CN1785192A - Eye-drops prepns. contg. tetrandrine and its application for preparing medicine therewith - Google Patents
Eye-drops prepns. contg. tetrandrine and its application for preparing medicine therewith Download PDFInfo
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Abstract
An eye medicine containing tetrandrine for treating ophthalmitis, allergic ophthalmopathy, glaucoma, catarart, etc is prepared from tetrandrine (0.001-2 Wt%), other medicines (0-5), and excipient (93-99.999).
Description
Technical field
The present invention relates to the medicine configuration product of the organic active ingredient of isoquinoline-containing derivatives class, specifically is ophthalmic preparation and the application in the ophthalmic preparation that contains tetrandrine of preparation treatment ophthalmic diseases thereof that contains tetrandrine.
Background technology
In the mechanism of oculopathy, inflammation is the main pathophysiological processes of most of oculopathy, and becomes the major decision sexual factor of disease prognosis.Controlling inflammation is the cardinal principle of Eye disease treating, so inflammation inhibitor is the most frequently used medicine of ophthalmologists, so that control the progress of ophthalmic effectively, it is blind to avoid the patient finally to cause.
The cataract extraction postoperative often because of the reaction that is inflamed of factors such as blood aqueous humor destruction, often could recover through a long period.
Clinical available eye inflammation inhibitor has diclofenac sodium, meticorten and dexamethasone etc. at present.Diclofenac sodium belongs to non-steroid antiinflammatory drug, and local result of use is relatively poor, and the eye zest is bigger, is only applicable to the adjuvant drug of the light oculopathy of minority inflammation.Meticorten, dexamethasone belong to hormones, and the eye inflammation inhibitory action is stronger, clinical comparatively extensive use, but the side effect appearance is more, and harm is bigger, is easy to the recurrence and the state of an illness after the drug withdrawal repeatedly, and the state of an illness heavier person can't effectively control.
Glaucoma experiment section common disease, with high intraocular pressure is genius morbi, need life-time service intraocular pressure lowering medicine, part needs of patients operative treatment, the main reason of glaucoma filtration surgery failure is that the tired trace that filters bubble forms, 2 years mortalitys of postoperative are up to 15-30%, especially intractable glaucoma, the operative failure rate is higher, in recent years, the expert has studied the medicine that multiple anti-short trace forms both at home and abroad, as mitomycin, 5-fluorouracil etc. owing to there is not the standard method of application, cause the unreasonable use of this medicine, a lot of complication have been produced, so still need explore better glaucoma treatment medicine.
Fibroblast proliferation can cause some often intractable ophthalmics of recurrence on clinical ophthalmology.Even can cause losing one's sight, as glaucoma filtration surgery, filter road block again, ribbon rope formation etc. in the formation of wing arrow meat and recurrence, the penetration injuries of eyeball rear vitreous body.Its treatment is with corticosteroid medication such as dexamethasone.Antimetabolite such as 5-fluorine clothes noise made in coughing or vomiting are warm, ametycin etc. is main.But, limited its clinical practice because these poisonous side effect of medicine are too big.
Tetrandrine (tetrandrine, Tet) a kind of alkaloid for extracting in the menispermaceous plants Radix stephaniae tetrandrae root has another name called tetrandrine, can separate from Chinese medicine Radix Stephaniae Tetrandrae, Radix stephaniae tetrandrae or Radix Stephaniae Japonicae, be Bisbenzylisoquinolinderivative derivative, mainly be present in the root of Radix Stephaniae Tetrandrae plant Radix stephaniae tetrandrae.Studies show that it has antiinflammatory, analgesia, analgesic, antiallergic, blood pressure lowering, coronary artery dilating, multiple pharmacological effect such as anticancer.Tet begins to be used for the treatment of diseases such as hypertension, pneumosilicosis, hepatic fibrosis the seventies, obtained better curative effect.
National drug standards WS-10001-(HD) 11001-2002 of National Drug Administration's promulgation classifies tetrandrine as rheumatism medicament used as adjuvant drug for antitumor.Tetrandrine tablet WS-10001-(HD-0700)-2002 mostly is coated tablet or Film coated tablets; The main component of tetrandrine injection WS-10001-(HD) 1380-2003 is that tetrandrine hydrochloride (HCMN) 15g, sodium pyrosulfite 1g, sodium chloride 5g, dilute hydrochloric acid are an amount of, disodium edetate, 0.3g, water for injection are an amount of.
