CN115634284A - Gonadotropin freeze-dried preparation and preparation method thereof - Google Patents
Gonadotropin freeze-dried preparation and preparation method thereof Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a gonadotropin freeze-dried preparation and a preparation method thereof, relating to the technical field of pharmaceutical preparations. The gonadotropin freeze-dried preparation comprises the following components in parts by weight: 0.01 to 0.15 portion of gonadotropin, 10 to 20 portions of buffering agent, 0.1 to 1 portion of surfactant, 200 to 300 portions of trehalose, 100 to 350 portions of mannitol and 50 to 100 portions of glycine. The freeze-dried preparation of the gonadotropin is prepared by adopting a specific formula, has high biological activity, good stability in the freeze-drying process and the storage process, and short re-dissolving time in use, and has good stability and re-dissolving property. The invention is especially suitable for preparing Luteinizing Hormone (LH) and variant freeze-dried preparations thereof, and has good application prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a gonadotropin freeze-dried preparation and a preparation method thereof.
Background
Gonadotropins (Gn) are glycoprotein hormones that regulate the development of gonads in vertebrates and promote the production and secretion of sex hormones, such as Luteinizing Hormone (LH) secreted from the anterior pituitary, follicle Stimulating Hormone (FSH), chorionic gonadotropin (HCG) secreted from the human placenta, and the like. The lack of gonadotropins in humans can lead to a variety of disorders, for example, hypogonadism of gonadotropins in women can affect fertility. For another example, LH, as a glycoprotein gonadotropin, promotes the conversion of cholesterol into sex hormones in gonads, and if LH is deficient, various diseases including reproductive diseases may occur, for example, women may suffer from irregular menstruation and infertility, and men may suffer from decreased testicular function. Luteinizing hormone alpha, also called recombinant human luteinizing hormone (rh-LH), has the same structural and physiological effects as naturally occurring Luteinizing Hormone (LH) of human body, is a glycoprotein hormone prepared by genetic engineering technology and cell culture technology, and can be combined with luteinizing hormone/chorionic gonadotropin (LH/CG) receptors on ovarian membrane (and granulosa) and testicular interstitial cell membrane. For women who lack LH and FSH and are not oviparous, rh-LH can promote the level of estradiol secreted by follicles to be increased and stimulate the development of the follicles.
It is seen that gonadotropin has an important regulation effect on the normal physiological function of human body, and the lack of gonadotropin can cause various diseases. For patients with gonadotropin deficiency clinically, the corresponding gonadotropin supplementation is often injected, for example, LH is prepared into Intramuscular (IM) or Subcutaneous (SC) injection medicament for injection supplementation when the LH is deficient, or rh-LH is injected and supplemented. At present, the medicinal injection preparation of the gonadotropin is mainly a freeze-dried preparation, and the freeze-dried preparation is re-dissolved for injection when in use. However, gonadotropins are poorly stable during the preparation of lyophilized formulations and during later storage and are easily denatured, resulting in off-specification products. For example, the commercial human Luteinizing Hormone (LH) antigen is dissolved in 0.02MpH7.4 PBS solution and is freeze-dried into freeze-dried powder, and the freeze-dried powder can be stored only at 2-8 ℃ for a short time and needs to be stored below-20 ℃ for a long time.
In order to improve the stability of the freeze-dried preparation of the gonadotropin during the preparation process and the stability of the freeze-dried preparation of the gonadotropin during long-term storage. Patent applications published under number WO2004087213A8 and WO2004112826A1 both disclose lyophilized formulations comprising Follicle Stimulating Hormone (FSH) or a variant thereof, and/or Luteinizing Hormone (LH) or a variant thereof, both of which use, for example, sucrose, dextrose, lactose, mannitol and/or glycerol as stabilizers and tonicity modifiers to ensure stability of the lyophilized formulation. EP0448146B1 discloses a stabilized gonadotropin-containing lyophilized powder for injection comprising gonadotropin and a stabilizing amount of a dicarboxylic acid salt, wherein the formulation comprises a sufficient amount of dicarboxylic acid salt, dicarboxylic acid salt and an additional saccharide as a stabilizer to ensure the stability of the lyophilized formulation during lyophilization and storage. However, in the above patent applications or patents, the preparation of the lyophilized preparation only takes into consideration the stability of the preparation, and does not take into consideration the re-solubility of the preparation.
