CN112076161B - Compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium - Google Patents
Compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium Download PDFInfo
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- CN112076161B CN112076161B CN202010787261.8A CN202010787261A CN112076161B CN 112076161 B CN112076161 B CN 112076161B CN 202010787261 A CN202010787261 A CN 202010787261A CN 112076161 B CN112076161 B CN 112076161B
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- QCCCFHDTBTUDEA-UHFFFAOYSA-M sodium;4-(dipropylsulfamoyl)benzoate Chemical compound [Na+].CCCN(CCC)S(=O)(=O)C1=CC=C(C([O-])=O)C=C1 QCCCFHDTBTUDEA-UHFFFAOYSA-M 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 19
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 19
- -1 cephalosporin sodium salt Chemical class 0.000 title claims abstract description 17
- 238000004108 freeze drying Methods 0.000 claims abstract description 37
- 238000000859 sublimation Methods 0.000 claims abstract description 23
- 230000008022 sublimation Effects 0.000 claims abstract description 23
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000007710 freezing Methods 0.000 claims abstract description 15
- 230000008014 freezing Effects 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 229960001958 cefodizime Drugs 0.000 claims description 15
- WBOBLQIRACJNPA-QQFCNTMUSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[[5-(carboxylatomethyl)-4-methyl-1,3-thiazol-2-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical group [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC([O-])=O)S1 WBOBLQIRACJNPA-QQFCNTMUSA-L 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 8
- URDOHUPGIOGTKV-JTBFTWTJSA-M Cefuroxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 URDOHUPGIOGTKV-JTBFTWTJSA-M 0.000 abstract description 20
- 229960000534 cefuroxime sodium Drugs 0.000 abstract description 20
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 abstract description 18
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 abstract description 18
- 229960003408 cefazolin sodium Drugs 0.000 abstract description 18
- 229960003016 cefoxitin sodium Drugs 0.000 abstract description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 6
- 239000011734 sodium Substances 0.000 abstract description 6
- 229910052708 sodium Inorganic materials 0.000 abstract description 6
- 229960001139 cefazolin Drugs 0.000 abstract description 3
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 abstract description 3
- 150000002923 oximes Chemical class 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 49
- ADLFUPFRVXCDMO-LIGXYSTNSA-M ceftizoxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=CCS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 ADLFUPFRVXCDMO-LIGXYSTNSA-M 0.000 description 13
- 229960000636 ceftizoxime sodium Drugs 0.000 description 13
- 229930182555 Penicillin Natural products 0.000 description 10
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 10
- 229940049954 penicillin Drugs 0.000 description 10
- 238000005096 rolling process Methods 0.000 description 9
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 238000011049 filling Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000005092 sublimation method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium, which is characterized in that the preparation contains the cephalosporin sodium salt according to the weight fraction conversion to dry and pure calculation: the probenecid sodium is 2-2.75, and the two raw materials are prepared into a uniformly mixed solution and then are freeze-dried; wherein the cephalosporin sodium salts are five of cefuroxime sodium, cefoxitin sodium, cefazolin sodium, cefdizime sodium and cefazolin oxime sodium; starting a freeze dryer for pre-freezing, carrying out sublimation drying, stably heating the plate layer to about 40 ℃ after the sublimation stage is finished, and keeping the temperature for 3 hours to enable the water to be fully volatilized, wherein the total freeze-drying time is 22 hours, and the freeze-drying time is shortened.
Description
Technical Field
The invention relates to a compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid, belonging to the technical field of medicines.
Background
At present, cephalosporin products are respectively cefuroxime sodium for injection, cefoxitin sodium for injection, cefazolin sodium for injection, cefodizime sodium for injection and ceftizoxime sodium for injection, and the products do not form compound preparations with other medicines. At present, probenecid sodium is available in the global market, and neither probenecid sodium injection nor probenecid sodium raw material medicine is available. The compound preparation is prepared by mixing medicinal powders. In the preparation of oral compound preparations, in order to increase the fluidity of the powder for uniform mixing, some excipients such as magnesium stearate and starch are usually added to increase the fluidity of the drug. However, in the compound preparation for injection, the addition of these adjuvants is prohibited. Therefore, in the process of preparing the compound preparation for injection, if the physicochemical properties of the two drugs are greatly different (such as fluidity and viscosity), the two drugs are difficult to be uniformly mixed, so that the difference of the filling amount of the finished product exceeds the standard range, and the reject ratio is increased. If such off-specification products are passed to the market, they can adversely affect clinical anti-infective therapy. Probenecid sodium has an obvious characteristic that flowability is very poor, hygroscopicity is high, and uniform mixing is difficult to achieve through a conventional raw material powder mixing mode, so that the filling quantity difference among medicine bottles is overlarge, and the reject ratio is greatly increased.
