CN114159384A - Low-irritation ketorolac tromethamine injection with stable chemical properties - Google Patents
Low-irritation ketorolac tromethamine injection with stable chemical properties Download PDFInfo
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- CN114159384A CN114159384A CN202110179099.6A CN202110179099A CN114159384A CN 114159384 A CN114159384 A CN 114159384A CN 202110179099 A CN202110179099 A CN 202110179099A CN 114159384 A CN114159384 A CN 114159384A
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- 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
- A61K9/08—Solutions
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a low-irritation ketorolac tromethamine injection with stable chemical properties. The chemical stability, especially the light stability of the product is improved by using the brown inner packaging material and further adding an antioxidant; and avoids using substances with serious irritation such as organic solvents, surfactants and the like in the prior art, and relieves pain at the injection part. The invention has simple and controllable production process and stable physico-chemical property of the liquid medicine, and improves the medication safety and compliance of patients.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a low-irritation ketorolac tromethamine injection with stable chemical properties.
Background
Ketorolac tromethamine is a powerful non-steroidal anti-inflammatory drug that inhibits prostaglandin biosynthesis, thereby producing an analgesic effect, and is suitable for short-term treatment of acute moderate to severe pain (adult treatment period is generally no more than 5 days) requiring use of opioid level analgesics. The product has few adverse central nervous reactions such as respiratory depression, and does not act on opioid receptors or stimulate in vivo release of opioid peptide, so it has high safety and can replace opioid drugs to a certain extent.
The products of ketorolac tromethamine on the market comprise various formulations such as oral tablets/capsules, injection, eye drops, nasal spray and the like, wherein the injection has the fastest effect, does not have the problem of bioavailability and is widely applied to the aspect of postoperative analgesia.
Ketorolac tromethamine injection was originally developed by rochon corporation and has specifications of 10mg:1mL and 30mg:1mL, and was packed in colorless transparent ampoules for intravenous or intramuscular administration. To increase chemical stability, especially light stability, 10% (w/v) ethanol is used in the Roche formulation, but while exerting a protective effect, this concentration of ethanol also brings about strong vascular irritation at the injection site, especially intramuscular injection, as an organic solvent. To avoid injection of organic solvents into patients and the additional process control and quality control resulting from the use of organic solvents, the pharmaceutical industry (Kunshan) Inc. has exchanged ethanol for potassium dihydrogen phosphate, but potassium salts are also irritating. In addition, in the prior art, surfactants are used for improving the product quality, such as cholesterol, oleic acid, sodium oleate, glycerol or poloxamer in CN201210365740.6, phospholipid in WO2008013822A2 and the like, but the functional auxiliary materials are complex in components, have certain quality control difficulty and do not solve the problem of irritation, and no mature product is sold on the market at present.
Therefore, the ketorolac tromethamine injection with better light stability, lower irritation, simple production process and controllable quality has definite clinical requirements.
Disclosure of Invention
The invention aims to solve the problems in the prior art, provides a low-irritation ketorolac tromethamine injection with stable chemical properties and a preparation method thereof, and particularly relates to a method for improving the chemical stability of liquid medicine by using a brown inner packaging material and further adding an antioxidant; and to reduce irritation by avoiding the use of organic solvents, surfactants, and the like. The ketorolac tromethamine injection prepared by the method has more stable chemical properties and higher safety, has still remarkable curative effect and can meet the clinical application.
The invention is mainly realized by the following technical scheme:
the invention provides a low-irritation ketorolac tromethamine injection with stable chemical properties,
a. the prescription of the injection comprises ketorolac tromethamine, a pH regulator, an osmotic pressure regulator and water for injection;
b. the injection inner packaging container is made of brown glass;
c. the prescription of the injection does not contain ethanol or other organic solvents, surfactants and other substances which have strong irritation to blood vessels.
The ketorolac tromethamine provided by the invention comprises a racemate, a levorotatory isomer and a dextrorotatory isomer.