However, during the actual use of the lyophilized preparation, the re-solubility of the lyophilized preparation is a key quality attribute of the lyophilized preparation, and the re-dissolution time of the lyophilized preparation of gonadotropins such as LH or its variant and FSH or its variant is generally required to be controlled within 2min, especially the re-dissolution time of rh-FSH in clinical use and related regulations is further controlled within 60s, if the lyophilized preparation is not dissolved or is not completely dissolved within a certain period of time, the active ingredients may be reduced in clinical use, and the pharmaceutical effectiveness may be affected. Therefore, both the stability and the re-solubility of the lyophilized preparation are considered in preparing the lyophilized preparation of gonadotropin. The patent application with the publication number of CN103432085A discloses that the temozolomide freeze-dried preparation is prepared by using amino acid as a solubilizer, so that the solubility and the stability of the solution of the temozolomide are improved, and the redissolution time is relatively fast, wherein the amino acid is arginine or lysine and the like. However, the effect of solubilization of amino acids may differ for different drugs. Whether gonadotropins can be solubilized by using amino acids or not and how the solubilization effect is unknown, and further research is needed to provide a gonadotropin lyophilized preparation with good stability and good re-solubility.
Disclosure of Invention
The invention provides a gonadotropin freeze-dried preparation and a preparation method thereof.
The invention provides a gonadotropin freeze-dried preparation which comprises the following components in parts by weight:
0.01 to 0.15 portion of gonadotropin, 10 to 20 portions of buffering agent, 0.1 to 1 portion of surfactant, 200 to 300 portions of trehalose, 100 to 350 portions of mannitol and 50 to 100 portions of glycine.
Further, the gonadotropin lyophilized preparation comprises the following components in parts by weight:
0.04 part of gonadotropin, 10-15 parts of buffering agent, 0.5-1 part of surfactant, 200-300 parts of trehalose, 200-300 parts of mannitol and 50-100 parts of glycine.
Further, the gonadotropin lyophilized preparation comprises the following components in parts by weight:
0.04 part of gonadotropin, 12-13 parts of buffering agent, 0.5 part of surfactant, 200-300 parts of trehalose, 200-300 parts of mannitol and 50-100 parts of glycine.
Furthermore, the weight ratio of the mannitol to the glycine is 2-4:1.
Further, the air conditioner is provided with a fan,
the gonadotropin is luteinizing hormone or a variant thereof, follicle stimulating hormone or a variant thereof, human placenta-secreted chorionic gonadotropin or a variant thereof;
and/or, the buffer is a phosphate buffer;
and/or, the surfactant is selected from polysorbate, tween 20, tween 40, tween 80;
preferably, the first and second electrodes are formed of a metal,
the phosphate buffer consists of disodium hydrogen phosphate and sodium dihydrogen phosphate;
and/or, the surfactant is tween 20.
Preferably, the mass ratio of the disodium hydrogen phosphate to the sodium dihydrogen phosphate is (2-3): 1.
in the present invention, the gonadotropin is preferably LH or a LH variant, which may be produced by a suitable method, such as recombinant methods, isolated or purified from a natural source if possible, or chemically synthesized, or any combination thereof. "LH variant" refers to a molecule that encompasses the amino acid sequence, glycosylation pattern or intersubunit linkage of human LH, but exhibits LH activity.
The term "recombinant" is used to refer to the preparation of LH or a LH variant prepared by the use of recombinant DNA techniques (see for example patent application publication WO 85/01958). An example of a method for expressing LH using recombinant technology is by transfecting eukaryotic cells with DNA sequences encoding the alpha and beta subunits of LH (whether provided on one or two vectors, each subunit having a separate promoter), as described in patent applications published as EP0211894 and EP 0487512.
LH is preferably produced recombinantly, and particularly preferably in Chinese Hamster Ovary (CHO) cells transfected with a DNA expression vector or vectors comprising the alpha-subunit of the human glycoprotein and the LH beta-subunit. The DNA encoding the alpha-and beta-subunits may be present on the same or different vectors.