Disclosure of Invention
The invention aims to provide a compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium.
The technical scheme of the invention is realized as follows: a compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium is characterized in that the preparation contains the cephalosporin sodium salt according to the weight fraction on a dry basis: the probenecid sodium is 2-2.75, and the two raw materials are prepared into a uniformly mixed solution and then subjected to a freeze-drying step.
The cephalosporin sodium salts are five of cefuroxime sodium, cefoxitin sodium, cefazolin sodium, cefdizime sodium and cefazolin oxime sodium.
The specific freeze-drying steps are as follows:
(1) And the freeze dryer is started in the pre-freezing stage
(1) Cooling the plate layer from room temperature to-25-40 ℃ at a speed of about 2-3.5 ℃/min, and preserving heat for 30-90 minutes;
(2) raising the temperature of the slab layer to 1-2 ℃ at the speed of 2 ℃/min, and preserving the heat for 40-60 minutes;
(3) cooling to-40 deg.C at a speed of about 3 deg.C/min, and maintaining for 40-60 min;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 12-17 hours to ensure that the sublimation line is basically invisible to naked eyes;
(3) And (3) analysis and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered, and the appearance and the moisture content are checked.
The compound freeze-dried preparation of cefuroxime sodium: the proportion of the prescription of probenecid sodium is 2-2.5:1.
the compound freeze-dried preparation cefoxitin sodium: the proportion of the prescription of the probenecid sodium is 2.25-2.75:1.
the compound freeze-dried preparation is cefazolin sodium: the proportion of the prescription of the probenecid sodium is 2.25-2.75:1.
the compound freeze-dried preparation cefodizime sodium: the proportion of the prescription of probenecid sodium is 2-2.5:1.
the compound freeze-dried preparation of ceftizoxime sodium: the proportion of the prescription of the probenecid sodium is 2.25-2.75:1.
the invention has the positive effects that: the addition of probenecid also shows some unexpected benefits besides the compound preparation of cephalosporin sodium salt and probenecid sodium prepared by a freeze-drying process for the first time. The probenecid sodium shows a dendritic needle crystal structure in a freeze-dried state to form a framework of the compound preparation, and the corresponding cephalosporin antibiotics can be uniformly attached to needle crystals of the probenecid sodium. Such characteristic can prevent on the one hand that some products from appearing spouting the bottle phenomenon in the sublimation process, causes the rejection rate to increase, and on the other hand, probenecid sodium makes whole compound preparation structure loose, easily moisture volatilizees. Regardless of the prescription proportion, the compound preparation and the single preparation both have the component of probenecid sodium, the probenecid sodium added in each bottle is different from 0.182 to 0.5g, and under the condition that the total freeze-drying time is the same and the filling amount of each bottle of solution is the same, the moisture of the compound preparation is still obviously lower than (cefuroxime sodium + probenecid sodium) or slightly lower than that of the single preparation, which indicates that the probenecid sodium also has the function of promoting the water volatilization, and the advantage can be finally reflected in that the freeze-drying time can be properly shortened. Three of the products (cefuroxime sodium, cefoxitin sodium and cefazolin sodium) need to be pre-frozen repeatedly to achieve uniform color and reduce the probability of bottle spraying.
TABLE 1 appearance and moisture of single and compound preparations and finished preparations with different prescription ratios
Detailed Description
The invention is further described with reference to the following examples: the compound freeze-dried preparation is characterized in that the compound freeze-dried preparation comprises the cephalosporin sodium salt and probenecid sodium according to the weight portion on a dry basis and the cephalosporin sodium salt: the probenecid sodium is 2-2.75.
The cephalosporin sodium salts are five of cefuroxime sodium, cefoxitin sodium, cefazolin sodium, cefdizime sodium and cefazolin oxime sodium.
