CN118236330A - Rubitidine freeze-dried composition, rubitidine injection and preparation method thereof - Google Patents
Rubitidine freeze-dried composition, rubitidine injection and preparation method thereof Download PDFInfo
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- CN118236330A CN118236330A CN202211657180.1A CN202211657180A CN118236330A CN 118236330 A CN118236330 A CN 118236330A CN 202211657180 A CN202211657180 A CN 202211657180A CN 118236330 A CN118236330 A CN 118236330A
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- 238000002347 injection Methods 0.000 title claims abstract description 8
- 239000007924 injection Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 41
- 239000006172 buffering agent Substances 0.000 claims abstract description 20
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 18
- 239000008103 glucose Substances 0.000 claims abstract description 18
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 10
- 229920002307 Dextran Polymers 0.000 claims abstract description 8
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims abstract description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 6
- 239000000600 sorbitol Substances 0.000 claims abstract description 6
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims abstract description 5
- 229940050526 hydroxyethylstarch Drugs 0.000 claims abstract description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 4
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- 239000000243 solution Substances 0.000 claims description 41
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- 238000004108 freeze drying Methods 0.000 claims description 25
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 10
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- 239000000872 buffer Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001508 potassium citrate Substances 0.000 claims description 4
- 229960002635 potassium citrate Drugs 0.000 claims description 4
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- 235000011082 potassium citrates Nutrition 0.000 claims description 4
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
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- 229960004109 potassium acetate Drugs 0.000 claims description 3
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- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229960004249 sodium acetate Drugs 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 239000001540 sodium lactate Substances 0.000 claims description 3
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- 229940005581 sodium lactate Drugs 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- 238000003860 storage Methods 0.000 description 10
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
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- 239000000126 substance Substances 0.000 description 6
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000001514 detection method Methods 0.000 description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
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- 238000012792 lyophilization process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 108091007743 BRCA1/2 Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- YDDMIZRDDREKEP-HWTBNCOESA-N lurbinectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1NC1=CC=C(C=C13)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 YDDMIZRDDREKEP-HWTBNCOESA-N 0.000 description 1
- 229950000680 lurbinectedin Drugs 0.000 description 1
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- 238000010979 pH adjustment Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicines, and relates to a lubitidne freeze-dried composition, a lubitidne injection and a preparation method thereof. The rubiperidine freeze-dried composition comprises rubiperidine, a first propping agent, a second propping agent and at least one buffering agent, wherein the first propping agent is glucose or sorbitol, and the second propping agent is any one or more of dextran, hydroxyethyl starch, sodium carboxymethyl cellulose and hydroxypropyl beta cyclodextrin. The lubifidine freeze-dried composition has high stability, low moisture content and low impurity, and is easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a lubitidne freeze-dried composition, a lubitidne injection and a preparation method thereof.
Background
Lubidine is an inhibitor of RNA polymerase ii, which is covalently bound to CG-rich sequences, which are mainly located around the promoter of the protein-encoding gene, causing an irreversible arrest of the prolonged RNA polymerase ii (Pol ii) on the DNA template and the subsequent generation of DNA breaks and apoptosis by specific degradation of the proteasome by DNA. In some types of tumors, tumor cells support their proliferation by virtue of a high-speed transcriptional process, and these tumor cells are particularly sensitive to lurbinectedin, including SCLC, BRCA1/2 mutant breast cancer, platinum-resistant ovarian cancer, sarcomas due to chromosomal translocation, and the like.
Lubitidine has been demonstrated to have potent in vitro activity against both solid and non-solid tumor cell lines, and to have significant in vivo activity in several xenograft human tumor cell lines of mice (such as those of breast, kidney and ovarian cancer). Preliminary clinical results show that lubidine as a single agent has two-wire therapeutic activity in SCLC.
The structure of lubitidine is as follows:
Lubidine is a complex compound with limited solubility in pure water, and adjusting the pH of the solution to 4 can increase the solubility of lubidine in water. However, the lubitidine has poor thermal stability and can be rapidly degraded at room temperature of 25 ℃, so that the lubidine can only be stored at-20 ℃ for a long time, and the application of the lubidine in clinic is greatly limited. Therefore, it is very necessary to improve the thermal stability of lubidine by means of pharmaceutical agents.
Disclosure of Invention
The invention aims to provide a lubitidne freeze-dried composition which is good in stability.
A second object of the present invention is to provide a method for preparing a freeze-dried composition of lubidine.
A third object of the present invention is to provide a lubitidne injection.