Another example of using recombinant technology to produce LH is the use of homologous recombination techniques to insert a heterologous regulatory fragment operably linked to the endogenous sequence encoding the LH subunit, as described in the patent application published as EP 0505500.
Further, the preparation of LH or LH variant comprises 1-15 μ g of LH or LH variant, 10-30mg of trehalose, 10-30mg of mannitol and 5-10mg of glycine.
Further, the formulation of the LH or LH variant further comprises from 0.01mg to or about 1mg of a surfactant.
The formulation of LH or LH variant further comprises a phosphate buffer. Phosphate buffers are preferred, with sodium or potassium being a preferred counterion. Phosphate buffered saline is well known in the art, for example, dulbecco's phosphate buffered saline. The buffer concentration in the total solution may vary between 5mM,9.5mM,10mM,50mM,100mM,150mM,200mM,250mM and 500mM or between. Preferably, the buffer concentration is at or about 10mM. Particularly preferred is a 10M phosphate ion buffer at pH 7.0.
The buffer is preferably adjusted in such a way that the pH of the reconstituted formulation of the lyophilized formulation of the invention is about 6.0 or about 6.0 to about 8.0, more preferably about 6.8 or about 7.8 to about 7.8, including about pH 7.0, pH 7.2 and 7.4.
Further, the Luteinizing Hormone (LH) is human Luteinizing Hormone (LH).
The Luteinizing Hormone (LH) is a human urinary Luteinizing Hormone (LH).
The Luteinizing Hormone (LH) is recombinant human luteinizing hormone (rh-LH).
Furthermore, the freeze-dried preparation is prepared by adding the components into water for injection to dissolve and freeze-drying.
Further, after the components are dissolved, the pH value is adjusted to 6.0-8.0; preferably 6.8 to 7.8; more preferably 7.2.
Further, the process of lyophilization comprises the following steps:
1) Pre-freezing: the temperature is-40 ℃ to-50 ℃, the time is 5-15h, and the vacuum degree is 1-5atm;
2) Sublimation: the temperature is-25 ℃ to-35 ℃, the time is 12-18h, and the vacuum degree is 8-16pa;
3) And (3) heating: the temperature is 10-35 ℃, the time is 1.5-2.5h, and the vacuum degree is 8-16pa;
4) And (3) resolving and drying: the temperature is 20-35 ℃, the time is 1-3h, and the vacuum degree is 8-16pa.
The invention also provides a preparation method of the gonadotropin freeze-dried preparation, which comprises the following steps:
(1) Weighing the components in parts by weight;
(2) Dissolving the components in water for injection, and adjusting the pH value to 6.0-8.0;
(3) Carrying out freeze-drying, wherein the freeze-drying process comprises the following steps: 1) Pre-freezing: the temperature is-40 ℃ to-50 ℃, the time is 5-15h, and the vacuum degree is 1-5atm; 2) Sublimation: the temperature is-25 ℃ to-35 ℃, the time is 12-18h, and the vacuum degree is 8-16pa; 3) And (3) heating: the temperature is 10-35 ℃, the time is 1.5-2.5h, and the vacuum degree is 8-16pa; 4) And (3) resolving and drying: the temperature is 20-35 ℃, the time is 1-3h, and the vacuum degree is 8-16pa.
The invention also provides application of the gonadotropin freeze-dried preparation in preparing a medicament for treating female infertility and/or male infertility.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a gonadotropin freeze-dried preparation, which is prepared by adopting a specific formula. The invention is especially suitable for preparing Luteinizing Hormone (LH) and variant freeze-dried preparations thereof, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw material sources are as follows: the raw materials of the present invention are commercially available without specific mention.
In the present invention, rh-LH 4. Mu.g activity is 99.4IU.
Examples 1 to 4 preparation of rh-LH lyophilized formulations
Inventive examples 1-4 formulations for preparing the rh-LH lyophilized formulation are shown in table 1 below.
