??????????????????????40℃ | ||
| ????4W | ????6W | ????13W | |
| ?HCG/5000/S01 | ????22201 (16648-29607) | ????14977 ??(12075-18576) | ?????- |
| ?HCG/5000/M01 | ????19508 (14201-26797) | ????14680 ??(11328-19022) | ????14606 (11580-18423) |
W=week
NV=does not have Validity Test
S01=sucrose
The M01=mannitol
*A Validity Test
Table 15 (continuing)
| ????LOT | ????????????????????????????25℃ | ||||
| ????T＝0 | ????5W | ????10W | ????13W | ????24W | |
| HCG/10000/S01 | ????20273 (15170-27091) | ????- | ????17812 *(11809-18996) | ?????- | ?????- |
| HCG/10000/M01 | ????18919 (14150-25295) | ????17890 (14467-22122) | ????15494 (12638-18996) | ????16419 (12890-20915) | ????18991 (15311-23556) |
| ????LOT | ????????????????????????4℃ | ||
| ????5W | ????13W | ????24W | |
| ??HCG/5000/S01 | ????21616 (17596-26555) | ?????- | ?????- |
| ??HCG/5000/M01 | ????20666 (17390-24559) | ????17096 ?(13503-21646) | ????19553 (14494-26377) |
W=week
NV=does not have Validity Test
S01=sucrose
The M01=mannitol
*A Validity Test
Claims (12)
1. composition of liquid medicine comprises the polyhydric alcohol or the non-reducing sugar of human chorionic gonadotropin and consistent dose.
2. composition of liquid medicine as claimed in claim 1, wherein polyhydric alcohol is a mannitol.
3. composition of liquid medicine as claimed in claim 1, wherein non-reducing sugar is a sucrose.
4. composition of liquid medicine as claimed in claim 1, wherein human chorionic gonadotropin is a recombinant.
5. as the described composition of liquid medicine of one of claim 1-4, wherein solution is buffered aqueous solution.
6. composition of liquid medicine as claimed in claim 5, wherein buffer solution is selected from one group that acetate, succinate and phosphate are formed.
7. composition of liquid medicine as claimed in claim 6, wherein buffer is a phosphate buffer.
8. as the described composition of liquid medicine of one of claim 5-7, wherein buffer solution is pH7.00.
9. as the described composition of liquid medicine of one of claim 5-8, wherein buffer solution is 0.01M.
10. composition of liquid medicine as claimed in claim 1 comprises 1,000-40,000IU/ml hCG and be mannitol 10-180mg/l in 7.00 the 0.01M phosphate buffer at pH.
11. prepare the method for the described composition of liquid medicine of claim 1, it is characterized in that: with the buffer dilution hCG storing solution that contains excipient.
12. the supply the market form of the described composition of liquid medicine of claim 1 is characterized in that in the container that sealed under aseptic conditions stores before being fit to use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197791A CN1082368C (en) | 1995-03-21 | 1995-03-21 | HCG liquid formulations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197791A CN1082368C (en) | 1995-03-21 | 1995-03-21 | HCG liquid formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1179724A true CN1179724A (en) | 1998-04-22 |
| CN1082368C CN1082368C (en) | 2002-04-10 |
Family
ID=5083355
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95197791A Expired - Lifetime CN1082368C (en) | 1995-03-21 | 1995-03-21 | HCG liquid formulations |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1082368C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309747A (en) * | 2008-09-17 | 2012-01-11 | 上海天伟生物制药有限公司 | Composition of glycoprotein scarcely containing subunits |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04191869A (en) * | 1990-11-27 | 1992-07-10 | Mita Ind Co Ltd | Multicolor developing device |
| JP2966592B2 (en) * | 1991-07-20 | 1999-10-25 | 萩原 義秀 | Stabilized human monoclonal antibody preparation |
-
1995
- 1995-03-21 CN CN95197791A patent/CN1082368C/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309747A (en) * | 2008-09-17 | 2012-01-11 | 上海天伟生物制药有限公司 | Composition of glycoprotein scarcely containing subunits |
| CN102309747B (en) * | 2008-09-17 | 2013-04-17 | 上海天伟生物制药有限公司 | High purity menopause gonadotropin freeze drying injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1082368C (en) | 2002-04-10 |
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