TABLE 2 prescription ratio of compound preparation product
| Product(s) | Prescription 1 | Prescription 2 | Prescription 3 |
| Cefuroxime sodium: probenecid sodium | 2：1 | 2.25：1 | 2.5：1 |
| Cefoxitin sodium: probenecid sodium | 2.25：1 | 2.5：1 | 2.75：1 |
| Cefazolin sodium: probenecid sodium | 2.25：1 | 2.5：1 | 2.75：1 |
| Cefodizime sodium: probenecid sodium | 2：1 | 2.25：1 | 2.5：1 |
| Ceftizoxime sodium: probenecid sodium | 2.25：1 | 2.5：1 | 2.75：1 |
Example 1
The product is as follows: cefuroxime sodium and probenecid sodium
1. Preparing a compound preparation solution (cefuroxime sodium and probenecid sodium):
prescription 1: the total amount of the solution is 1,500ml, and the solution contains: 250 g of cefuroxime sodium (calculated on a dry basis and a pure basis), and 125 g of probenecid sodium (calculated on a dry basis and a pure basis). Each bottle contains 3 ml of cefuroxime sodium 0.5g and probenecid sodium 0.25g.
Recipe 2: the total amount of the solution was 1,500ml, which contained: 250 g (calculated on dry basis and on pure basis) of cefuroxime sodium and 111.1 g (calculated on dry basis and on pure basis) of probenecid sodium. Each bottle contains 3 ml of cefuroxime sodium 0.5g and probenecid sodium 0.222g.
Prescription 3: the total amount of the solution is 1,500ml, and the solution contains: 250 g of cefuroxime sodium (calculated on a dry basis and a pure basis), and 100 g of probenecid sodium (calculated on a dry basis and a pure basis). Each bottle contains 3 ml of cefuroxime sodium 0.5g and probenecid sodium 0.2g.
2. Preparing a single preparation solution (cefuroxime sodium):
the total amount of the solution is 1,500ml, and the solution contains: 250 g of cefuroxime sodium (dry basis and pure basis). Each bottle contains 3 ml of cefuroxime sodium (0.5 g) and contains no probenecid sodium.
And (3) half plugging penicillin bottles filled with the compound preparation solution and the single preparation solution, freeze-drying the penicillin bottles in a freeze dryer plate layer, and freeze-drying the two solution samples in the same freeze dryer for comparison.
3. The specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started in the pre-freezing stage
(1) Cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
(2) raising the temperature of the slab layer to 1 ℃ at the speed of 2 ℃/min, and preserving the heat for 40-60 minutes;
(3) cooling to-40 deg.C at a speed of about 3 deg.C/min, and maintaining for 40-60 min;
(3) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 12-14 hours to ensure that the sublimation line is basically invisible to naked eyes;
(3) And analysis and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered, and the appearance and the moisture content are checked.
Example 2
The product is as follows: cefoxitin sodium and probenecid sodium
1. Preparing a compound preparation solution (cefoxitin sodium and probenecid sodium):
prescription 1: the total amount of the solution was 2,000ml, which contained: 375 g cefoxitin sodium (calculated on dry basis and on pure basis) and 166.67 g probenecid sodium (calculated on dry basis and on pure basis). Each bottle contains 4 ml, which contains 0.75 g cefoxitin sodium and 0.333g probenecid sodium.
Recipe 2: the total amount of the solution was 2,000ml, which contained: 375 g cefoxitin sodium (dry basis and pure basis) and 150 g probenecid sodium (dry basis and pure basis). Each bottle contains 4 ml, which contains 0.75 g cefoxitin sodium and 0.3 g probenecid sodium.
Prescription 3: the total amount of the solution was 2,000ml, which contained: 375 g cefoxitin sodium (dry basis and pure basis) and 136.36 g probenecid sodium (dry basis and pure basis). Each bottle contains 4 ml, which contains 0.75 g cefoxitin sodium and 0.273 g probenecid sodium.
2. Preparing a single preparation solution (cefoxitin sodium):
the total amount of the solution was 2,000ml, which contained: 375 g cefoxitin sodium (dry basis, pure basis). Each bottle contains 4 ml of cefoxitin sodium (0.75 g) and no probenecid sodium.
And (3) half plugging penicillin bottles filled with the compound preparation solution and the single preparation solution, freeze-drying the penicillin bottles in a freeze dryer plate layer, and freeze-drying the two solution samples in the same freeze dryer for comparison.