The rubiperidine freeze-dried composition comprises rubiperidine, a first propping agent, a second propping agent and at least one buffering agent, wherein the first propping agent is glucose or sorbitol, the second propping agent is any one or more of dextran, hydroxyethyl starch, sodium carboxymethyl cellulose and hydroxypropyl beta cyclodextrin, and the buffering agent is any one or more of phosphate buffering agent, lactate buffering agent, acetate buffering agent and citrate buffering agent.
Further, the buffer is any one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, potassium citrate, sodium lactate, potassium lactate, sodium acetate and potassium acetate.
The first propping agent of the freeze-dried composition of the lubitidine has the main effect of improving the stability of the active ingredient lubitidine in the freeze-drying process. The second proppant plays a protective role mainly during storage. The first propping agent and the second propping agent are matched for use, so that the appearance of the freeze-dried product is improved, and the storage stability is improved; the specific freeze-drying process comprises the following steps: the hydroxyl in the protective agent can compete with the hydroxyl in the water so as to play a role in protection; the storage process comprises the following steps: the amorphous material in the protective agent can keep lower relative humidity in a closed environment, such as a penicillin bottle, so as to play a role in protection.
The weight ratio of the lubitidine to the first propping agent is 1:10-2000, and the weight ratio of the lubitidine to the second propping agent is 1: 10-1000, and the mass ratio of the lubidine to the buffering agent is 1:10-100.
Preferably, the weight ratio of lubidine to the first proppant is from 1:20 to 1500, more preferably from 1:30 to 1000, most preferably from 1:40 to 500.
Preferably, the weight ratio of lubidine to the second proppant is from 1:10 to 500, more preferably from 1:10 to 1:300, most preferably from 1:10 to 1:100.
Since a change in pH affects the stability of lubidine, a buffer is required to maintain the pH of the system within a specific range. The mass ratio of the rubitidine to the buffer is preferably 1:10-100, more preferably 1:10-50.
The above-mentioned lubidine freeze-dried composition, wherein the first propping agent is glucose, and the second propping agent is dextran. The dextran is preferably dextran 40.
The weight ratio of the glucose to the dextran is 1-10:1; preferably 1-2:1.
In the above-mentioned lubidine freeze-dried composition, the first propping agent is glucose, and the second propping agent is hydroxypropyl beta cyclodextrin.
The pH value of the solution of the lubidine freeze-dried composition before freeze-drying is 3-5. The aforementioned ingredients are first formulated into a pre-lyophilization solution prior to lyophilization, which may have a pH of from 3 to 5, preferably from 3.5 to 45, more preferably from 3.6 to 4.2, and most preferably from 3.9 to 4.1. If the pH is outside the desired range when formulated using only the aforementioned ingredients, the pH adjustment may be performed using a pH adjuster, for example, one or more pH adjusters selected from the group consisting of phosphoric acid, acetic acid, tartaric acid, citric acid, sodium hydroxide, and potassium hydroxide, preferably phosphoric acid and potassium hydroxide may be used.
In the solution before freeze-drying, the content of the lubidine is 0.1-0.5 mg/mL; the content of the first propping agent is 20-80 mg/mL, and the content of the second propping agent is 5-50 mg/mL.
An injection of lubitidine, which is obtained by re-dissolving the lubitidine freeze-dried composition.
The preparation method of the lubidine freeze-dried composition comprises the following steps:
1) Mixing lubidine with acid to obtain a solution A;
2) Mixing water, a first propping agent, a second propping agent and a buffering agent to obtain a solution B;
3) Uniformly mixing the solution A and the solution B, and regulating the pH value to obtain a mixed solution;
4) And 3) freeze-drying the mixed solution obtained in the step 3) to obtain the product.
The acid in the step 1) is any one or more of phosphoric acid, lactic acid, citric acid and acetic acid.
The buffer in the step 2) is any one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, potassium citrate, sodium lactate, potassium lactate, sodium acetate and potassium acetate.
Step 3) adjusting the pH to 3-5.
The freeze-drying in step 4) may be prepared using lyophilization processes conventional in the art. For example, the lyophilization process of the present invention comprises three stages of pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is-25 to-50 ℃, the primary drying temperature is-10 to-40 ℃, the secondary drying temperature is 15 to 30 ℃, and the vacuum degree is 0.1 to 0.5mbar in the primary drying and secondary drying processes. After the freeze-drying process was completed, nitrogen was introduced.
The rubiperidine freeze-dried composition provided by the invention has the advantages of high stability, low moisture content and impurities, mild storage conditions and easiness in realization of industrial production and long-term storage.
Examples
In order to make the objects and technical solutions of the present invention more apparent, embodiments of the present invention will be described in detail with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention.
The reagents or apparatus used in the examples are all conventional products commercially available. Those not specifying the specific conditions were carried out according to the conventional conditions or the conditions recommended by the manufacturer.
