CN117224494A - Lornoxicam pharmaceutical composition for injection and preparation method thereof - Google Patents
Lornoxicam pharmaceutical composition for injection and preparation method thereof Download PDFInfo
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- CN117224494A CN117224494A CN202311367395.4A CN202311367395A CN117224494A CN 117224494 A CN117224494 A CN 117224494A CN 202311367395 A CN202311367395 A CN 202311367395A CN 117224494 A CN117224494 A CN 117224494A
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- lornoxicam
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- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 title claims abstract description 57
- 229960002202 lornoxicam Drugs 0.000 title claims abstract description 57
- 238000002347 injection Methods 0.000 title claims abstract description 27
- 239000007924 injection Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 83
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000004108 freeze drying Methods 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000008215 water for injection Substances 0.000 claims abstract description 13
- 239000000843 powder Substances 0.000 claims abstract description 10
- 238000007710 freezing Methods 0.000 claims abstract description 6
- 230000008014 freezing Effects 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 20
- 238000000137 annealing Methods 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 238000000859 sublimation Methods 0.000 claims description 16
- 230000008022 sublimation Effects 0.000 claims description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 229930182555 Penicillin Natural products 0.000 claims 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 claims description 10
- 229940049954 penicillin Drugs 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 6
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 4
- 238000005086 pumping Methods 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 230000000052 comparative effect Effects 0.000 description 46
- 239000000047 product Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 230000007794 irritation Effects 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000013068 control sample Substances 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 229960000281 trometamol Drugs 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 3
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- WLHQHAUOOXYABV-UHFFFAOYSA-N lornoxicam Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 WLHQHAUOOXYABV-UHFFFAOYSA-N 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Abstract
The application provides a lornoxicam pharmaceutical composition for injection and a preparation method thereof, wherein the pharmaceutical composition comprises lornoxicam, sodium carbonate and water for injection, the pH value is 9.5-11, and the lornoxicam solution is repeatedly annealed in the pre-freezing step of the freeze-drying procedure to form a specific crystalline compound of lornoxicam and sodium carbonate, and the crystalline compound lornoxicam freeze-dried powder injection has the advantages of high stability, good re-solubility, high clarity after re-dissolution and the like.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and in particular relates to a lornoxicam pharmaceutical composition for injection and a preparation method thereof.
Background
Lornoxicam, chemical name: 6-chloro-4-hydroxy-2-methyl-3- (2-pyridylcarbamoyl) -2H-thieno [2,3-e ] -1, 2-thiazine-1, 1-dioxide belongs to thiazine derivatives, and is a chloride of tenoxicam. Its action is similar to piroxicam, inhibiting prostaglandin synthesis by inhibiting the activity of Cyclooxygenase (COX); however, lornoxicam does not inhibit the activity of 5-lipoxygenase, and therefore does not inhibit the synthesis of leukotrienes, nor shunts arachidonic acid to the 5-lipoxygenase pathway, while metabolites of arachidonic acid and 5-lipoxygenase inhibit the processes of impulses of nociceptors of the spinal cord, thereby causing lornoxicam to exert an analgesic effect similar to that of opioid analgesic drugs. Clinical studies have shown that it is suitable for use in gynaecology and obstetrics and for acute pain, acute sciatica or lumbago after orthopedic surgery. Can also be used for treating chronic lumbago, arthritis, rheumatoid arthritis and ankylosing spondylitis.
Lornoxicam is unstable in aqueous solutions and is therefore generally used in the form of lyophilized formulations in practical applications.
The original ground product of lornoxicam freeze-dried powder injection is marketed in Danish application 10 months 1997, and has the trade name XeFo and the specification of 8mg; the prescription composition comprises: lornoxicam, tromethamine, mannitol, disodium edetate. The product is unstable under the condition of long-term placement, the clarity of the solution after compatibility is poor, and the like, and the clinical medication has a certain risk.