3. The specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started in the pre-freezing stage
(1) The temperature of the plate layer is reduced to minus 30 ℃ from the room temperature at the speed of about 3.5 ℃/min, and the temperature is preserved for 30 to 60 minutes;
(2) raising the temperature of the slab layer to 1-2 ℃ at the speed of 2 ℃/min, and preserving the heat for 40-60 minutes;
(3) cooling to-40 deg.C at a speed of about 3 deg.C/min, and maintaining for 40-60 min;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 14-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
(4) And (3) resolving and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of a freeze dryer is released, the sample is taken out, and a rolling cover is taken out, and the appearance and the moisture content are inspected.
Example 3
The product is as follows: cefazolin sodium and probenecid sodium
1. Preparing a compound preparation solution (cefazolin sodium and probenecid sodium):
recipe 1: the total amount of the solution was 2,000ml, which contained: 250 g of cefazolin sodium (dry basis and pure basis) and 111.1 g of probenecid sodium (dry basis and pure basis). Each bottle contains 4 ml of cefazolin sodium 0.5g and probenecid sodium 0.222g.
Recipe 2: the total amount of the solution was 2,000ml, which contained: 250 g of cefazolin sodium (dry basis and pure basis) and 100 g of probenecid sodium (dry basis and pure basis). Each bottle contains 4 ml, which contains 0.5g of cefazolin sodium and 0.2g of probenecid sodium.
Prescription 3: the total amount of the solution was 2,000ml, which contained: 250 g of cefazolin sodium (dry basis and pure basis) and 90.91 g of probenecid sodium (dry basis and pure basis). Each bottle contains 4 ml, which contains 0.5g of cefazolin sodium and 0.182 g of probenecid sodium.
2. Preparing a single-prescription preparation solution (cefazolin sodium):
the total amount of the solution was 2,000ml, which contained: 250 g of cefazolin sodium (dry basis and pure basis). Each bottle contains 4 ml of cefazolin sodium (0.5 g) and contains no probenecid sodium.
And (3) half plugging penicillin bottles filled with the compound preparation solution and the single preparation solution, freeze-drying the penicillin bottles in a freeze dryer plate layer, and freeze-drying two solution samples in the same freeze dryer for comparison.
3. The specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started at the pre-freezing stage
(1) Cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
(2) raising the temperature of the plate layer to 1 ℃ at the speed of 2 ℃/min, and preserving the heat for 40-60 minutes;
(3) cooling to-40 deg.C at a speed of about 3 deg.C/min, and maintaining for 40-60 min;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 12-14 hours to ensure that the sublimation lines are basically invisible to naked eyes;
(3) And (3) analysis and drying: after the sublimation stage is finished, the plate layer is stably heated to about 40 ℃ and is kept warm for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the judgment of the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of a freeze dryer is released, the sample is taken out, and a rolling cover is taken out, and the appearance and the moisture content are inspected.
Example 4
The product is as follows: cefodizime sodium and probenecid sodium
1. Preparing a compound preparation solution (cefodizime sodium and probenecid sodium):
prescription 1: the total amount of the solution was 2,500ml, which contained: 500 g of cefodizime sodium (dry basis and pure basis) and 250 g of probenecid sodium (dry basis and pure basis). Each bottle contains 5 ml, which contains 1.0 g of cefodizime sodium and 0.5g of probenecid sodium.
Prescription 2: the total amount of the solution was 2,500ml, which contained: 500 g (calculated on dry basis and on pure basis) of cefodizime sodium and 222.2 g (calculated on dry basis and on pure basis) of probenecid sodium. Each bottle contains 5 ml, which contains 1.0 g of cefodizime sodium and 0.44 g of probenecid sodium.
Prescription 3: the total amount of the solution was 2,500ml, which contained: 500 g (dry basis and pure basis) of cefodizime sodium and 200 g (dry basis and pure basis) of probenecid sodium. Each bottle contains 5 ml of cefodizime sodium 1.0 g and probenecid sodium 0.4 g.
2. Preparing a single preparation solution (cefodizime sodium):
the total amount of the solution was 2,500ml, which contained: 500 g of cefodizime sodium (dry basis and pure basis). Each bottle contains 5 ml of cefodizime sodium 1.0 g and contains no probenecid sodium.
And (3) half plugging penicillin bottles filled with the compound preparation solution and the single preparation solution, freeze-drying the penicillin bottles in a freeze dryer plate layer, and freeze-drying the two solution samples in the same freeze dryer for comparison.