Still there is not the report of using the ophthalmic preparation that contains tetrandrine both at home and abroad.
Summary of the invention
The present invention be for glaucoma after solving ophthalmia disease, operation back ophthalmia disease, anaphylaxis ophthalmic, intraocular pressure lowering treatment glaucoma and suppressing the cicatrization iatrotechnics, after the effective treatment of cataract, retina vitreous body proliferative lesion of turning white, and provide a kind of ophthalmic preparation and application in the ophthalmic preparation that contains tetrandrine of preparation treatment ophthalmic diseases thereof that contains tetrandrine.
Theoretical foundation of the present invention,
Tetrandrine is a kind of alkaloid, use separately or with combination with medication (medicine except that tetrandrine such as antibacterials or hormone or anti-inflammatory agent or antihistaminic or immunoregulation medicament or vitamins or nutrient drug or with blood circulation promoting medicine or Chinese medicine and effective ingredient thereof) compatibility use to treatment ophthalmia disease, operation back ophthalmia disease, anaphylaxis ophthalmic, intraocular pressure lowering treat glaucoma after glaucoma and the inhibition cicatrization iatrotechnics, after turn white cataract, retina vitreous body proliferative lesion good curative effect is arranged.
The ophthalmic preparation that contains tetrandrine can be made solution, perhaps makes suspensoid, perhaps makes the milkiness liquid preparation, perhaps makes Eye ointments, perhaps ocular inserts.
Tetrandrine is water insoluble, for this reason, makes aqueous solution a kind of dissolved lytic agent of tetrandrine that makes must be provided, through screening, demineralizing acid, or sulphuric acid, or nitric acid, or outside the phosphoric acid, acetic acid, or carbonic acid, or citric acid, or salicylic acid, or maleic acid, or tartaric acid, or hydrobromic acid or succinic acid also are a kind of comparatively ideal cosolvents.Sodium pyrosulfite is an antioxidant.Disodium edetate is the complexing of metal ion agent, can eliminate the influence of the metal ion that may exist in the solution, increases the stability of eye drop of the present invention.Sodium chloride is osmotic pressure regulator.Hibitane is an antibacterial, to improve the effect duration of eye drop of the present invention.Methylcellulose, or hyprolose, or ethyl cellulose, or hydroxyethyl-cellulose or hyaluronic acid sodium or carbomer be thickening agent, can prolong drug retention time within the eye.Keatolytics Borneolum Syntheticum or Mentholum can promote that medicine penetrates to ocular tissue.
The present invention realizes by following technical scheme.
A kind of ophthalmic preparation that contains tetrandrine, the weight percent content of each raw material components of said preparation is:
Tetrandrine: Radix stephaniae tetrandrae ground caustic 0.001-2%,
Combination with medication: the levofloxacin hydrochloride 0-5% in the anti-microbial type,
Excipient: water for injection 93-99.999g.
The described ophthalmic preparation that contains tetrandrine, the excipient in its tetrandrine eye ointment is lanoline 0-20%, liquid paraffin 0-20% and vaseline add to 1000g.
The described ophthalmic preparation that contains tetrandrine, its tetrandrine type gel-type eye ointment adds substrate: ethyl cellulose sodium 0.1-10%.
The described ophthalmic preparation that contains tetrandrine, it contains in the collyrium of water for injection and also contains:
The complexing of metal ion agent: disodium edetate 0-5%,
Osmotic pressure regulator: sodium chloride 0-10%,
Cosolvent: hydrochloric acid 0.1-2mol/L 0.05-50ml,
Thickening agent: hydroxy methocel 0-5%,
Keatolytics: Borneolum Syntheticum 0-5%,
Antioxidant: sodium pyrosulfite 0-5%.
The described ophthalmic preparation that contains tetrandrine, it contains in the gel-type eye ointment of thickening agent hydroxy methocel 0-5% and also contains:
The complexing of metal ion agent: disodium edetate 0-5%,
Osmotic pressure regulator: sodium chloride 0-10%,
Cosolvent: hydrochloric acid 0.1-2mol/L 0.05-50ml,
Keatolytics: Borneolum Syntheticum 0-5%,
Antioxidant: sodium pyrosulfite 0-5%.