Example 1
The preparation method comprises the steps of taking lubidine as an active ingredient, taking glucose as a first excipient, hydroxypropyl beta cyclodextrin as a second excipient, taking monopotassium phosphate as a buffer, taking phosphoric acid/potassium hydroxide as a pH value regulator, and taking water for injection as a solvent to prepare lubidine pre-freeze-dried solution, wherein the specific prescription comprises the following components in percentage by weight:
Table 1 example 1 lubitidine pre-lyophilization solution formulation
The preparation method of the rubitidine freeze-dried composition of the embodiment comprises the following steps:
1. Preparing a solution A: taking a beaker, weighing, adding the prescription amount of lubidine and phosphoric acid (0.1M) into the beaker, and stirring until the raw materials are completely dissolved to obtain a solution A;
2. Preparing a solution B: taking another beaker, weighing, adding 70% of injection water with a prescription amount into the beaker, adding glucose, hydroxypropyl beta cyclodextrin and potassium dihydrogen phosphate with the prescription amount into the beaker, and stirring until the glucose, the hydroxypropyl beta cyclodextrin and the potassium dihydrogen phosphate are completely dissolved to obtain a solution B;
3. Adding the solution A into the solution B under stirring, measuring the pH value of the solution after uniformly stirring, and adjusting the pH value of the mixed solution to 3.9 (+ -0.3) by using phosphoric acid (0.1M) or potassium hydroxide (0.1M) if necessary;
4. The mixed solution obtained in the step 3 is fixed to a final volume or weight (the reference density of the liquid medicine is 1.04 g/ml), and half-filling and plugging are carried out;
and (3) freeze-drying the intermediate solution obtained in the step (4) to prepare the rubitidine freeze-dried preparation. The appearance, moisture, re-solubility and pH value were examined, and the change of the related substances after lyophilization and the stability of the related substances after storage under high temperature conditions (40 ℃) and long-term conditions (2-8 ℃) were examined.
Table 2 appearance, moisture, re-solubility and pH of the lyophilized product:
| Appearance of | Moisture content | Resolubility of | PH value of | Property after reconstitution |
| White cake shape | 1.22％ | Good quality | 4.12 | Clear transparent solution |
TABLE 3 detection of substances and stability of the placed
Conclusion of experiment and analysis: the freeze-dried product prepared by taking glucose as a first propping agent and hydroxypropyl beta cyclodextrin as a second propping agent has qualified appearance, moisture and pH value, good product re-solubility and good stability of the freeze-dried preparation under long-term and acceleration conditions, and the glucose/hydroxypropyl beta cyclodextrin composition can be used as a freeze-drying protective agent of a rubitidine customizing agent, so that the stability of the rubitidine in the freeze-drying process and the storage process is improved.
Example 2
The preparation method comprises the steps of taking lubitidine as an active ingredient, taking glucose as a first propping agent, dextran 40 as a second propping agent, monopotassium phosphate as a buffering agent, phosphoric acid/potassium hydroxide as a pH value regulator, and water for injection as a solvent to prepare lubitidine pre-freeze-dried solution, wherein the specific prescription composition and the specific dosage are as follows:
Table 4 example 2 formulation of lubitidine pre-lyophilization solution
The preparation method comprises the following steps:
1. Preparing a solution A: taking a beaker, weighing, adding the prescription amount of lubidine and phosphoric acid (0.1M) into the beaker, and stirring until the raw materials are completely dissolved to obtain a solution A;
2. Preparing a solution B: taking another beaker, weighing, adding 70% of prescribed amount of water for injection into the beaker, adding prescribed amount of glucose, dextran 40 and potassium dihydrogen phosphate into the beaker, and stirring until the solution is completely dissolved to obtain solution B;
3. And adding the solution A into the solution B under the condition of stirring, and measuring the pH value of the solution after uniformly stirring to obtain a mixed solution. If necessary, the pH of the mixed solution is adjusted to 3.9 (+ -0.3) with phosphoric acid (0.1M) or potassium hydroxide (0.1M);
4. The mixed solution obtained in the step 3 is fixed to the total weight, and half-filling and plugging are carried out;
and freeze-drying the intermediate solution to prepare the lubidine freeze-dried preparation. The appearance, moisture, re-solubility and pH value were examined, and the change of the related substances after lyophilization and the stability of the related substances after storage under high temperature conditions (40 ℃) and long-term conditions (2-8 ℃) were examined.