According to the embodiment of the present invention, the inner packaging container made of brown glass includes, but is not limited to, a brown ampoule, a brown cartridge bottle, and a brown tube injection bottle, preferably a brown ampoule.
According to the embodiment of the invention, the content of ketorolac tromethamine in the injection is 1-60 mg/mL, preferably 10-30 mg/mL.
According to the embodiment of the invention, the pH regulator is used for regulating the pH of the ketorolac tromethamine injection to be 6.5-8.0, preferably 7.0-7.5; the pH adjusting agent includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, tromethamine, acetic acid, hydrochloric acid, lactic acid, maleic acid, phosphoric acid, tartaric acid, preferably sodium hydroxide and/or hydrochloric acid.
According to an embodiment of the present invention, the tonicity modifier includes, but is not limited to, one or more of glycerol, glucose, sucrose, lactose, fructose, mannitol, sorbitol, sodium chloride, preferably sodium chloride.
According to an embodiment of the present invention, an antioxidant is further included, including but not limited to one or more of sodium sulfite, sodium thiosulfate, cysteine, ascorbic acid, citric acid, tartaric acid, preferably citric acid.
The ketorolac is an acidic compound, the inherent solubility of the ketorolac is 0.084mg/mL and the pKa of the ketorolac is about 4.3 after the ketorolac is retrieved, the pKa of the ketorolac is about 3.5 after the ketorolac is salified with tromethamine, ketorolac tromethamine dissolved in water has strong buffer capacity, according to the theory of acid-base equilibrium, when the pH is more than 2 units, the solubility of the compound can be increased by 100 times, the pH range of a commercially available ketorolac tromethamine injection is 6.9-7.9 and is about 3.5-4.5 units higher than the pKa of the ketorolac tromethamine, therefore, under the condition that the concentration of the ketorolac tromethamine is 60mg/mL, as long as the pH of a solvent system is maintained in the quality control range of a commercially available product, no active ingredient is separated out, and the treatment effect can be guaranteed.
Based on the analysis, the invention provides the ketorolac tromethamine injection with a simple formula, wherein an inner packaging container is made of brown glass, and the formula comprises ketorolac tromethamine, a pH regulator, an osmotic pressure regulator and water for injection, wherein the content of the ketorolac tromethamine is 1-60 mg/mL; the injection further comprises antioxidant, but does not contain ethanol or other organic solvent, surfactant, etc. with strong irritation.
In a preferred embodiment of the invention, the inner packaging container in the injection is a brown glass ampoule; the content of ketorolac tromethamine is 10-30 mg/mL; the pH regulator is sodium hydroxide and/or hydrochloric acid, and the pH is 7.4; the osmotic pressure regulator is sodium chloride; the antioxidant is citric acid.
In a preferred embodiment, the ketorolac tromethamine injection of the present invention comprises the following components:
| ketorolac tromethamine | 30mg |
| Sodium chloride | 4.35mg |
| Citric acid | 5mg |
| Sodium hydroxide | Adjusting the pH to 7.4 |
| Water for injection | Adding to 1mL |
| Inner packing container | Brown glass ampoule |
The invention also provides a preparation method of the ketorolac tromethamine injection, which comprises the following steps:
(1) weighing and dissolving a prescription amount of osmotic pressure regulator, an antioxidant and a part of prescription amount of injection water;
(2) adding ketorolac tromethamine according to the prescription amount, and dissolving;
(3) adding a pH regulator to regulate the pH of the solution to be within the range of 7.0-8.0;
(4) adding the rest water for injection, and fixing the volume;
(5) filtering to reduce the biological load;
(6) filling;
(7) performing damp-heat sterilization;
(8) visual inspection;
(9) and (6) packaging.