CN102846558B discloses a lyophilized preparation of lornoxicam and a preparation method thereof, poloxamer 188 is used as a cosolvent, sodium hydroxide is used as a PH regulator, so that the dissolution rate of lornoxicam is improved, the stability and the re-solubility are ensured, but poloxamer 188 cannot be metabolized by human body, and the safety risk is uncontrollable.
CN100467024C discloses a lornoxicam injection composition and a preparation method thereof, which utilizes basic amino acid to improve the dissolution rate of lornoxicam. But the final impurity content is still higher, and the product stability is lower.
CN115919757a discloses a lornoxicam injection preparation and a preparation method thereof, by increasing the temperature of water for injection and the adding sequence of raw materials, the equilibrium of the dissolution temperature and dissolution time of lornoxicam is realized, the dissolution time is shortened, the production of byproducts is reduced, and the stability is improved. However, the whole operation process needs to be strictly controlled, which is not beneficial to large-scale popularization.
Because lornoxicam has small solubility in water, is insoluble in acid and water, is slightly soluble under alkaline conditions, when the pH of the prepared solution is less than 8.0, a clear pre-lyophilization solution cannot be obtained, the re-solubility after lyophilization is poor, and the alkalinity is too strong, so that the human body is more irritative.
Therefore, the field is urgent to find a lornoxicam injection with high solubility, high stability, good re-solubility, high clarity, small irritation to human body and suitability for mass production.
The inventor finds that in the long-term study of the lornoxicam pharmaceutical composition for injection, the pH of the composition is controlled by adopting sodium carbonate, and the lornoxicam freeze-dried powder injection prepared from the lornoxicam-sodium carbonate crystalline compound is formed by a special freeze-drying treatment procedure, which has excellent characteristics in the aspects of stability, solubility, re-dissolution clarity and the like, so that the quality, performance, safety and the like of the product are obviously improved, thereby completing the application.
Disclosure of Invention
In order to overcome the defects in the prior art, the main purpose of the application is to provide a lornoxicam pharmaceutical composition for injection and a preparation method thereof, and the lornoxicam pharmaceutical composition for injection has the advantages of simple composition, good product stability, simple and convenient process, low cost and easy mass production.
The technical scheme of the application is as follows:
a lornoxicam pharmaceutical composition for injection comprising lornoxicam, sodium carbonate and water for injection, having a pH of 9.5-11, preferably 9.8-10.5; the concentration of lornoxicam is 4mg/ml.
Further, the mass ratio of lornoxicam to sodium carbonate is 1:1.5-1:6, preferably the mass ratio of lornoxicam to sodium carbonate is 1:2-1:3
The application also provides a preparation method of the lornoxicam freeze-dried powder injection, which comprises the following steps:
step 1: weighing raw materials and auxiliary materials according to the prescription amount;
step 2: taking 80% of the prescription amount of water for injection, adding the prescription amount of sodium carbonate to adjust the pH to 9.5-11, adding the prescription amount of lornoxicam, stirring and dissolving, and then fixing the volume to the full volume by using the water for injection to obtain a medicine solution; further, the temperature of the 80% of the prescribed amount of water for injection in step 2 is 40 ℃. In some embodiments, the sodium carbonate in step 2 adjusts the pH to 9.8-10.5.
Step 3: and (3) carrying out two-stage sterilization and filtration on the medicine solution obtained in the step (2), filling the medicine solution into a penicillin bottle, and sending the penicillin bottle into a freeze dryer for freeze drying. Further, the two-stage sterilization filtration in the step 3 specifically comprises: the first filtration stage used a 0.45 μm PTFE cartridge and the second filtration stage used a 0.22 μm PTFE cartridge.
Still further, the freeze drying process in step 3 includes the steps of:
step 3.1: placing the penicillin bottle filled with the liquid medicine into a box, pre-freezing to below-40 ℃ within 60min, and preserving heat for 120-180 min;
step 3.2: annealing the pre-frozen liquid medicine within 60min, heating to-10deg.C, and maintaining the temperature for 90min;
step 3.3: repeating the operation of step 3.1-3.2 for 2-3 times, cooling to-40deg.C, and maintaining for 120min;
step 3.4: performing sublimation drying when the vacuum is pumped to less than 50pa, wherein the sublimation drying temperature is not higher than-5 ℃, and the sublimation drying time is 10-12 h;
step 3.5: and after the sublimation drying is finished, pumping extreme vacuum, raising the temperature to 40 ℃, and resolving and drying for 10-15 hours to obtain the crystalline lornoxicam freeze-dried powder injection.
