CN104856990A - Phenylephrine ketorolac solution and preparation method - Google Patents
Phenylephrine ketorolac solution and preparation method Download PDFInfo
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- CN104856990A CN104856990A CN201510228758.5A CN201510228758A CN104856990A CN 104856990 A CN104856990 A CN 104856990A CN 201510228758 A CN201510228758 A CN 201510228758A CN 104856990 A CN104856990 A CN 104856990A
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- phenylephrine
- ketorolac
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- 229960004752 ketorolac Drugs 0.000 title claims abstract description 47
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 47
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 title claims abstract description 46
- 229960001802 phenylephrine Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000000243 solution Substances 0.000 claims abstract description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229960004384 ketorolac tromethamine Drugs 0.000 claims description 16
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 claims description 16
- 229960003733 phenylephrine hydrochloride Drugs 0.000 claims description 16
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
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- 239000002253 acid Substances 0.000 description 2
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- GBIJOCNCFGEIHD-NPULLEENSA-N 5-benzoyl-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid;3-[(1r)-1-hydroxy-2-(methylamino)ethyl]phenol Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 GBIJOCNCFGEIHD-NPULLEENSA-N 0.000 description 1
- -1 Alkaloid salt Chemical class 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
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- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to phenylephrine ketorolac solution and a preparation method, and provides intraocular operation washing concentrated solution without a preservative, an antioxidant and a buffer system. The phenylephrine ketorolac solution is capable of preventing the intraoperative miosis and relieving the postoperation pain, and avoiding the side effects caused by the preservative, the antioxidant and the buffer system.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, being specifically related to containing phenylephrine and ketorolac is sterile liquid formulations of active component and preparation method thereof.
Technical background
Cataract is a kind of common disease in daily life, and is the first blinding ocular disease in the world, the most often betides more than 50 years old person.Along with China enters aging society fast, cataract patient gets more and more.In the U.S., cataract or other various crystal replacement operations need to carry out about 4,000,000 every year, about have 2,000 ten thousand every year in the world.In China, increase 1,200,000 routine cataract patients newly every year according to statistics.General office of national health State Family Planning Commission circulates a notice of China in 2013 and reports and submits cataract operation 120.8 ten thousand example altogether, within 2012, reports and submits 1,110,000 examples, within nearly 5 years, reports and submits 558.8 ten thousand examples altogether.The cataractous medicine of clinical treatment is a lot, but there is no curative effect medicine certainly at present, especially in, posterior cataracts, there is no specific medicament and muddy crystal can be made to recover transparent, operative treatment is the unique definite effective Therapeutic Method of cataract recognized in the world.
Usually need in ophthalmologic operation to apply physiologic irrigation solution with protection and the physiological integrity maintaining ophthalmic.In operation process, myosis and postoperative pain are very common and usually unpredictable in this type of operation, and this brings great trouble to surgeon, also causes huge misery to patient simultaneously.So in operation, some have the application of antiinflammatory, platycoria, alleviation postoperative pain medicine, cause everybody concern.
Phenylephrine hydrochloride to be molecular weight be 203.67 α-1 adrenoceptor agonists, in eyes, can shrink the radial muscle of iris as iridodilator, its structural formula is as follows:
Ketorolac tromethamine to be molecular weight be 376.40 NSAID (non-steroidal anti-inflammatory drug), Cycloxygenase (COX-1 and COX-2) can be suppressed, reduce the concentration of the prostaglandin in tissue, thus alleviate the pain that surgical wound causes.Ketorolac, by the synthesis of prostaglandin after the mechanical stimulus that suppresses ocular surgical damage or iris, also can stop the contracted pupil caused in operation, its structural formula is as follows:
In order to myosis and alleviation postoperative pain in art can be suppressed in this type of operation, consider two kinds of drug regimens to use.FDA approval
expecting 2015 will in U.S.'s list marketing, and clinical data shows, when not changing routine operation flow process, the use of Omidria can allow ophthalmologist effectively control procedure.