In a preferred embodiment, the method for preparing ketorolac tromethamine injection specifically comprises the following steps:
(1) at room temperature, adding about 90% of prescription amount of injection water cooled to room temperature into a liquid preparation container, adding prescription amount of sodium chloride and citric acid, and stirring to dissolve;
(2) adding ketorolac tromethamine into the solution in the step (1), and stirring until the ketorolac tromethamine is dissolved;
(3) adding a proper amount of 2M sodium hydroxide aqueous solution into the solution in the step (2), and adjusting the pH to 7.4;
(4) adding the rest of water for injection into the solution in the step (3), and fixing the volume to the target concentration;
(5) filtering the solution in the step (4) by a filter with the pore diameter not more than 0.45 mu m;
(6) under the protection of nitrogen, filling the liquid medicine into a 1mL brown ampoule, and sealing by fusing;
(7) moist Heat Sterilization, F0≥12；
(8) Detecting leakage of the sterilized colored water, performing lamp inspection, and removing unqualified products;
(9) and (5) coating the qualified product with label.
The ketorolac tromethamine injection uses a brown glass inner packaging container, and the photoprotection effect of the container on liquid medicine is obviously superior to that of ethanol in the existing commercial products. On the basis of ensuring the chemical stability, the formula does not contain organic solvent or surfactant, so that irritant components are completely avoided, the phlebitis risk is greatly reduced, and the medication safety of patients is remarkably improved. The product of the invention is easy for industrial production and has stable quality.
The ketorolac tromethamine injection can be used for subcutaneous injection, intrathecal injection, intramuscular injection, intravenous injection or intravenous drip after dilution.
Compared with the prior art, the ketorolac tromethamine injection has the following remarkable advantages:
(1) ketorolac tromethamine is poor in light stability after being dissolved, and specifications of commercial products clearly indicate that: the patient is prohibited from taking out the product from the package before injection, but the product is not packaged by a single package for saving the production cost and the hospital management cost, and the poor light stability of the product adds additional time constraint and management burden to clinical use. The ketorolac tromethamine injection uses the brown glass container, can realize chemical stability superior to the existing products sold on the market by using a simple formula under the protection of the brown glass container, can prepare medicines for patients in advance under indoor natural light or incandescent lamps, and has the same treatment effect as the products sold on the market because the content of active ingredients has guarantee and degradation products are controllable.
(2) The brown glass container is used for providing a photoprotective effect, the antioxidant can be synergistic, the potential safety hazards of blood vessel irritation of an organic solvent and irritation, hemolysis and the like of a surfactant (such as phospholipid, poloxamer and polysorbate) with complex components can be thoroughly avoided on the formula, the discomfort of a patient during injection is reduced, and the compliance is remarkably improved.
(3) The ketorolac tromethamine injection does not contain substances with stronger volatility and substances easy to oxidize and degrade, does not need to add strict intermediate control steps in the production process, and has stable process, easy amplification and better reproducibility; and the finished injection does not need to add additional detection items such as ethanol content, lysophospholipid, peroxide, aldehyde substances and the like, so that the quality controllability is better.
Drawings
FIG. 1 is a high performance liquid chromatogram of ketorolac tromethamine injection of example 2 of the present invention under light for 12 days.
FIG. 2 is a high performance liquid chromatogram of the ketorolac tromethamine injection of comparative example 2 after 12 days of light irradiation.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It is to be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention, which is to be given the full breadth of the appended claims and any and all equivalent modifications thereof which may occur to those skilled in the art upon reading the present specification.
Test example 1: study of ethanol Effect
Organic solvents are more potent vascular irritants and are not the most preferred vehicle for injection, but commercial formulations of ketorolac tromethamine injection use ethanol at concentrations as high as 10% (w/v), which produces a strong pain sensation during intramuscular injection. The functionality of ethanol in ketorolac tromethamine injection was examined as follows.
The test method comprises the following steps:
1. the product is marketed according to the specification of 1mL to 30mg
Preparing ketorolac tromethamine injection according to the formula, and replacing 10% ethanol with water for injection in the same proportion to serve as negative control;
2. heating the two samples at 121 ℃ for 1 hour respectively, introducing oxygen into the container from the inside of the solution, sealing for 4 hours, illuminating for 1 day, detecting related substances, and comparing the difference of key impurities between the two samples.