The application also provides a lornoxicam-sodium carbonate crystalline compound, which is obtained by the freeze drying process, and the X-ray powder diffraction pattern of the crystalline compound has characteristic diffraction peaks at the following 2 theta positions by using Cu-K alpha radiation: 9.11°±0.2°, 10.52°±0.2°, 19.59°±0.2°, 20.03°±0.2°, 20.55°±0.2°, 23.30°±0.2°, 25.47°±0.2°, 26.43°±0.2°, 27.33°±0.2°, 29.05°±0.2°.
The application has the beneficial effects that: the inventor unexpectedly discovers that when the sodium carbonate is adopted to adjust the pH of the liquid medicine to 9.5-11 (preferably to pH 9.8-10.5), and repeatedly anneals the lornoxicam solution (namely, repeatedly steps 3.1 and 3.2) in the pre-freezing step of the freeze-drying procedure, so that lornoxicam and sodium carbonate form a specific crystalline complex, and the lornoxicam freeze-dried powder injection containing the crystalline complex has the advantages of high stability, good re-solubility, high clarity of the liquid medicine after re-dissolution and the like. The raw materials and the auxiliary materials of the application have simple components, simple and convenient process and easy mass production.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of crystalline lornoxicam-sodium carbonate complex prepared in example 1 of the present application.
FIG. 2 is an X-ray powder diffraction pattern of lornoxicam lyophilized powder for injection prepared in comparative example 3 (without repeated annealing).
Detailed Description
The application is further illustrated by the following specific examples. It should be understood that: the examples of the present application are merely illustrative of the present application and are not intended to be limiting. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The raw materials of specific origin are not noted in the following examples, and are generally commercially available conventional products. The technical scheme obtained by simply improving the application or adopting conventional means or components to perform equivalent substitution on the basis of the technical scheme of the application belongs to the protection scope of the application.
EXAMPLE 1 Lornoxicam pharmaceutical composition for injection
Prescription:
lornoxicam 4g, which is used for treating the common cold,
2g of sodium carbonate, and the total weight of the sodium carbonate,
injection water was added to 1000mL;
the preparation method comprises the following steps:
step 1: weighing 4g of lornoxicam, 2g of sodium carbonate and 1000mL of water for injection;
step 2: heating 800mL of water for injection to 40 ℃, adding prescribed amount of sodium carbonate to adjust the pH to 9.8, adding prescribed amount of lornoxicam, stirring for dissolution, and then fixing the volume to 1000mL by using the water for injection to obtain a drug solution;
step 3: and (3) filtering the medicine solution obtained in the step (2) by adopting a PTFE filter element with the diameter of 0.45 mu m for the first stage, filtering by adopting a PTFE filter element with the diameter of 0.22 mu m for the second stage, filtering by two stages of sterilization, filling the medicine solution into a penicillin bottle, and sending the penicillin bottle into a freeze dryer for freeze drying.
Step 3.1: placing the penicillin bottle filled with the liquid medicine into a box, pre-freezing to below-40 ℃ within 60min, and preserving heat for 120-180 min;
step 3.2: annealing and heating the liquid medicine pre-frozen in the step 1 to-10 ℃ within 60min, and preserving heat for 90min;
step 3.3: repeating the operation of step 3.1-3.2 for 2 times, cooling to-40deg.C, and maintaining the temperature for 120min;
step 3.4: performing sublimation drying when the vacuum is pumped to less than 50pa, wherein the sublimation drying temperature is not higher than-5 ℃, and the sublimation drying time is 10-12 h;
step 3.5: and after the sublimation drying is finished, pumping extreme vacuum, raising the temperature to 40 ℃, and resolving and drying for 10-15 hours to obtain lornoxicam freeze-dried powder injection (lornoxicam-sodium carbonate crystalline compound).