Chinese patent CN1684701B, for Omeros Medical Systems, Inc. 2003.07.30 applies for, authorizes.Openly provide a kind of in ophthalmology operation by the solution of the ophthalmic applications of continual rinsing Perinatal Therapy.These solution comprise inflammation-inhibiting, inhibition of pain, effectively mydriasis (expansion pupil) and/or reduce the multi-medicament of intrinsic pressure effect, multi-medicament targeting polymolecular target selected in it, to reach multiple different physiological function, and described multi-medicament is contained in balanced salt solution carrier with diluted concentration.Wherein the first medicine is the ketorolac as anti-inflammatory agent, and the second medicine is the neophryn as mydriatic, and the concentration of ketorolac is not more than 100000nM, and the concentration of neophryn is not more than 500000mM.Wherein flush vehicle contains the electrolyte of the saline solution providing physiological equilibrium, cell energy, buffer agent and free radical scavenger and composition thereof.
CN103143022A is the divisional application of CN1684701B, and Ye Shi Omeros Medical Systems, Inc. applies in 2003.07.30, provide a kind of in ophthalmology operation by the solution of the ophthalmic applications of continual rinsing Perinatal Therapy.The anti-inflammatory agent that often kind of medicine is selected from different physiological roles classification (is selected from steroid, NSAID (non-steroidal anti-inflammatory drug), antihistaminic, mast cell inhibitor and nitric oxide synthase type inhibitor), analgesic (being selected from local anesthesia and OPIOIDS), mydriatic (being selected from α-1 adrenoceptor agonists and anticholinergic), reduce intraocular pressure and (be selected from the portable antagonist of beta adrenergic, carbonic anhydrase inhibitors, α-2 adrenoceptor agonists and prostaglandin agonists) medicine.Concrete medicine is selected from above at least one or multiple drug combination, and the concentration of each medicine is not more than 100000nM.This patent is examined.
CN101327325A is that Omeros Medical Systems, Inc. 2003.07.30 applies for, disclose a kind of is the solution of ophthalmic applications of operation by continual rinsing in ophthalmology operation, comprise the multi-medicament playing inflammation-inhibiting, inhibition of pain, effectively mydriasis and/or reduce intraocular pressure effect, and described multi-medicament is contained in balanced salt solution carrier with diluted concentration.
In above patent, all fabulous being applied to is selected from the NSAID (non-steroidal anti-inflammatory drug) ketorolac of inflammation-inhibiting and the phenylephrine of α-1 adrenoceptor agonists, the drug combination successful clinically of these two kinds of medicines.
WO2014066485A1 is world patent disclosed in Omeros Medical Systems, Inc., the patent provides a kind of aseptic, preservative free and the liquid preparation without antioxidant, an aseptic liquid pharmaceutical formulation, comprises by phenylephrine, ketorolac and buffer system at water carrier.Wherein this preparation preservative free and antioxidant, and store at the temperature of 5 ± 3 DEG C to 25 ± 2 DEG C, be stable at least 6 months.Wherein buffer system gets selection from sodium phosphate buffer system and sodium citrate buffer system, and what this preparation before use can be stable is expelled in a kind of ophthalmic flush vehicle, for rinsing eye inner tissue in operation.Avoid the potential side effect relevant with antioxidant with highly stable antiseptic.
This patent well avoids the potential side effect relevant with the application of antioxidant of highly stable antiseptic, except main component ketorolac and phenylephrine, adds buffer system, regulates pH with hydrochloric acid or sodium hydroxide.
The buffer system combined by weak acid and salt thereof has cushioning effect, mainly contains the systems such as borate, phosphoric acid, citric acid, carbonic acid, acetic acid at biochemical laboratory buffer system usually.In drug research work, we make formulation and technology simple possible as far as possible, general all more prudent to the selection of antioxidant, antiseptic and buffer system.Because the factor sometimes affecting experimental result is not the pH value of buffer, but certain ion in buffer.As the buffer agents such as borate, citrate, phosphate and Pehanorm all may produce unwanted chemical reaction.As borate can form double salt, as sucrose with chemical compound lot, citrate ion is easily combined with calcium (so can not use when having calcium ion), phosphate some experiment in be enzyme inhibitor or or even a metabolite, heavy metal is easily precipitated out in the form of phosphate from solution.