TABLE 1 ethanol/no ethanol sample Destruction test
The above data show that: ketorolac tromethamine is relatively stable at high temperatures, and ethanol has the effect of increasing chemical stability under oxidation and illumination conditions.
Test example 2: investigation of packaging materials of different colors
Samples were prepared according to the method of test example 1, filled in 1mL colorless glass ampoules and 1mL brown glass ampoules, sealed by melting, and sterilized by moist heat at 121 ℃ for 15 min. Since the data in table 1 show that the degree of difference between the substances of ethanol-containing/ethanol-free samples under the illumination condition is higher than that under the oxidation condition, the influence of the packaging containers in different colors on the chemical stability of the samples was examined by using the illumination condition.
TABLE 2 Effect of color of packaging Container in glass on illumination stability of ethanol/ethanol-free samples
The above data show that: when the inner packaging container is a brown glass ampoule, the photodegradation of the product can be inhibited. The protective effect of the brown ampoule is stronger than that of ethanol.
Test example 3: study of antioxidant Properties
0.5% antioxidant was added to the ethanol-free formulation, and the effect of the antioxidant on the chemical stability of the samples under light was examined using a colorless glass ampoule as the inner packaging container.
TABLE 3 Effect of antioxidants on the light stability of ethanol-free samples
The above data show that: the formula without ethanol uses a colorless ampoule, and the antioxidant is added to improve the chemical stability of the ketorolac tromethamine injection liquid, wherein the protective effect of the citric acid is optimal.
The following examples further illustrate the present invention and all of them can achieve the effects described in the above test examples, but the examples are only for illustrating the present invention and not for limiting the present invention.
Example 1
(1) Prescription composition
| Ketorolac tromethamine | 30g |
| Sodium chloride | 4.35g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH of about 7.4 |
| Water for injection | To 1L |
| Batch size | 1000 pieces |
| Inner packing container | 1mL brown glass ampoule |
(2) The preparation method comprises the following steps:
1. adding sodium chloride into 90% prescription dose of injection water cooled to room temperature, and stirring until the sodium chloride is completely dissolved;
2. adding ketorolac tromethamine, and stirring until the ketorolac tromethamine is completely dissolved;
3. adding 2M sodium hydroxide aqueous solution to adjust the pH of the liquid medicine to about 7.39;
4. adjusting the concentration of ketorolac tromethamine to 30mg/mL by using the residual amount of water for injection;
5. filtering the liquid medicine by a filter element with the diameter of 0.2 mu m;
6. filling under the protection of nitrogen, and sealing by fusing;
7. sterilizing with damp heat at 121 deg.C for 15 min;
8. visual inspection is carried out, and unqualified products are removed;
9. and (5) labeling and outsourcing the qualified products.
Example 2
(1) Prescription composition
| Ketorolac tromethamine | 30g |
| Sodium chloride | 4.35g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH of about 7.4 |
| Citric acid | 5g |
| Water for injection | To 1L |
| Batch size | 1000 pieces |
| Inner packing container | 1mL brown glass ampoule |
(2) The preparation method comprises the following steps:
1. adding sodium chloride and citric acid into 90% prescription dose of water for injection cooled to room temperature, and stirring until the sodium chloride and the citric acid are completely dissolved;
2. adding ketorolac tromethamine, and stirring until the ketorolac tromethamine is completely dissolved;
3. adding 2M sodium hydroxide aqueous solution to adjust the pH of the liquid medicine to about 7.40;
4. adjusting the concentration of ketorolac tromethamine to 30mg/mL by using the residual amount of water for injection;
5. filtering the liquid medicine by a filter element with the diameter of 0.2 mu m;
6. filling under the protection of nitrogen, and sealing by fusing;
7. sterilizing with damp heat at 121 deg.C for 15 min;
8. visual inspection is carried out, and unqualified products are removed;
9. and (5) labeling and outsourcing the qualified products.