Using Cu-ka radiation, the X-ray powder diffraction pattern of the resulting lornoxicam-sodium carbonate crystalline complex is shown in fig. 1, having characteristic diffraction peaks at the following 2θ positions: 9.11°±0.2°, 10.52°±0.2°, 19.59°±0.2°, 20.03°±0.2°, 20.55°±0.2°, 23.30°±0.2°, 25.47°±0.2°, 26.43°±0.2°, 27.33°±0.2°, 29.05°±0.2°.
Example 2
This example is essentially the same as example 1 except that 3g of sodium carbonate is added to adjust the pH to 10.5 in step 2, and the resulting lornoxicam-sodium carbonate crystalline complex has an X-ray powder diffraction pattern essentially corresponding to FIG. 1.
Example 3
This example is essentially the same as example 1 except that 1.5g of sodium carbonate is added to adjust the pH to 9.5 in step 2, and the resulting lornoxicam-sodium carbonate crystalline complex has an X-ray powder diffraction pattern essentially corresponding to FIG. 1.
Example 4
This example is essentially the same as example 1 except that 6g of sodium carbonate is added to adjust the pH to 11 in step 2 and the resulting crystalline lornoxicam-sodium carbonate complex has an X-ray powder diffraction pattern substantially in accordance with FIG. 1.
Example 5
This example is essentially the same as example 1, except that the freeze drying process of step 3, specifically step 3.3: repeating the steps 3.1-3.2 for 3 times, cooling to-40 ℃, and preserving heat for 120min to obtain the lornoxicam-sodium carbonate crystalline compound with an X-ray powder diffraction pattern basically consistent with figure 1.
Comparative example 1
This comparative example is essentially the same as example 1, except that in step 2 tromethamine is used instead of sodium carbonate to adjust the pH to 9.8.
Comparative example 2
This comparative example is essentially the same as example 1, except that arginine is used in place of sodium carbonate to adjust the pH to 9.8 in step 2.
Comparative example 3
This comparative example is essentially the same as example 1, except that the freeze-drying process of step 3, in particular:
step 3.1: placing the penicillin bottle filled with the liquid medicine into a box, pre-freezing to below-40 ℃ within 60min, and preserving heat for 120-180 min;
step 3.2: performing sublimation drying when the vacuum is pumped to less than 50pa, wherein the sublimation drying temperature is not higher than-5 ℃, and the sublimation drying time is 10-12 h;
step 3.3: and after the sublimation drying is finished, pumping extreme vacuum, and raising the temperature to 40 ℃ and resolving and drying for 10-15 hours to obtain the lornoxicam freeze-dried powder injection.
Comparative example 4
This comparative example is essentially the same as example 1, except that the freeze drying process of step 3, specifically step 3.3: repeating the operation of step 3.1-3.2 for 1 time, cooling to-40deg.C, and maintaining the temperature for 120min.
Comparative example 5
This comparative example is essentially the same as example 1, except that the freeze drying process of step 3, specifically step 3.3: repeating the operation of step 3.1-3.2 for 4 times, cooling to-40deg.C, and maintaining the temperature for 120min.
Comparative example 6
This comparative example is essentially the same as example 1, except that the freeze drying process of step 3, specifically step 3.2: and (3) carrying out annealing heating to-15 ℃ within 60min on the liquid medicine pre-frozen in the step (1), and carrying out heat preservation for 90min.
Comparative example 7
This comparative example is essentially the same as example 1, except that the freeze drying process of step 3, specifically step 3.2: and (3) carrying out annealing heating to-5 ℃ within 60min on the liquid medicine pre-frozen in the step (1), and carrying out heat preservation for 90min.
Comparative example 8
The information of the original preparation is shown in Table 1, using the original preparation as comparative example 8.