TABLE 1 formulation composition of each rh-LH lyophilized formulation
The preparation method of the freeze-dried preparation of the formulas 1 to 4 is as follows:
mixing rh-LH, na 2 HPO 4 ·2H 2 O、NaH 2 PO 4 ·H 2 Adding O, tween 20, trehalose, mannitol, glycine and water for injection into a container, stirring to dissolve completely, adjusting pH to 7.2, filtering, filling the filtered solution into a glass container containing lyophilized preparation, placing a stopper, and placing the filled glass container into a stainless steel tray. The trays were loaded into a freeze-dryer and the product was lyophilized using the following freeze-drying cycle.
The lyophilization process can be performed as follows:
step 1, pre-freezing: the temperature is-40 ℃ to-50 ℃, the time is 5-15h, and the vacuum degree is 1atm;
step 2, sublimation: the temperature is-25 ℃ to-35 ℃, the time is 12-18h, and the vacuum degree is 8-16pa;
step 3, temperature rising: the temperature is 10-35 ℃, the time is 1.5-2.5h, and the vacuum degree is 8-16pa;
and 4, resolving and drying: the temperature is 20-35 ℃, the time is 1-3h, and the vacuum degree is 8-16pa;
and (5) finishing the freeze-drying.
The lyophilized formulations prepared in examples 1 to 4 were stored at a temperature of 25 ± 2 ℃, and were analytically tested for stability and re-solubility of the lyophilized formulations immediately after preparation (at 0 th storage), 1 month, 3 months and 6 months of storage, respectively. The results of the stability and reconstitution time related analytical tests of the lyophilized formulations of examples 1-4 are shown in tables 2 and 3.
The stability indicators include:
1. biologically active rh-LH: determination by SE-HPLC
2. The percentage of oxidation products: reverse phase HPLC (RP-HPLC) method measurement
3. Dimer/aggregate percentage: determination by SDS-PAGE
4. Percent free subunit: non-reduced SDS-PAGE assay
High biological activity, less oxidation products, less dimer/aggregate and less free subunit, which indicates that the freeze-dried preparation has good stability. And adding water for injection to reconstitute the injection during stability detection.
The re-solubility indexes include:
1. and (3) detecting the redissolution time: taking 5 bottles of the test article, adding 1.0ml of sterile water for injection along the bottle wall, immediately starting timing and observing the dissolution condition of the test article, and slightly shaking to assist dissolution, and recording the re-dissolution time (taking seconds as a time unit and keeping the seconds as an integer) when the test article (freeze-dried block or powder) is completely dissolved. If the time exceeds 2min, substances which can not be completely dissolved are always in the solution, and the solution is counted as insoluble/incomplete-soluble.
TABLE 2 stability results for lyophilized formulations of examples 1-4
TABLE 3 reconstitution time of lyophilized formulations of examples 1-4
Tables 2 and 3 the results illustrate that: the rh-LH freeze-dried preparations prepared by the formulas 1-4 of the invention have good stability and redissolution, each index is still stable even after being kept for 6 months at normal temperature, and the rh-LH freeze-dried preparations can be quickly redissolved when in use.
The invention details the beneficial effects of the formulation of the invention through the following experiments.
Experimental example 1 screening of Freeze-drying protective Agents
1. Formulations 5-10 in table 4 were designed for the preparation of rh-LH lyophilized formulations, respectively, prepared according to the methods of the examples of the present invention. The protective effect of trehalose, sucrose, glycine, sorbitol, lysine and mannitol on products in the freeze-drying process is researched.
TABLE 4 composition of the formulations
Formulations 5 to 10 were prepared as lyophilized formulations, water for injection was added to reconstitute the injection solution, and the stability of the lyophilized formulations was examined according to the method described in the examples, with the results shown in table 5.
TABLE 5 stability results for formulations 5-10 lyophilized formulations
As can be seen from the data in table 5, trehalose and mannitol, which are used as protective agents among trehalose, sucrose, glycine, sorbitol, lysine and mannitol, have better protective effects on the lyophilized preparation than sucrose, glycine, sorbitol and lysine, and the prepared lyophilized preparation has better stability. Therefore, trehalose and mannitol were initially selected as protecting agents.
2. In the present invention, formulations 11-15 in Table 4 were designed to prepare rh-LH lyophilized formulations prepared according to the methods of the examples of the present invention. And (3) detecting the stability of each freeze-dried preparation, investigating the protection effect of the protective agent compounding on the freeze-dried preparation, and detecting the re-dissolving time of the freeze-dried preparation. Formulations 11 to 15 were prepared as lyophilized formulations, and water for injection was added to reconstitute the injection solution, and the stability and reconstitution properties of the lyophilized formulations were examined as described in the examples, and the results are shown in table 6.