Our emphasis has searched the related content of sodium phosphate buffer system and sodium citrate buffer system.Known according to adjuvant data base querying in CDE, sodium dihydrogen phosphate is ackd salt, can not apply, can make carbonate effervescent with alkaline matter and carbonate compatibility.With aluminum, calcium or magnesium salt and use, because these salt can be combined with phosphate, gastrointestinal can not be affected and absorbs, and when calcium ion and phosphate hybrid injection use, insoluble calcium phosphate precipitation can be formed; And citric acid acid sodium dihydrate is in storage, its aqueous solution may attack glass container and cause the separation of comminutions.And our packaging is glass container substantially, there is potential danger.Its aqueous solution has alkalescence, can react with acidic materials.Alkaloid salt may precipitate by its aqueous solution or water-ethanol solution, and calcium salt and strontium salt will with corresponding citrate effects and form sediment in the vast expense of water.We think that citrate buffer system has the probability producing particulate matter.
The display of above data, phosphate buffer and citrate buffer system be applied in compatibility and container aspect, all have some potential risks.
The more simple formulation and technology of development, preparation contains the compositions of phenylephrine and ketorolac, and making this medicine safer, effective, is object of the present invention.
Summary of the invention
Object of the present invention is comprising sterile liquid formulations of iridodilator phenylephrine and anti-inflammatory agent ketorolac and preparation method thereof to provide a kind of.
Phenylephrine ketorolac solution of the present invention be in water carrier containing effective ingredient be phenylephrine and ketorolac, wherein this preparation is without buffer system.
The present invention is in phenylephrine ketorolac solution formulation study and development process, wonderful discovery, waterborne compositions containing phenylephrine hydrochloride, ketorolac tromethamine, sterilized water and pH adjusting agent prepares the effective concentrated solution of stability and safety when not adding buffer system, can reach the effect of the superposition of two kinds of drug effects.Prove that prescription stability indicator of the present invention is better than using the prescription of citrate buffer by experiment, decrease the application of adjuvant simultaneously, the safety of drug irrigation can be increased, prove that composing prescription preparation of the present invention is better than patent prescription preparation in particulate matter by experiment, along with the prolongation of storage time, particulate matter number is all less than patent prescription preparation.Its beneficial effect is shown in embodiment 3-7.
Phenylephrine ketorolac solution of the present invention, is the phenylephrine hydrochloride of 0.769-1.271% (w/v) containing the amount based on phenylephrine, is preferably 1.016% (w/v); Amount based on ketorolac is the ketorolac tromethamine of 0.217-0.358% (w/v), is preferably 0.288% (w/v).
Phenylephrine ketorolac solution of the present invention, regulate pH with hydrochloric acid or sodium hydroxide, pH value range is 5.3-7.3, is preferably 5.8-6.8.
Phenylephrine ketorolac solution of the present invention, dense volume of joining is 50% to 80%, is preferably 60%.
Phenylephrine ketorolac solution of the present invention, the consumption of active carbon is 0.025-0.1% (w/v), and whipping temp is 50 ± 10 DEG C, and mixing time is 10-30min.Preferred activated carbon dosage is 0.05%, and whipping temp is 50 DEG C, and mixing time is 20min.
Phenylephrine ketorolac solution of the present invention, pH adjusting agent is hydrochloric acid or sodium hydroxide.
In the present invention, w/v refers to the quantity that unit of weight in every 1 ml volumes is gram, i.e. g/ml.
The preparation method of phenylephrine ketorolac solution of the present invention is realized by step below: taking based on phenylephrine amount by recipe quantity is the phenylephrine hydrochloride of 0.769-1.271% (w/v), amount based on ketorolac is the ketorolac tromethamine of 0.217-0.358% (w/v), join batch cumulative volume 50-80% to be cooled in the water for injection of 50 ± 10 DEG C, stirring and dissolving is complete.Add the needle-like active carbon of 0.025-0.1% (w/v), at 50 ± 10 DEG C, stir 10-30min, coarse filtration, then use 0.22 μm of filtering with microporous membrane.Regulate pH to about 6.3 with hydrochloric acid solution or sodium hydroxide solution, stir 5-10min, detect the pH (5.8-6.8) of medicinal liquid, detect by intermediate quality standard, qualified rear inflated with nitrogen protection embedding in the ampoule of 5ml, 121 DEG C of autoclaving 12-20min.By ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely, packaging.