TABLE 1 information on the original developer
| Name of the name | Lornoxicam for injection |
| Trade name | Xefo |
| Certificate-holding merchant | TakedaAustriaGmbH |
| Specification of specification | 8mg |
| Prescription composition | Lornoxicam, mannitol, tromethamine, disodium edetate |
| Preparation method | Vacuum freeze drying |
The inventors conducted further screening optimization for parameters such as buffer, pH, annealing times, annealing temperature, etc., and set the above examples 1 to 5 and comparative examples 1 to 7, and specific comparisons are shown in table 2.
Table 2 auxiliary material and process parameter screening optimization comparison table
| Buffering agents | pH | Annealing temperature | Number of anneals | |
| Example 1 | Sodium carbonate | 9.8 | -10℃ | 2 times |
| Example 2 | Sodium carbonate | 10.5 | -10℃ | 2 times |
| Example 3 | Sodium carbonate | 9.5 | -10℃ | 2 times |
| Example 4 | Sodium carbonate | 11 | -10℃ | 2 times |
| Example 5 | Sodium carbonate | 9.8 | -10℃ | 3 times |
| Comparative example 1 | Tromethamine | 9.8 | -10℃ | 2 times |
| Comparative example 2 | Arginine (Arg) | 9.8 | -10℃ | 2 times |
| Comparative example 3 | Sodium carbonate | 9.8 | / | / |
| Comparative example 4 | Sodium carbonate | 9.8 | -10℃ | 1 time |
| Comparative example 5 | Sodium carbonate | 9.8 | -10℃ | 4 times |
| Comparative example 6 | Sodium carbonate | 9.8 | -15℃ | 2 times |
| Comparative example 7 | Sodium carbonate | 9.8 | -5℃ | 2 times |
Test example 1: investigation of the influence of pH on the key quality index
To verify the effect of pH on the key quality of the product, examples 1-4 were set for verification and the results are shown in Table 3.
TABLE 3 influence of pH on key quality of product results
From Table 3, it is clear that the reconstitution times and clarity of examples 1-4 are not quite different, but the total impurity content of examples 1 and 2 is lower than that of examples 3 and 4. I.e. the key quality of the product is overall optimal when the pH is 9.8-10.5.
Test example 2: investigation of the influence of buffering agent on key quality index
In order to verify the effect of the buffer on the critical quality of the product, examples 1 and comparative examples 1-2 were set for verification, and the results are shown in Table 4.
TABLE 4 impact of buffer on key quality of product results
As can be seen from Table 4, the clarity of both example 1 and comparative examples 1-2 was clear, but the reconstitution time and total impurity content of example 1 were significantly lower than that of comparative examples 1-2. Sodium carbonate is preferred as the buffer.
Test example 3: examine the influence of the annealing times on the key quality index
In order to verify the effect of the number of anneals on the key quality index of the product, example 1 and comparative examples 6 to 7 were set up and the results are shown in Table 5.
TABLE 5 effect of annealing temperature on critical quality of product results
As can be seen from Table 5, the data of example 1 and example 5 are substantially the same and the effect is optimal, the total impurity content of comparative example 5 is slightly increased with increasing annealing times compared with those of example 1 and example 5, the reconstitution time and total impurity content of comparative example 3 are worst for comparative example 4 times. Preferably annealing temperature 2-3 times.
Test example 4: investigation of the influence of annealing temperature on key quality index
In order to verify the effect of annealing temperature on the key quality index of the product, examples 1 and 5 and comparative examples 3 to 5 were set up and the results are shown in table 6.
TABLE 6 impact of buffer on key quality of product results
As can be seen from Table 6, the effect of example 1 was optimal, and the effects of comparative example 6 and comparative example 7 were slightly worse. Preferably the annealing temperature is-10 ℃.
Test example 5: stability test
Through the screening of test examples 1-4, three groups of examples 1,2 and 5 with optimal effects are finally selected as experimental examples, and comparative examples 3 and 8 are used as comparative examples for stability investigation.