Example 3
(1) Prescription composition
| Ketorolac tromethamine | 15g |
| Sodium chloride | 6.68g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH of about 7.4 |
| Citric acid | 5g |
| Water for injection | To 1L |
| Batch size | 1000 pieces |
| Inner packing container | 2mL brown glass tube injection bottle, brominated butyl rubber plug |
(2) The preparation method comprises the following steps:
1. adding sodium chloride and citric acid into 90% prescription dose of water for injection cooled to room temperature, and stirring until the sodium chloride and the citric acid are completely dissolved;
2. adding ketorolac tromethamine, and stirring until the ketorolac tromethamine is completely dissolved;
3. adding 2M sodium hydroxide aqueous solution to adjust the pH of the liquid medicine to about 7.40;
4. adjusting the concentration of ketorolac tromethamine to 15mg/mL by using the residual amount of water for injection;
5. filtering the liquid medicine by a filter element with the diameter of 0.2 mu m;
6. filling, plugging and capping under the protection of nitrogen;
7. sterilizing with damp heat at 121 deg.C for 15 min;
8. visual inspection is carried out, and unqualified products are removed;
9. and (5) labeling and outsourcing the qualified products.
Test example 4 light stability test of sample without outer packaging
The samples of example 1, the samples of example 2, and the commercial products were mixed
(the formula contains ethanol and a colorless transparent ampoule),
(the formulation does not contain ethanol, colorless transparent ampoule) is placed in a light box, the ampoule is exposed to a cold white fluorescent lamp and a near ultraviolet lamp, and the total illumination of the light source is not less than 1.2 multiplied by 106lux & h, energy of near ultraviolet lamp not less than 200W & hr/m2. Samples were taken at 12 days to observe whether the appearance of the samples changed, and the relevant substances were detected.
TABLE 4 materials relating to the products of the invention and comparative examples illuminated for 12 days
The above data show that: the brown ampoule has a significant photoprotective effect. The citric acid is added on the basis of the brown packaging container, and the chemical stability of the sample under illumination is more advantageous.
Comparative example 1
According to the commercial products
Formulation samples were prepared.
(1) Prescription composition
| Ketorolac tromethamine | 30g |
| Sodium chloride | 4.35g |
| Ethanol | 100g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH of about 7.4 |
| Water for injection | To 1L |
| Batch size | 1000 pieces |
| Inner packing container | 1mL colorless glass ampoule |
(2) Preparation method
1. Adding sodium chloride and ethanol into 90% prescription dose of injection water cooled to room temperature, and stirring until the sodium chloride and the ethanol are completely dissolved;
2. adding ketorolac tromethamine, and stirring until the ketorolac tromethamine is completely dissolved;
3. adding 2M sodium hydroxide aqueous solution to adjust the pH of the liquid medicine to about 7.42;
4. adjusting the concentration of ketorolac tromethamine to 30mg/mL by using the residual amount of water for injection;
5. filtering the liquid medicine by a filter element with the diameter of 0.2 mu m;
6. filling under the protection of nitrogen, and sealing by fusing;
7. sterilizing with damp heat at 121 deg.C for 15 min;
8. visual inspection is carried out, and unqualified products are removed;
9. and (5) labeling and outsourcing the qualified products.
Comparative example 2
According to the commercial products
Formulation samples were prepared.