Phenylephrine ketorolac solution provided by the invention may be used in cataract or crystal replacement operation, uses as flushing liquor, can prevent platycoria and alleviation postoperative pain in art.
The preparation method of phenylephrine ketorolac solution provided by the invention, the injection prepared is safe, stable, effective.
Specific embodiments
Following case study on implementation is used for illustrating the present invention further, but does not limit the scope of the invention.
Embodiment 1: one of preparation of phenylephrine ketorolac solution
(4ml: phenylephrine 40.64mg and ketorolac 11.52mg)
Remarks: phenylephrine hydrochloride feeds intake by 100%, ketorolac tromethamine feeds intake by 104%.
Preparation technology: take phenylephrine hydrochloride 49.6g, ketorolac tromethamine 17.64g by recipe quantity, join in the water for injection of 50 DEG C, stirring and dissolving is complete.With the needle-use activated carbon of 0.05% (w/v), 50 DEG C are stirred 20min.By the filter membrane coarse filtration of 0.45 μm, filtrate regulates pH to about 6.3 with the hydrochloric acid solution of the sodium hydroxide solution of 1% (w/v) or 1M after 0.22 μm of membrane filtration, and finally add water for injection and be settled to 4000ml, intermediate detects.Logical nitrogen protection, embedding is in 5ml ampoule bottle, and 4ml/ props up.121 DEG C, 15min high pressure steam sterilization, leak detection, by ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely.
Embodiment 2: according to the prescription in WO2014066485A1, prepares phenylephrine ketorolac solution.
(4ml: phenylephrine 40.64mg and ketorolac 11.52mg)
Remarks: phenylephrine hydrochloride feeds intake by 100%, ketorolac tromethamine feeds intake by 104%.
Preparation technology: take phenylephrine hydrochloride 49.6g, ketorolac tromethamine 17.64g, citric acid (monohydrate) 0.96g, sodium citrate (dihydrate) 23.53g by recipe quantity, join in the water for injection of 50 DEG C, stirring and dissolving is complete.With the needle-use activated carbon of 0.05% (w/v), 50 DEG C are stirred 20min.By the filter membrane coarse filtration of 0.45 μm, filtrate regulates pH to about 6.3 with the hydrochloric acid solution of the sodium hydroxide solution of 1% (w/v) or 1M after 0.22 μm of membrane filtration, and finally add water for injection and be settled to 4000ml, intermediate detects.Logical nitrogen protection, embedding is in 5ml ampoule bottle, and 4ml/ props up.121 DEG C, 15min high pressure steam sterilization, leak detection, by ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely.
Embodiment 3: in the preparation process of embodiment 1 and embodiment 2, we investigate pH value.And with reference to medicine stability guideline, the sample that embodiment 1 and embodiment 2 are prepared is carried out factors influencing respectively, placed under the condition of temperature 60 C and illumination 4500 ± 500lx, took out sample at the 5th day, 10 days respectively and carry out pH detection.The results are shown in Table 1.
Table 1 is from grinding and the change of patent prescription at preparation process and factors influencing pH
Result of the test shows: certainly grind prescription and patent prescription after preparation process adjustment pH and high temperature 60 DEG C, illumination 4500 ± 500lx two conditions place 5 days, 10 days pH value all more stable.Prove thus, certainly grind prescription in the application reducing adjuvant, when not adding buffer system, also can have more stable pH value.
Embodiment 4: with reference to medicine stability guideline, we have carried out factors influencing test to the phenylephrine ketorolac solution prepared by embodiment 1 and embodiment 2.Under the condition of temperature 60 C and illumination 4500 ± 500lx, carry out the primary contributions factorial experiments of 10 days respectively, sample is detected, the results are shown in Table 2.