Taking five batches of RS-01-P1 (sample of example 1), RS-01-P2 (sample of example 2), RS-01-P3 (sample of example 5), control sample 1 (sample of comparative example 8) and control sample 2 (sample of comparative example 3), respectively placing for 3 months under the condition of 40 ℃ +/-2 RH75% +/-5%, respectively sampling for l, 2 and 3 months, checking according to stability key inspection projects, and comparing with test results of 0 month, wherein the results are shown in table 7.
TABLE 7 results summary of results of accelerated experiments
From the stability test results in Table 7, it was shown that the content of the control samples 1 and 2 was significantly reduced and the related substances were rapidly increased when the acceleration test was left for 3 months compared with that for 0 day. The related substances of the optimal prescription sample are slowly increased, the sample re-dissolution time and the clarity are better than those of the control sample, and all the quality meets the regulations, so that the quality is stable and controllable.
The inventors have found, when carrying out a cause analysis, that products prepared according to the formulations and processes of the present application (examples 1-5), when analyzed and tested, showed that a specific crystalline complex of lornoxicam-sodium carbonate was formed in the solution (diffraction pattern shown in fig. 1), which was different from the XRD 2 theta characteristic peaks of the lyophilized crystalline form of lornoxicam prepared according to comparative example 3 (control sample 2) (diffraction pattern shown in fig. 2). Using Cu-ka radiation, the X-ray powder diffraction pattern of the lornoxicam-sodium carbonate crystalline complex was found to have characteristic diffraction peaks at the following 2θ positions: 9.11°±0.2°, 10.52°±0.2°, 19.59°±0.2°, 20.03°±0.2°, 20.55°±0.2°, 23.30°±0.2°, 25.47°±0.2°, 26.43°±0.2°, 27.33°±0.2°, 29.05°±0.2°. Example 1 lornoxicam-sodium carbonate crystalline complex X-ray powder diffraction peaks are shown in table 8. The X-ray powder diffraction peaks of the freeze-dried crystalline form of lornoxicam prepared in comparative example 3 are shown in Table 9.
Table 8 example 1 peak X-ray powder diffraction of crystalline lornoxicam-sodium carbonate complex
| No. | Pos.[°2Th.] | d-spacing[A] | Rel.Int.[％] |
| 1 | 9.106503 | 9.71129 | 60.8 |
| 2 | 10.5178 | 8.41117 | 35.66 |
| 3 | 16.62641 | 5.3321 | 17.67 |
| 4 | 17.27144 | 5.13439 | 15.73 |
| 5 | 17.87383 | 4.96268 | 18.99 |
| 6 | 18.46301 | 4.80562 | 28.23 |
| 7 | 19.01104 | 4.66831 | 15.03 |
| 8 | 19.58832 | 4.53202 | 74.18 |
| 9 | 20.03185 | 4.43266 | 35.59 |
| 10 | 20.54503 | 4.32309 | 77.94 |
| 11 | 21.97655 | 4.04462 | 19.77 |
| 12 | 23.29834 | 3.81806 | 100 |
| 13 | 25.46549 | 3.49784 | 42.79 |
| 14 | 26.42842 | 3.37254 | 31.92 |
| 15 | 27.32634 | 3.26373 | 35.5 |
| 16 | 28.21781 | 3.16261 | 14.36 |
| 17 | 28.74631 | 3.10566 | 35.36 |
| 18 | 29.05366 | 3.0735 | 63.45 |
| 19 | 29.81627 | 2.99661 | 18.11 |
| 20 | 31.45576 | 2.84406 | 25.68 |
| 21 | 31.89695 | 2.80573 | 13.09 |
| 22 | 32.53302 | 2.75231 | 13.12 |
| 23 | 33.48709 | 2.67604 | 20.94 |
| 24 | 33.95871 | 2.63995 | 8.36 |
| 25 | 36.95919 | 2.43223 | 10.96 |
| 26 | 37.54822 | 2.39542 | 3.63 |
Table 9 peak X-ray powder diffraction of lyophilized crystalline form of lornoxicam prepared in comparative example 3
Test 6: vascular irritation test
Vascular stimulation experiments: the rabbits were randomly divided into 7 groups of 28 rabbits, each group having a male and female half. Test group: the medicines of examples 1-5 are respectively injected into the vein of the left auricle of the rabbit; control group: the medicine of the comparative example 8 is injected into the left ear margin of the rabbit intravenously; blank group: the rabbit left ear margin was injected with an equal volume of physiological saline. Each group was administered 1 time a day for 5 days continuously, and whether or not there was irritation such as redness, swelling, and the like in the injection site and surrounding tissues was observed visually. The products of examples 1 to 5 and comparative example 8 were subjected to vascular irritation test, and the results are shown in Table 10.