TABLE 6 stability and reconstitution results for lyophilized formulations 11-15
From the results of the above table 6, it can be seen that the trehalose compound glycine of formula 12 has the best stability protection effect, and during the storage process, the bioactivity is high, the percentage of oxidation products and the percentage of dimers/aggregates are low, but the re-solubility is not good, and the re-dissolution is not complete after 2 min. The freeze-dried preparation prepared by compounding trehalose with mannitol can be redissolved for 38-40s, but the freeze-dried preparation has poor stability. The freeze-dried preparation prepared at the moment can not have good stability and re-solubility at the same time, and the effect is not good.
3. Based on the results of the formula 12 and the formula 15, trehalose, glycine and mannitol are compounded to be used as freeze-drying auxiliary materials, the compounding proportion of each auxiliary material is screened, and the formula design is shown in table 7. The rh-LH lyophilized formulations were prepared according to the formulations 16 to 21 in table 7, and the lyophilized formulations were prepared according to the methods of the examples of the present invention. Formulations 16-21 lyophilized formulations prepared were tested for stability and re-solubility as described in the examples, and the results are shown in table 8.
TABLE 7 composition of each formulation
TABLE 8 stability and reconstitution results for formulations 16-21 lyophilized formulations
As can be seen from the results in Table 8 above, the combination of trehalose, mannitol and glycine in specific amounts can ensure the stability and rehydration of the lyophilized preparation. And the ratio of mannitol to glycine is 2-4:1, if the amount of glycine is more, the re-solubility of the freeze-dried preparation is poor; if mannitol is present in a large amount, the lyophilized preparation has poor stability.
4. Comparative example: 4 μ gh-LH, 1.11mg Na 2 HPO 4 ·2H 2 O、0.45mg NaH 2 PO 4 ·H 2 O, 0.05mg of Tween 20, 30mg of trehalose, 30mg of mannitol and 10mg of lysine. The lyophilized preparation was prepared according to the methods described in examples, and the stability and re-solubility of the lyophilized preparation were examined according to the methods described in examples, and the results are shown in table 9.
TABLE 9 stability and redissolution results for the lyophilized formulations of the control examples
In the comparative example, lysine was used instead of glycine according to the present invention, and it was found that the stability and re-solubility of the lyophilized preparation obtained were deteriorated.
5. The invention uses the specific formula in the patent with publication (notice) numbers of WO2004087213A8, WO2004112826A1 and EP0448146B1 to prepare the freeze-dried preparation according to the method in the document, and the freeze-dried preparation is added with water for injection to be reconstructed and then the redissolution time of the freeze-dried preparation is detected.
WO2004087213A8:65.5 μ g recombinant FSH, 18.0 μ g recombinant LH, 30.0mg sucrose, 0.104mg NaH 2 PO 4 ·H 2 O、1.65mg Na 2 HPO 4 ·2H 2 O, 0.10mg of Pluronic F68 and 0.10mg of L-methionine.
WO2004112826A1:12.0 μ g (165 IU) FSH, 3.7 μ g (92 IU) LH, 30.0mg sucrose, 0.45mg NaH 2 PO 4 ·H 2 O、1.11mg Na 2 HPO 4 ·2H 2 O, 0.05mg of Tween 20 and 0.1mg of L-methionine.
EP0448146B1:75IU rFSH, 75IU LH, 15mg sodium citrate, 50mg sucrose and 0.2mg polysorbate 20.
The re-solubility of the lyophilized preparation was examined by the method described in the examples of the present invention, and the results are shown in Table 10.
TABLE 10 redissolution of similar lyophilized formulations in other patents
As can be seen from table 10: the re-solubility of the freeze-dried preparation of the gonadotropin prepared in the prior art is poor. The lyophilized formulation prepared by the present invention overcomes this problem in the prior art.