Table 2 is from grinding prescription and patent formula preparation sample 0 day testing result
Table 3 is from grinding prescription and patent formula preparation sample effects factor 10 daylight result
Result of the test shows: certainly grind the sample that prescription is prepared through identical technique with patent prescription, and character when detecting for 0 day, pH, visible foreign matters, particulate matter, content, related substance aspect are all qualified, basic zero difference.Under high temperature and strong illumination condition 10 days, outward appearance and pH value were all without significantly changing, and stable content, related substance, all in controlled range, shows that this product has good stability, and the related substance certainly grinding prescription sample is slightly better than patent prescription sample.
Embodiment 5: the phenylephrine ketorolac solution prepared by embodiment 1 has been carried out the compatibility mechanism of the balanced salt solution commonly used with ophthalmologic operation by us, by the self-control preparation diluent of 4ml in the ophthalmic douche can fluid injection of 500ml, investigate 0h, 2h, 4h, 8h respectively, the sample of cold preservation 2h, 4h, 8h, 16h, 24h, detect, the results are shown in Table 4 and table 5.
Table 4 phenylephrine ketorolac solution and ophthalmic douche can fluid injection compatibility test result (room temperature)
Table 5 phenylephrine ketorolac solution and ophthalmic douche can fluid injection compatibility test result (cold preservation)
Result of the test shows: after certainly grinding the compatibility of prescription preparation and the fluid injection of ophthalmic douche can, in room temperature 8h cold preservation 24h, pH value, visible foreign matters, particulate matter etc. all conform with the regulations, and content and related substance are all more stable, its compatibility is good, can be applied in ophthalmologic operation preferably.
Embodiment 6: phenylephrine ketorolac solution toxicology test
For understanding the safety of phenylephrine ketorolac solution, we have carried out eye irritant test according to " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline " (issue on May 13rd, 2014).Get healthy white rabbit 4, carry out ophthalmologic operation.In art, the phenylephrine ketorolac solution 4ml of left eye the invention process case 1 preparation is diluted in the ophthalmic douche can fluid injection of 500ml and rinses eyes, and right eye directly does contrast with the fluid injection of ophthalmic douche can and rinses eyes.Be that slit lamp observation was to the irritative response of conjunctiva, cornea, iris with fluorescent staining in after administration 1,2,4,24,48 and 72 hour respectively at single-dose.
Each inspection all should record eye abnormal response, calculates score value according to table 6.Stimulation degree is judged according to table 7.
Table 6 Eye irritation reaction score criteria
| Eye irritation reacts | Score value |
| Cornea | |
| Without muddy | 0 |
| Be dispersed in or diffusivity muddiness, iris is high-visible | 1 |
| Translucent areas is easily differentiated, and iris is smudgy | 2 |
| Occur canescence translucent areas, iris details is unclear, and pupil size is visible reluctantly | 3 |
| Cornea is opaque, and iris is beyond recognition | 4 |
| Iris | |
| Normally | 0 |
| Gauffer is obviously deepened, congested, swelling, and mild hyperaemia around cornea, pupil still responds to light | 1 |
| Eye irritation reacts | Score value |
| The visible necrosis of hemorrhage/naked eyes/to light reactionless (or wherein a kind of) | 2 |
| Conjunctiva | |
| Congested (referring to palpebral conjunctiva and bulbar conjunctiva) | |
| Blood vessel is normal | 0 |
| The congestion of blood vessel is cerise | 1 |
| The congestion of blood vessel is peony, and blood vessel is not easily differentiated | 2 |
| Diffusivity hyperemia is in aubergine | 3 |
| Edema | |
| Without edema | 0 |
| Slight edema (containing eyelid) | 1 |
| Obvious edema companion part ectropion of lid | 2 |
| Edema is to the nearly semi-closed of eyelid | 3 |
| Edema exceedes semi-closed to eyelid | 4 |
| Secretions | |
| Without secretions | 0 |
| A small amount of secretions | 1 |
| Secretions makes eyelid and eyelashes are moist or adhesion | 2 |
| Secretions makes whole eye district humidity or adhesion | 3 |
| Maximum total mark | 16 |
Table 7 eye irritation evaluation criterion
| Score value | Evaluate |
| 0-3 | Nonirritant |
| 4-8 | Slight zest |
| 9-12 | Moderate zest |
| 13-16 | Severe zest |
Scoring results is in table 8:
Table 8 phenylephrine ketorolac solution eye irritation result of the test
Conclusion: to testing result with score value statistical calculations, the embodiment of the present invention 1 and eye irrigation infusion liquid after single-dose, equal nonirritant.Illustrate that the safety of prescription of the present invention is good.