The described ophthalmic preparation that contains tetrandrine, its combination with medication are the erythromycin in the anti-microbial type, or kanamycin, or gentamycin, or amikacin, or tobramycin, or Sisomicin, or netilmicin, or micronomicin, or isepamicin, or astromicin, or etimicin, or spectinomycin, or neomycin, or paromomycin, or tetracycline, or doxycycline, or minocycline, or sulphacetamide, or norfloxacin, or ofloxacin, or levofloxacin, or enoxacin, or ciprofloxacin, or lomefloxacin, or pefloxacin, or Lu's Flucloxacillin, or sparfloxacin, or fleroxacin, or moxifloxacin, or rifampicin, or metronidazole, or tinidazole, or the acyclovir of antiviral apoplexy due to endogenous wind, or ganciclovir, or valaciclovir, or ribavirin; Or the dexamethasone phosphate in the hormones, or fluorometholone powder, or hydrocortisone, or methyl meticortelone, or dexamethasone, or betamethasone, fluocinolone acetonide, or beclometasone, or halcinonide, or fluticasone; Or the vitamin B in the vitamins
1, or vitamin B
2, or vitamin B
6, or vitamin B
12, or vitamin C, or nicotiamide, or folic acid; Or the indomethacin of anti-inflammatory agent apoplexy due to endogenous wind, or ibuprofen, or meloxicam, or piroxicam, or diclofenac sodium, or the acetparaminosalol sweet smell, or nimesulide; Or the chlorphenamine in the antiallergic class medicine, or diphenhydramine, or tripelennamine, or levocabastine, or astemizole, or loratadine, or cetirizine, or terfenadine, or sodium cromoglicate, or zaprinast, or tranilast; Or the husky dynamics amine of immunomodulating apoplexy due to endogenous wind, or ciclosporin A, or the Radix Tripterygii Wilfordii total glycosides, or tacrolimus, or leflunomide, or cyclophosphamide, or methotrexate; Or the aminoacid in the nutrient drug; Or the nicotinic acid of microcirculation improvement apoplexy due to endogenous wind, or Inositol Hexanicotinate, or vinpocetine; Or the Herba Erigerontis in the middle pharmaceutically active ingredient, or puerarin, or ligustrazine, or garlicin, or berberine, or Radix Isatidis, or fibrauretin, or houttuynine sodium bisulfite, or punching is even, or Radix Sophorae Flavescentis total alkaloids.
The described ophthalmic preparation that contains tetrandrine, its antioxidant is a sodium sulfite, or sodium thiosulfate, or methionine (methionine), or thiourea, or butylated hydroxyarisol (BHA), or Butylated Hydroxytoluene (BHT), or nor-pair of hydrogen guaiaretic acid (CDGA), or tocopherol or gallate esters osmotic pressure regulator are boric acid, or sodium dihydrogen phosphate, or sodium hydrogen phosphate, or glucose; Thickening agent is a methylcellulose, or ethyl cellulose, or hydroxyethyl-cellulose, or propyl methocel, or hydroxypropyl emthylcellulose, or carboxymethyl cellulose, or hydroxypropyl cellulose, or above-mentioned sodium salt, or hyaluronic acid sodium, or carbomer; Keatolytics is a Mentholum; The 0-5% that is weight percentage of sodium pyrosulfite wherein; The 0.1-0.5% that sodium thiosulfate is weight percentage; Methylcellulose in the thickening agent, concentration range 0-10%; The hyprolose concentration range is 0-10%.
The described ophthalmic preparation that contains tetrandrine, its tetrandrine are the hydrochloric acid tetrandrine; The sulfate powder menispermine; Or nitric acid tetrandrine; Or phosphoric acid tetrandrine; Or acetic acid tetrandrine; Or carbonic acid tetrandrine; Or tartaric acid tetrandrine; Or hydrobromic acid tetrandrine; Or citric acid tetrandrine; Or succinic acid tetrandrine.
The described ophthalmic preparation that contains tetrandrine, its combination with medication belongs to the non-antibiotic time-like, add with antibacterial hibitane 0-5%, or bromination benzene first hydroxylamine 0-5%, or phenylmercuric nitrate 0-5%, or phenylmercuric acetate 0-5%, with 1/2 water 40-50 ℃ dissolving, or three glass container of packing into after the neoprene tertiary alcohol 0-5% heating for dissolving, or thimerosal 0-5% dissolving, or mercuric oxycyanide 0-5%, or the oxybenzene first, second, third, butyl ester 0-5%%, or phenethanol 0-5%, or sorbic acid 0-5%, or sorbic acid, or parabens 0-5%, or bromination benzalkonium 0-5%, or domiphen bromide 0-5%, or phenylmercuric nitrate 0-5%, or thimerosal 0-5%, or benzoic acid 0-5%, or phenethanol 0-5%.