3. The specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started at the pre-freezing stage
The temperature of the plate layer is reduced to-40 ℃ from the room temperature at the speed of about 2 ℃/min, and the temperature is kept for 60-90 minutes;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 15-17 hours to ensure that the sublimation line is basically invisible to naked eyes;
(3) And analysis and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of a freeze dryer is released, the sample is taken out, and a rolling cover is taken out, and the appearance and the moisture content are inspected.
Example 5
The product is as follows: ceftizoxime sodium and probenecid sodium
1. Preparing a compound preparation solution (ceftizoxime sodium and probenecid sodium):
prescription 1: the total amount of the solution was 2,000ml, which contained: 250 g of ceftizoxime sodium (calculated on a dry basis and a pure basis), and 111.1 g of probenecid sodium (calculated on a dry basis and a pure basis). Each bottle is filled with 4 ml of ceftizoxime sodium 0.5g and probenecid sodium 0.222g.
Prescription 2: the total amount of the solution was 2,000ml, which contained: 250 g of ceftizoxime sodium (calculated on a dry basis and a pure basis), and 100 g of probenecid sodium (calculated on a dry basis and a pure basis). Each bottle contains 4 ml, wherein the contents comprise 0.5g of ceftizoxime sodium and 0.2g of probenecid sodium.
Prescription 3: the total amount of the solution was 2,000ml, which contained: 250 g of ceftizoxime sodium (calculated on a dry basis and a pure basis), and 90.91 g of probenecid sodium (calculated on a dry basis and a pure basis). Each bottle contains 4 ml of cefuroxime sodium 0.5g and probenecid sodium 0.182 g.
2. Preparing a single preparation solution (ceftizoxime sodium):
the total amount of the solution was 2,000ml, which contained: 250 g of ceftizoxime sodium (calculated on a dry basis and a pure basis). Each bottle contains 4 ml of ceftizoxime sodium and 0.5g of probenecid sodium.
And (3) half plugging penicillin bottles filled with the compound preparation solution and the single preparation solution, freeze-drying the penicillin bottles in a freeze dryer plate layer, and freeze-drying the two solution samples in the same freeze dryer for comparison.
3. The specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started in the pre-freezing stage
The temperature of the plate layer is reduced to-40 ℃ from the room temperature at the speed of about 2 ℃/min, and the temperature is kept for 60-90 minutes;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 15-17 hours to ensure that the sublimation lines are basically invisible to naked eyes;
(3) And analysis and drying: after the sublimation stage is finished, the plate layer is stably heated to about 40 ℃ and is kept warm for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the change condition of the pressure in the freeze-drying box, and the total freeze-drying time is about 22 hours;
4. and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered, and the appearance and the moisture content are checked.
Claims (1)
1. A compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium is characterized in that the preparation contains the cephalosporin sodium salt according to the weight fraction on a dry basis: the probenecid sodium is 2-2.5, and the two raw materials are prepared into a uniformly mixed solution and then are freeze-dried; wherein the cephalosporin sodium salt is cefodizime sodium;
the specific freeze-drying method comprises the following steps:
(1) And the freeze dryer is started at the pre-freezing stage
The temperature of the plate layer is reduced to-40 ℃ from the room temperature at the speed of 2 ℃/min, and the temperature is kept for 60-90 minutes;
(2) And sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 30 ℃ within 15-17 hours to make the sublimation line invisible to naked eyes;
(3) And (3) analysis and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the change condition of the pressure in the freeze-drying box, and the total freeze-drying time is 22 hours;
(4) And capping: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered, and the appearance and the moisture content are checked.
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| JPS6055486B2 (en) * | 1976-02-28 | 1985-12-05 | 富山化学工業株式会社 | Composition for rectal administration of a compound having a β-lactam ring |
| CN100387574C (en) * | 2004-12-01 | 2008-05-14 | 吴晓辉 | Process for preparing probenecid sodium and probenecid potassium |
| EP2968274B1 (en) * | 2013-03-15 | 2019-10-16 | Kala Pharmaceuticals, Inc. | Meropenem derivatives and uses thereof |
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| Title |
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| Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation;M. Ogawa et al.;《Am J Physiol.》;19940201;第266卷(第2期);第R239页 * |
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