Embodiment 7: the investigation of phenylephrine ketorolac solution particulate matter.
Phenylephrine ketorolac solution room temperature reserved sample observing embodiment 1 and embodiment 2 prepared, regularly took out sample in 24 months.Carry out pH value, clarity test, and the light blockage method adopting Chinese Pharmacopoeia to specify, check visible foreign matters and particulate matter.
After 24 months, the stability of solution of certainly grinding prescription preparation and patent prescription patent compares
Table 9 is from grinding prescription and patent formula preparation sample particulate matter investigation result
Result shows: certainly grind prescription preparation in particulate matter, be better than patent prescription preparation, along with the prolongation of storage time, particulate matter number is all less than patent prescription preparation.
Embodiment 8: the preparation two of phenylephrine ketorolac solution
(4ml: phenylephrine 40.64mg and ketorolac 11.52mg)
Remarks: phenylephrine hydrochloride feeds intake by 98%, ketorolac tromethamine feeds intake by 102%.
Preparation technology: take phenylephrine hydrochloride 48.61g, ketorolac tromethamine 17.30g by recipe quantity, join in the water for injection of 40 DEG C, stirring and dissolving is complete.With the needle-use activated carbon of 0.025% (w/v), 40 DEG C are stirred 10min.By the filter membrane coarse filtration of 0.45 μm, filtrate regulates pH to about 5.8 with the hydrochloric acid solution of the sodium hydroxide solution of 1% (w/v) or 1M after 0.22 μm of membrane filtration, and finally add water for injection and be settled to 4000ml, intermediate detects.Logical nitrogen protection, embedding is in 5ml ampoule bottle, and 4ml/ props up.121 DEG C, 15min high pressure steam sterilization, leak detection, by ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely.
Embodiment 9: the preparation three of phenylephrine ketorolac solution
(4ml: phenylephrine 40.64mg and ketorolac 11.52mg)
Remarks: phenylephrine hydrochloride feeds intake by 102%, ketorolac tromethamine feeds intake by 106%.
Preparation technology: take phenylephrine hydrochloride 50.59g, ketorolac tromethamine 17.98g by recipe quantity, join in the water for injection of 60 DEG C, stirring and dissolving is complete.With the needle-use activated carbon of 0.1% (w/v), 60 DEG C are stirred 30min.By the filter membrane coarse filtration of 0.45 μm, filtrate regulates pH to about 6.8 with the hydrochloric acid solution of the sodium hydroxide solution of 1% (w/v) or 1M after 0.22 μm of membrane filtration, and finally add water for injection and be settled to 4000ml, intermediate detects.Logical nitrogen protection, embedding is in 5ml ampoule bottle, and 4ml/ props up.121 DEG C, 15min high pressure steam sterilization, leak detection, by ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely.
Claims (7)
1. an aseptic liquid pharmaceutical formulation, its component is: phenylephrine hydrochloride, ketorolac tromethamine, water.
2. liquid preparation according to claim 1, it is characterized in that: its amount containing based on phenylephrine is the phenylephrine hydrochloride of 0.769-1.271% (w/v), and the amount based on ketorolac is the ketorolac tromethamine of 0.217-0.358% (w/v).
3. liquid preparation according to claim 2, is characterized in that: its amount containing based on phenylephrine is the phenylephrine hydrochloride of 1.016% (w/v) and is the ketorolac tromethamine of 0.288% (w/v) based on the amount of ketorolac.
4. liquid preparation according to claim 1, is characterized in that: the scope using hydrochloric acid or sodium hydroxide adjustment pH, pH is 5.3-7.3.