A kind of application in the ophthalmic preparation that contains tetrandrine of preparation treatment ophthalmic diseases:
A. to experimental uveitic therapeutical effect, tetrandrine is faced upward the experimental uveitis of system, except its antiinflammatory action, also relevant with cell immune response with its inhibition body fluid, and do not cause knock-on after the drug withdrawal, tetrandrine also significantly suppresses the Mus uveitis that endotoxin and IL-1-α cause by the noncompetitive mode;
B. the effect of corneal inflammation, whole body powder application menispermine can be regulated the development of Mus herpetic keratitis to immunity/inflammatory reaction of virus by modifying the host, and tetrandrine is by suppressing the inflammatory reaction that IL-1 β generates cornea after the infection that alleviates the herpes simplex disease;
C. to the inhibitory action of uveitis before experimental, tetrandrine can significantly delay and suppress the inflammatory reaction of uveitis before the rabbit that crystalline protein causes, reduce prostaglandin E total amount in the iris, suppress leukocytic oozing out, and the intraocular pressure that can not raise, its anti-inflammatory mechanisms is main relevant with the calcium antagonism of tetrandrine;
D. the therapeutical effect of inflammation behind the ocular operation, tetrandrine can effectively suppress the inflammatory reaction of ultrasonic emulsification postoperative, alleviates aqueous humor protein content, promotes blood-aqueous barrier to recover;
E. to the effect of anaphylaxis ophthalmic, sinomenine has obviously suppressed the inflammatory reaction of conjunctiva, the oxyphil cell who has significantly alleviated conjunctiva is soaked into, and significantly reduced the mastocyte number of complete threshing, can adjust the anaphylaxis conjunctivitis that ragweed pollen causes significantly, the oxyphil cell who reduces conjunctiva significantly infiltrates and cytomegalic quantity complete and threshing, treatment anaphylaxis ophthalmic;
F. intraocular pressure lowering treatment glaucoma and suppress cicatrization and glaucoma after the iatrotechnics, 0.1% tetrandrine eye drop has the effect of remarkable reduction normal intra-ocular tension, 0.1% tetrandrine eye drop has remarkable reduction intraocular pressure, thereby has the effect of treatment glaucoma, 0.1% tetrandrine eye drop filters the cicatrization of bubble and other filtration surgery after having remarkable inhibition glaucoma operation, thereby has the glaucomatous effect of further treatment;
G. the cataract of turning white after suppressing forms, and tetrandrine can effectively suppress the formation of lagophthalmos lens extraction postoperative posterior lens capsule film muddiness, and the cataract of turning white after the inhibition forms;
H. suppress retina vitreous body proliferative lesion, the tetrandrine eye drop has certain preventive and therapeutic effect to experimental proliferative vitreoretinopathy.
The preparation method of tetrandrine eye drop is with the tetrandrine powder 0.001-2% 0.25mol hydrochloric acid 0.05-50ml dissolving of percentage by weight, obtains the tetrandrine hydrochlorate, and is standby; With non-antibiotic class combination with medication 0-5%, antibacterial hibitane 0-5%, keatolytics Borneolum Syntheticum 0-5% are dissolved in 40-80 ℃ the water for injection, add antioxidant sodium pyrosulfite 0-5%, complexing of metal ion agent disodium edetate 0-5% and osmotic pressure regulator sodium chloride 0-10% then, thickening agent-10% also stirs, after treating its cooling, with tetrandrine hydrochloric acid salt solution mix, add the injection water to 1000ml, mixing, filter, with 100 flowing steam sterilizations 30 minutes, packing, clear, the packing of inspection.
The preparation Preparation Method of tetrandrine eye ointment.