Table 5 product appearance, moisture, re-solubility and pH after lyophilization of this example:
| Appearance of | Moisture content | Resolubility of | PH value of | Property after reconstitution |
| White cake shape | 1.49％ | Good quality | 4.09 | Clear transparent solution |
TABLE 6 detection of substances on products after lyophilization and stability in storage of the products according to this example
Conclusion of experiment and analysis: the freeze-dried product prepared by taking glucose as a first propping agent and dextran 40 as a second propping agent has the advantages of qualified appearance, moisture and pH value, good product re-solubility and good stability of the freeze-dried preparation under long-term and acceleration conditions, and the glucose/dextran 40 composition can be used as a freeze-drying protective agent of a rubi-customizing agent, so that the stability of the rubi-dine in the freeze-drying process and the storage process is improved.
Example 3
The preparation method comprises the steps of taking lubitidine as an active ingredient, taking sorbitol as a first propping agent, sodium carboxymethyl cellulose as a second propping agent, potassium citrate as a buffering agent, citric acid/potassium hydroxide as a pH value regulator, and water for injection as a solvent to prepare lubitidine pre-freeze-dried solution, wherein the specific prescription composition and the specific dosage are as follows:
Table 7 example 3 formulation of solution before lyophilization of lubidine
Example 4
The preparation method comprises the steps of taking lubidine as an active ingredient, taking sorbitol as a first propping agent, hydroxyethyl starch as a second propping agent, monopotassium phosphate as a buffering agent, phosphoric acid/potassium hydroxide as a pH value regulator, and water for injection as a solvent to prepare lubidine pre-freeze-dried solution, wherein the specific prescription composition and the specific dosage are as follows:
table 8 example 4 formulation of solution before lyophilization of lubidine
| Composition of the components | Unit dosage form | Batch size: 240mL |
| Lubi-tidine | 4mg | 120mg |
| Phosphoric acid (0.1M) | 0.32ml | 9.6ml |
| Sorbitol | 200mg | 6g |
| Hydroxyethyl starch | 100mg | 3g |
| Monopotassium phosphate | 48mg | 1440mg |
| Phosphoric acid (0.1M) | Proper amount of | Proper amount of |
| Potassium hydroxide (0.1M) | Proper amount of | Proper amount of |
| Water for injection | Added to 8ml | Added to 240ml |
Claims (10)
1. The rupitidine freeze-dried composition is characterized by comprising rupitidine, a first propping agent, a second propping agent and at least one buffering agent, wherein the first propping agent is glucose or sorbitol, the second propping agent is any one or more of dextran, hydroxyethyl starch, sodium carboxymethyl cellulose and hydroxypropyl beta cyclodextrin, and the buffering agent is any one or more of phosphate buffering agent, lactate buffering agent, acetate buffering agent and citrate buffering agent.
2. The lubitidine freeze-dried composition according to claim 1, characterized in that the weight ratio of lubitidine to the first proppant is 1: 10-2000, the weight ratio of the lubidine to the second propping agent is 1: 10-1000, and the mass ratio of the lubidine to the buffering agent is 1:10-100.
3. The lubitidine freeze-dried composition according to claim 1, characterized in that the first proppant is glucose and the second proppant is dextran.
4. The lyophilized composition of lubidine as claimed in claim 3, wherein the weight ratio of glucose to dextran is 1-10:1.
5. The lyophilized composition of lubidine of claim 1, wherein the first proppant is glucose and the second proppant is hydroxypropyl beta cyclodextrin.
6. The lyophilized composition of lubidine as claimed in claim 1, wherein the composition has a pH of 3-5 in the solution prior to lyophilization.
7. An injection of lubidine, characterized in that it is obtained after reconstitution of a lyophilized composition as defined in any one of claims 1 to 6.
8. The method for preparing a freeze-dried composition of lubidine as claimed in any one of claims 1 to 6, comprising the steps of:
1) Mixing lubidine with acid to obtain a solution A;
2) Mixing water, a first propping agent, a second propping agent and a buffering agent to obtain a solution B;
3) Uniformly mixing the solution A and the solution B, and regulating the pH value to obtain a mixed solution;
4) And 3) freeze-drying the mixed solution obtained in the step 3) to obtain the product.
9. The method according to claim 8, wherein the acid in step 1) is phosphoric acid, lactic acid, acetic acid or citric acid.
10. The method according to claim 8, wherein the buffer in step 2) is any one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, potassium citrate, sodium lactate, potassium lactate, sodium acetate, and potassium acetate.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211657180.1A CN118236330A (en) | 2022-12-22 | 2022-12-22 | Rubitidine freeze-dried composition, rubitidine injection and preparation method thereof |
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| CN202211657180.1A CN118236330A (en) | 2022-12-22 | 2022-12-22 | Rubitidine freeze-dried composition, rubitidine injection and preparation method thereof |
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