5. liquid preparation according to claim 4, is characterized in that: the scope of pH is 5.8-6.8.
6. liquid preparation according to claim 1, is characterized in that: the consumption of active carbon is 0.025-0.1% (w/v), and whipping temp is 50 ± 10 DEG C, and mixing time is 10-30min.
7. the liquid preparation according to any one of claim 1-6, its preparation method is:
Taking based on phenylephrine amount by recipe quantity is the phenylephrine hydrochloride of 0.769-1.271% (w/v), amount based on ketorolac is the ketorolac tromethamine of 0.217-0.358% (w/v), join batch cumulative volume 50-80% to be cooled in the water for injection of 50 ± 10 DEG C, stirring and dissolving is complete.Add the needle-like active carbon of 0.025-0.1% (w/v), at 50 ± 10 DEG C, stir 10-30min, coarse filtration, then use 0.22 μm of filtering with microporous membrane.PH to 5.8-6.8 is regulated with hydrochloric acid solution or sodium hydroxide solution; stir 5-10min, detect the pH (5.8-6.8) of medicinal liquid, detect by intermediate quality standard; qualified rear inflated with nitrogen protects embedding in the ampoule of 5ml, 121 DEG C of autoclaving 12-20min.By ampoule by Zhi Jinhang lamp inspection, sampling is examined entirely, packaging.
Wherein, w/v refers to the quantity that unit of weight in every 1 ml volumes is gram, i.e. g/ml.
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| CN111388468A (en) * | 2020-04-24 | 2020-07-10 | 鲁南制药集团股份有限公司 | Application of ketorolac tromethamine in preparation of drugs for treating mental diseases |
| US11234965B2 (en) | 2014-12-01 | 2022-02-01 | Omeros Corporation | Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions |
| US20230042072A1 (en) * | 2021-07-23 | 2023-02-09 | Somerset Therapeutics, Llc | Buffer-free, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
| US12029729B2 (en) | 2021-07-23 | 2024-07-09 | Somerset Therapeutics, Llc | Chelated, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
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| CN101327325A (en) * | 2002-07-30 | 2008-12-24 | 奥默罗斯公司 | Ophthalmologic irrigation solutions and method |
| WO2014015183A1 (en) * | 2012-07-19 | 2014-01-23 | JUANG, Agnes | Ophthalmic formulation and method for ameliorating presbyopia |
| WO2014066485A1 (en) * | 2012-10-24 | 2014-05-01 | Omeros Corporation | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
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| CN101327325A (en) * | 2002-07-30 | 2008-12-24 | 奥默罗斯公司 | Ophthalmologic irrigation solutions and method |
| WO2014015183A1 (en) * | 2012-07-19 | 2014-01-23 | JUANG, Agnes | Ophthalmic formulation and method for ameliorating presbyopia |
| WO2014066485A1 (en) * | 2012-10-24 | 2014-05-01 | Omeros Corporation | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11234965B2 (en) | 2014-12-01 | 2022-02-01 | Omeros Corporation | Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions |
| US12167999B2 (en) | 2014-12-01 | 2024-12-17 | Rayner Intraocular Lenses Limited | Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions |
| CN111388468A (en) * | 2020-04-24 | 2020-07-10 | 鲁南制药集团股份有限公司 | Application of ketorolac tromethamine in preparation of drugs for treating mental diseases |
| US20230042072A1 (en) * | 2021-07-23 | 2023-02-09 | Somerset Therapeutics, Llc | Buffer-free, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
| US20230039551A1 (en) * | 2021-07-23 | 2023-02-09 | Somerset Therapeutics, Llc | Buffer- and chelator-free, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
| US11696910B2 (en) * | 2021-07-23 | 2023-07-11 | Somerset Therapeutics, Llc | Buffer-free, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
| US11883382B2 (en) * | 2021-07-23 | 2024-01-30 | Somerset Therapeutics, Llc | Buffer-free ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
| US12029729B2 (en) | 2021-07-23 | 2024-07-09 | Somerset Therapeutics, Llc | Chelated, stable ophthalmological compositions of ketorolac and phenylephrine and applications thereof |
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