TABLE 10 results of vascular irritation test on the products of examples 1-5 and comparative example 8
As can be seen from Table 10, the irritation of the present examples 1-5 was lower than that of comparative example 8.
The above embodiments are only for illustrating the technical solution of the present application and not for limiting the same, and although the present application has been described in detail with reference to examples, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the scope of the technical solution of the present application, which is intended to be covered by the claims of the present application.
Claims (10)
1. The lornoxicam pharmaceutical composition for injection is characterized by comprising lornoxicam, sodium carbonate and water for injection, wherein the pH value is 9.5-11; the concentration of lornoxicam is 4mg/ml.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of lornoxicam to sodium carbonate is 1:1.5-1:6.
3. The pharmaceutical composition according to claim 2, wherein the mass ratio of lornoxicam to sodium carbonate is 1:2-1:3.
4. The pharmaceutical composition of claim 1, wherein the pH is 9.8-10.5.
5. The preparation method of the lornoxicam freeze-dried powder injection is characterized by comprising the following steps:
step 1: weighing raw materials and auxiliary materials according to the prescription amount;
step 2: taking 80% of the prescription amount of water for injection, adding the prescription amount of sodium carbonate to adjust the pH to 9.5-11, adding the prescription amount of lornoxicam, stirring and dissolving, and then fixing the volume to the full volume by using the water for injection to obtain a medicine solution;
step 3: and (3) carrying out two-stage sterilization and filtration on the medicine solution obtained in the step (2), filling the medicine solution into a penicillin bottle, and sending the penicillin bottle into a freeze dryer for freeze drying.
6. The method of claim 5, wherein the 80% of the prescribed amount of water for injection in step 2 has a temperature of 40 ℃.
7. The method according to claim 5, wherein the sodium carbonate in step 2 is adjusted to pH9.8 to 10.5.
8. The method according to claim 5, wherein the two-stage sterilization filtration in step 3 is specifically: the first filtration stage used a 0.45 μm PTFE cartridge and the second filtration stage used a 0.22 μm PTFE cartridge.
9. The method of any one of claims 5-8, wherein the freeze-drying process in step 3 comprises the steps of:
step 3.1: placing the penicillin bottle filled with the liquid medicine into a box, pre-freezing to below-40 ℃ within 60min, and preserving heat for 120-180 min;
step 3.2: annealing the pre-frozen liquid medicine within 60min, heating to-10deg.C, and maintaining the temperature for 90min;
step 3.3: repeating the operation of step 3.1-3.2 for 2-3 times, cooling to-40deg.C, and maintaining for 120min;
step 3.4: performing sublimation drying when the vacuum is pumped to less than 50pa, wherein the sublimation drying temperature is not higher than-5 ℃, and the sublimation drying time is 10-12 h;
step 3.5: and after the sublimation drying is finished, pumping extreme vacuum, raising the temperature to 40 ℃, and resolving and drying for 10-15 hours to obtain crystalline lornoxicam freeze-dried powder injection.
10. Crystalline lornoxicam-sodium carbonate complex obtainable by the freeze-drying process according to claim 9, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ positions using Cu-ka radiation: 9.11°±0.2°, 10.52°±0.2°, 19.59°±0.2°, 20.03°±0.2°, 20.55°±0.2°, 23.30°±0.2°, 25.47°±0.2°, 26.43°±0.2°, 27.33°±0.2°, 29.05°±0.2°.
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