In conclusion, the invention provides a gonadotropin freeze-dried preparation, the gonadotropin freeze-dried preparation is prepared by adopting a specific formula, the freeze-dried preparation has high biological activity, good stability in the freeze-drying process and the storage process, and short redissolution time in use, and the freeze-dried preparation can have good stability and redissolution property at the same time. The invention is especially suitable for preparing Luteinizing Hormone (LH) and variant freeze-dried preparations thereof, and has good application prospect.
Claims (10)
1. A freeze-dried preparation of gonadotropin, which is characterized in that: the paint comprises the following components in parts by weight:
0.01 to 0.15 portion of gonadotropin, 10 to 20 portions of buffering agent, 0.1 to 1 portion of surfactant, 200 to 300 portions of trehalose, 100 to 350 portions of mannitol and 50 to 100 portions of glycine.
2. The lyophilized formulation of gonadotropin according to claim 1, characterized in that: the paint comprises the following components in parts by weight:
0.04 part of gonadotropin, 10-15 parts of buffering agent, 0.5-1 part of surfactant, 200-300 parts of trehalose, 200-300 parts of mannitol and 50-100 parts of glycine.
3. The lyophilized formulation of gonadotropin according to claim 2, characterized in that: the paint comprises the following components in parts by weight:
0.04 part of gonadotropin, 12-13 parts of buffering agent, 0.5 part of surfactant, 200-300 parts of trehalose, 200-300 parts of mannitol and 50-100 parts of glycine.
4. The lyophilized formulation of gonadotropin according to any one of claims 1 to 3, wherein: the weight ratio of the mannitol to the glycine is 2-4:1.
5. The lyophilized formulation of gonadotropin according to any one of claims 1 to 3, wherein:
the gonadotropin is luteinizing hormone or a variant thereof, follicle stimulating hormone or a variant thereof, human placenta-secreted chorionic gonadotropin or a variant thereof;
and/or, the buffer is a phosphate buffer;
and/or, the surfactant is selected from polysorbate, tween 20, tween 40, tween 80;
preferably, the first and second electrodes are formed of a metal,
the phosphate buffer consists of disodium hydrogen phosphate and sodium dihydrogen phosphate;
and/or, the surfactant is tween 20.
6. The lyophilized formulation of gonadotropin according to any one of claims 1 to 3, wherein: the freeze-dried preparation is prepared by adding the components into water for injection to dissolve and freeze-drying.
7. The lyophilized formulation of gonadotropin according to claim 6, wherein: after the components are dissolved, the pH value is adjusted to 6.0-8.0; preferably 6.8 to 7.8; more preferably 7.2.
8. The lyophilized formulation of gonadotropin according to claim 6, wherein: the process of lyophilization comprises the following steps:
1) Pre-freezing: the temperature is-40 ℃ to-50 ℃, the time is 5-15h, and the vacuum degree is 1-5atm;
2) Sublimation: the temperature is-25 ℃ to-35 ℃, the time is 12-18h, and the vacuum degree is 8-16pa;
3) And (3) heating: the temperature is 10-35 ℃, the time is 1.5-2.5h, and the vacuum degree is 8-16pa;
4) And (3) resolving and drying: the temperature is 20-35 ℃, the time is 1-3h, and the vacuum degree is 8-16pa.
9. The process for preparing a lyophilized formulation of gonadotropin according to any one of claims 1 to 8, characterized in that: it comprises the following steps:
(1) Weighing the components in parts by weight;
(2) Dissolving the components in water for injection, and adjusting the pH value to 6.0-8.0;
(3) Carrying out freeze-drying, wherein the freeze-drying process comprises the following steps: 1) Pre-freezing: the temperature is-40 ℃ to-50 ℃, the time is 5-15h, and the vacuum degree is 1-5atm; 2) Sublimation: the temperature is-25 ℃ to-35 ℃, the time is 12-18h, and the vacuum degree is 8-16pa; 3) And (3) heating: the temperature is 10 ℃ to 35 ℃, the time is 1.5 h to 2.5h, and the vacuum degree is 8 pa to 16pa; 4) And (3) resolving and drying: the temperature is 20-35 ℃, the time is 1-3h, and the vacuum degree is 8-16pa.
10. Use of a lyophilized formulation of gonadotropin according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of female infertility and/or male infertility.
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