(1) Prescription composition
| Ketorolac tromethamine | 30g |
| Sodium chloride | 4.35g |
| Potassium dihydrogen phosphate | 5g |
| Sodium hydroxide | Proper amount of the mixture is adjusted to pH of about 7.4 |
| Water for injection | To 1L |
| Batch size | 1000 pieces |
| Inner packing container | 1mL colorless glass ampoule |
(2) Preparation method
1. Adding sodium chloride and potassium dihydrogen phosphate into 90% of prescription dose of injection water cooled to room temperature, and stirring until the sodium chloride and the potassium dihydrogen phosphate are completely dissolved;
2. adding ketorolac tromethamine, and stirring until the ketorolac tromethamine is completely dissolved;
3. adding 2M sodium hydroxide aqueous solution to adjust the pH of the liquid medicine to about 7.38;
4. adjusting the concentration of ketorolac tromethamine to 30mg/mL by using the residual amount of water for injection;
5. filtering the liquid medicine by a filter element with the diameter of 0.2 mu m;
6. filling under the protection of nitrogen, and sealing by fusing;
7. sterilizing with damp heat at 121 deg.C for 15 min;
8. visual inspection is carried out, and unqualified products are removed;
9. and (5) labeling and outsourcing the qualified products.
Test example 5 accelerated test and intermediate Condition test of samples containing outer packages
Samples of example 1, example 2, comparative example 1 and comparative example 2 were wrapped in a white paper box, placed in a stability box, and subjected to sampling at 30. + -. 2 ℃ and 65. + -. 5% RH and 40. + -. 2 ℃ and 75. + -. 5% RH for 6 months, sampled and examined at 3 months and 6 months, respectively, and compared with 0 hours.
Based on the experience of the skilled person, the samples of example 1 and example 2,
Although there are significant differences in chemical stability in light tests, the trends for chemical stability are consistent during long-term storage in the packaging boxes and all can meet quality requirements.
The products of comparative examples 1 and 2 have the risk of photodegradation in the production processes (sterilization, visual inspection and external packaging) after sealing; when the medicine is clinically used, the medicine needs to be taken out of the packaging box before injection, and if the medicine needs to be prepared in advance, additional protective measures such as dark protective bags or other small boxes need to be added in a subpackaging way. In contrast, the products of embodiments 1 and 2 do not need to add extra control measures in the sealed production process, and clinical nurses can flexibly dispense drugs according to the actual conditions of patients.
On the basis of not reducing the curative effect of ketorolac tromethamine, the invention increases the chemical stability, the medication safety and the drug preparation flexibility, reduces multi-party risks, and belongs to a better solution in clinic.
Claims (10)
1. A chemically stable, low-irritation ketorolac tromethamine injection characterized by:
a. the prescription of the injection comprises ketorolac tromethamine, a pH regulator, an osmotic pressure regulator and water for injection;
b. the injection inner packaging container is made of brown glass;
c. the prescription of the injection does not contain ethanol or other organic solvents, surfactants and other substances which have strong irritation to blood vessels.
2. The ketorolac tromethamine injection according to claim 1, wherein the brown glass inner packaging container comprises but is not limited to a brown ampoule, a brown bottle, a brown tube injection bottle, preferably a brown ampoule.
3. The ketorolac tromethamine injection according to claim 1, wherein the content of ketorolac tromethamine in the injection is 1 to 60mg/mL, preferably 10 to 30 mg/mL.
4. The ketorolac tromethamine injection according to claim 1, wherein the pH adjusting agent is used to adjust the pH of the ketorolac tromethamine injection to between 6.5 and 8.0, preferably between 7.0 and 7.5; the pH adjusting agent includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, tromethamine, acetic acid, hydrochloric acid, lactic acid, maleic acid, phosphoric acid, tartaric acid, preferably sodium hydroxide and/or hydrochloric acid.
5. The ketorolac tromethamine injection according to claim 1, characterized in that the tonicity modifier includes but is not limited to one or more of glycerol, glucose, sucrose, lactose, fructose, mannitol, sorbitol, sodium chloride, preferably sodium chloride.
6. The ketorolac tromethamine injection according to claim 1, further comprising an antioxidant including but not limited to one or more of sodium sulfite, sodium thiosulfate, cysteine, ascorbic acid, citric acid, tartaric acid, preferably citric acid.