Earlier preparation eye ointment excipient is got liquid Paraffin 0-20% and placed suitable container with lid, and is in 150 ℃ of dry heat sterilizations 1 hour, standby; Other gets lanoline 0-20% and vaseline 60-100%, puts in the suitable container with lid, and heat fused adds the sterilization liquid Paraffin, mixing, and filtered while hot got final product through 150 ℃ of dry heat sterilizations in 1 hour in case of necessity,
Then, according to aseptic manipulation, get tetrandrine 0.001-2%, combination with medication 0-5%, place the adding of the suitable sterilization thin pasty state of liquid Paraffin furnishing of sterilizing on a small quantity, it is even with adding with stirring to 1000g that gradation adds the eye ointment excipient again, is sub-packed in the eye ointment pipe promptly.
The preparation Preparation Method of tetrandrine eye ointment.
Get tetrandrine 0.001-2%, combination with medication 0-5% puts in the suitable sterilization container, is ground into fine powder, crosses sieve No. 8, and is standby; Get the eye ointment excipient after the sterilization, heating makes eye pasting substrate keep molten state under aseptic condition, and tetrandrine fine powder sterile working is added, and stirs to ointment to form.
The preparation Preparation Method of tetrandrine eye ointment.
Get the hydrochloric acid that tetrandrine 0.001-2% adds concentration 0.1-2mol/L according to aseptic manipulation, 0.05-50ml dissolving adds that a small amount of excipient grinds and is absorbed fully to aqueous solution, adds residue sterilization eye pasting substrate more gradually.
The preparation method of tetrandrine type gel-type eye ointment.
Get the hydrochloric acid that tetrandrine 0.001-2% adds dilute concentration 0.1-2mol/L by weight percentage, the 0.05-50ml dissolving, standby; Other gets non-antibiotic class combination with medication 0.00-5%, antibacterial 0-5%, antioxidant 0-5%, metal chelating agent 0-5%, keatolytics 0-5% are dissolved in the suitable quantity of water, after adding the abundant swelling of carbomer 0.1-10%, add triethanolamine 10-17% and form the gel excipient, the tetrandrine that dissolving is good joins in the above-mentioned gel excipient, add the injection water to 1000g, mix homogeneously, deaeration; In 100-125 ℃ of flowing steam sterilization 30-60 minute, be sub-packed in after the cooling in the eye ointment pipe promptly.
The preparation method of tetrandrine type gel-type eye ointment.
Get the hydrochloric acid that tetrandrine 0.001-2% adds concentration 0.1-2mol/L by weight percentage, the 0.05-50ml dissolving is standby; Other gets non-antibiotic class combination with medication 0-5%, antibacterial 0-5%, antioxidant 0-5%, metal chelating agent 0-5%, keatolytics 0-5% are dissolved in the suitable quantity of water, in water-bath, be heated to 40-80 ℃, after adding the abundant swelling of cellulose family 20-50%, stirring and dissolving, the tetrandrine that dissolving is good joins in the above-mentioned gel excipient, adds the injection water to 1000g, mix homogeneously, deaeration.In 100-125 ℃ of flowing steam sterilization 30-60 minute, be sub-packed in after the cooling in the eye ointment pipe promptly.
Zhi Bei the present invention is through evidence like this, contains the ophthalmic preparation of tetrandrine and ophthalmic medicine that oneself has technology relatively, and it has the curative effect height, and stability of drug products is good, the advantage that side effect is little.
The specific embodiment
A kind of preparation method that contains the ophthalmic preparation of tetrandrine, its tetrandrine eye drop are that tetrandrine powder 1g is dissolved with 0.25mol hydrochloric acid 10-20ml, obtain the tetrandrine hydrochlorate, and be standby; With levofloxacin hydrochloride 3g, be dissolved in 50-70 ℃ the water for injection, add sodium pyrosulfite 1g, disodium edetate 0.3 and sodium chloride 6.3g and stirring then, after treating its cooling, mix, add the injection water to 1000ml with the tetrandrine hydrochlorate, mixing, filter, with 90-110 ℃ flowing steam sterilization 30-40 minute, packing, clear, the packing of inspection.
A kind of preparation method that contains the ophthalmic preparation of tetrandrine, its tetrandrine eye drop are that tetrandrine powder 1g is dissolved with 0.25mol hydrochloric acid 10-20ml, obtain the tetrandrine hydrochlorate, and be standby; With dexamethasone phosphate 3g, hibitane 0.3g, Borneolum Syntheticum 0.05g are dissolved in 50-70 ℃ the water for injection, add sodium pyrosulfite 1g, disodium edetate 0.3 and sodium chloride 6.3g then, methylcellulose 0.5g also stirs, treat its cooling after, mix with the tetrandrine hydrochlorate, add the injection water to 1000ml, mixing filters, with 90-110 ℃ of flowing steam sterilization 30-40 minute, packing, clear, the packing of inspection.
A kind of preparation method that contains the ophthalmic preparation of tetrandrine, its tetrandrine eye drop are that tetrandrine powder 1g is dissolved with 0.25mol hydrochloric acid 10-20ml, obtain the tetrandrine hydrochlorate, and be standby; With VITAMIN B15 g, hibitane 0.3g, Borneolum Syntheticum 0.05g are dissolved in 50-70 ℃ the water for injection, add sodium pyrosulfite 1g, disodium edetate 0.3 and sodium chloride 6.3g then, hyprolose 0.5g also stirs, treat its cooling after, mix with the tetrandrine hydrochlorate, add the injection water to 1000ml, mixing filters, with 90-110 ℃ of flowing steam sterilization 30-40 minute, packing, clear, the packing of inspection.
A kind of preparation method that contains the ophthalmic preparation of tetrandrine, its tetrandrine eye drop are that tetrandrine powder 1g is dissolved with 0.25mol hydrochloric acid 10-20ml, obtain the tetrandrine hydrochlorate, and be standby; Borneolum Syntheticum 0.05g is dissolved in 50-70 ℃ the water for injection, add cefoperazone 5g sodium pyrosulfite 1g, disodium edetate 0.3 and sodium chloride 6.3g then, hyprolose 0.5g also stirs, after treating its cooling, mix, add the injection water to 1000ml with the tetrandrine hydrochlorate, mixing, filter, with 90-110 ℃ flowing steam sterilization 30-40 minute, packing, clear, the packing of inspection.
A kind of preparation Preparation Method of tetrandrine eye ointment.
Earlier preparation eye ointment excipient is got liquid Paraffin 100g and placed suitable container with lid, and is in 140-160 ℃ of dry heat sterilization 1 hour, standby; Other gets lanoline 100g and vaseline 800g, puts in the suitable container with lid, and heat fused adds the sterilization liquid Paraffin, mixing, and filtered while hot got final product through 150 ℃ of dry heat sterilizations in 1 hour in case of necessity.
Then, according to aseptic manipulation, get tetrandrine 1g, fluorometholone powder 3g puts and adds a small amount of sterilization liquid Paraffin in the appropriate vessel of sterilization and be ground into thin pasty state, again gradation add the eye ointment excipient to 1000g with adding with grinding well, be sub-packed in the eye ointment pipe promptly.
A kind of preparation Preparation Method of tetrandrine eye ointment.
Get tetrandrine 1g and put in the sterilization mortar, be ground into fine powder, cross sieve No. 8, standby;
Get the eye ointment excipient after the sterilization, heating makes the eye ointment excipient keep molten state 99.4g under aseptic condition, and with tetrandrine fine powder 1g, the adding of erythromycin 5g sterile working stirs to ointment and forms.
A kind of preparation Preparation Method of tetrandrine eye ointment.
Get the hydrochloric acid 0.05-50ml dissolving that tetrandrine 1g adds concentration 0.1-2mol/L according to aseptic manipulation, add that a small amount of excipient grinds and absorbed fully to aqueous solution, add diphenhydramine 5g again, add residue sterilization eye ointment excipient more gradually to 1000g.
A kind of preparation method of tetrandrine type gel-type eye ointment.
Get tetrandrine 1g by weight percentage and add the hydrochloric acid 0.05-50ml dissolving of concentration 0.1-2mol/L, standby; Other gets tobramycin sulfate 3g, antioxidant sodium pyrosulfite 1g, metal chelating agent disodium edetate 0.3g, keatolytics Borneolum Syntheticum 0.05g are dissolved in the suitable quantity of water, after adding the abundant swelling of carbomer 40g, add triethanolamine 13.5g and form the gel excipient, the tetrandrine that dissolving is good joins in the above-mentioned gel excipient, add the injection water to 1000g, mix homogeneously, deaeration; In 100 ℃ of flowing steam sterilizations 30 minutes, be sub-packed in after the cooling in the eye ointment pipe promptly.
A kind of preparation method of tetrandrine type gel-type eye ointment.