7. The ketorolac tromethamine injection according to any one of claims 1 to 6, wherein the injection is for subcutaneous injection, intrathecal injection, intramuscular injection, intravenous bolus injection or intravenous drip after dilution.
8. A ketorolac tromethamine injection is characterized by comprising the following components:
。
9. A method for preparing the ketorolac tromethamine injection according to claim 8, which comprises the steps of:
weighing and dissolving a prescription amount of osmotic pressure regulator, an antioxidant and a part of prescription amount of injection water;
adding ketorolac tromethamine according to the prescription amount, and dissolving;
adding a pH regulator to regulate the pH of the solution to be within the range of 7.0-8.0;
adding the rest water for injection, and fixing the volume;
filtering to reduce the biological load;
filling;
performing damp-heat sterilization;
visual inspection;
and (6) packaging.
10. A method for preparing the ketorolac tromethamine injection according to claim 8, which comprises the steps of:
at room temperature, adding about 90% of prescription amount of injection water cooled to room temperature into a liquid preparation container, adding prescription amount of sodium chloride and citric acid, and stirring to dissolve;
adding ketorolac tromethamine into the solution in the step (1), and stirring until the ketorolac tromethamine is dissolved;
adding a proper amount of 2M sodium hydroxide aqueous solution into the solution in the step (2), and adjusting the pH to 7.4;
adding the rest of water for injection into the solution in the step (3), and fixing the volume to the target concentration;
filtering the solution in the step (4) by a filter with the pore diameter not more than 0.45 mu m;
under the protection of nitrogen, filling the liquid medicine into a 1mL brown ampoule, and sealing by fusing;
moist Heat Sterilization, F0≥12；
Detecting leakage of the sterilized colored water, performing lamp inspection, and removing unqualified products;
and (5) coating the qualified product with label.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110179099.6A CN114159384B (en) | 2021-02-07 | 2021-02-07 | Low-irritation ketorolac tromethamine injection with stable chemical properties |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167722A (en) * | 2007-10-22 | 2008-04-30 | 鲁南制药集团股份有限公司 | Ketorolac tromethamine freezing-dried power injection and preparation method thereof |
| WO2009087658A2 (en) * | 2007-11-07 | 2009-07-16 | Sun Pharma Advanced Research Company Limited | Composition suitable for parenteral administration |
| WO2012127497A1 (en) * | 2011-03-04 | 2012-09-27 | Cadila Healthcare Limited | Stable pharmaceutical compositions of ketorolac or salts thereof |
| CN108703948A (en) * | 2010-10-21 | 2018-10-26 | Rtu制药有限责任公司 | Ready to use ketorolac formulations |
| CN111481501A (en) * | 2020-05-19 | 2020-08-04 | 南京锐志生物医药有限公司 | Ketorolac tromethamine injection capable of reducing irritation and free of organic solvent |
-
2021
- 2021-02-07 CN CN202110179099.6A patent/CN114159384B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167722A (en) * | 2007-10-22 | 2008-04-30 | 鲁南制药集团股份有限公司 | Ketorolac tromethamine freezing-dried power injection and preparation method thereof |
| WO2009087658A2 (en) * | 2007-11-07 | 2009-07-16 | Sun Pharma Advanced Research Company Limited | Composition suitable for parenteral administration |
| CN108703948A (en) * | 2010-10-21 | 2018-10-26 | Rtu制药有限责任公司 | Ready to use ketorolac formulations |
| WO2012127497A1 (en) * | 2011-03-04 | 2012-09-27 | Cadila Healthcare Limited | Stable pharmaceutical compositions of ketorolac or salts thereof |
| CN111481501A (en) * | 2020-05-19 | 2020-08-04 | 南京锐志生物医药有限公司 | Ketorolac tromethamine injection capable of reducing irritation and free of organic solvent |
Non-Patent Citations (1)
| Title |
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| 成都倍特药业股份有限公司: "《https://zy.yaozh.com/instruct/sms20220809/wh202207051039》", 27 December 2019 * |
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