Getting tetrandrine 1g by weight percentage, to add 0.25mol/ml hydrochloric acid 10-20ml dissolving standby; Other gets acyclovir 1g, antibacterial hibitane 0.3g, keatolytics Borneolum Syntheticum 0.05g, antioxidant sodium pyrosulfite 1g, metal chelating agent disodium edetate 0.3g are dissolved in the suitable quantity of water, in water-bath, be heated to 50-70 ℃, after adding the abundant swelling of sodium carboxymethyl cellulose 30g, stirring and dissolving, the tetrandrine that dissolving is good joins in the above-mentioned gel excipient, add injection water 1000g, mix homogeneously, deaeration. in 100 ℃ of flowing steam sterilizations 30 minutes, be sub-packed in after the cooling in the eye ointment pipe promptly.
Table 1 is listed to be the influence of hydrochloric acid addition to drug solubility.Get tetrandrine 0.1g, add not commensurability 0.5mol/L hydrochloric acid, make its dissolving, add and steam Evaporated water, observe the dissolving situation under room temperature and cryogenic conditions to the 100ml mixing.
Table 1 hydrochloric acid addition is to the influence of tetrandrine dissolubility:
| Addition ml | 0.3 | 0.4 | 0.5 | 0.6 |
| Room temperature | Dissolved particles not | Dissolved particles not | Dissolved particles not | Solution is clear and bright |
| Cryopreservation 24h | -- | -- | -- | Solution is clear and bright |
Variable concentrations hydrochloric acid is to the dissolved influence of tetrandrine.During screening, get tetrandrine 0.1g respectively, add variable concentrations etc. behind the dissolve with hydrochloric acid solution of amount adding distil water to 100ml, and get partly to do and strengthen (90 ℃ of transconversion into heat tests, 4h) and exposure experiments to light (daylight down irradiation 10 days), observe the variation of its outward appearance and pH value, the results are shown in Table 2.
The influence of table 2 variable concentrations hydrochloric acid:
| HCl(mol/L) | Illumination | 90℃ | pH | Operability |
| 0.125 | YG-1 | YG-3 | 3.99 | Better |
| 0,25 | YG-1 | YG-3 | 4.04 | Good |
| 0.5 | YG-1 | YG-3 | 4.11 | Better |
| 1 | YG-1 | YG-3 | 3.97 | Better |
| 2 | YG-1 | YG-3 | 4.09 | Good |
From above-mentioned table listed result as can be seen, concentration of hydrochloric acid is best with 0.25mol/L.
Antioxidant is to the influence of preparation stability.Press following five kinds of prescription formulated:
1, tetrandrine 0.1g with dissolving with hydrochloric acid after, adding distil water 100ml;
2, tetrandrine 0.1g with dissolving with hydrochloric acid after, add normal saline to 100ml;
3, compound method adds disodium edetate (EDTA) 0.03g with 1;
4, compound method adds sodium pyrosulfite 0.1g with 1;
5, compound method adds sodium pyrosulfite 0.1g and EDTA 0.03g with 1.
With the preparation of above-mentioned five kinds of prescription preparations do the heating strenuous test (90 ℃ or 80 ℃, 4h) and exposure experiments to light (daylight irradiation 10 days) down, observe its cosmetic variation, the results are shown in Table 3:
| Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | ||
| 90℃ | Colorimetric | YG-3 | YG-3 | YG-2 | YG-2 | YG-1 |
| 90℃ | Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright |
| 80℃ | Colorimetric | YG-1 | YG-1 | YG-1 | YG-1 | YG-1 |
| 80℃ | Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright |
| Exposure experiments to light | Colorimetric | YG-2 | YG-2 | YG-1 | YG-1 | YG-1 |
| Exposure experiments to light | Clarity | Clear and bright | Clear and bright | Clear and bright | Clear and bright | Clear and bright |
Table 3 antioxidant is to the influence of preparation stability
The above results shows that sodium pyrosulfite and EDTA share and can strengthen stability of formulation, selects prescription 5 to be advisable.
Preparation method:
1. get tetrandrine 1g, make the tetrandrine hydrochlorate with the 0.25mol/L dissolving with hydrochloric acid;
2. get in the water for injection that hibitane is dissolved in 70 ℃;
3. in liquor hibitane, add sodium pyrosulfite 1g, disodium edetate 0.3g, and sodium chloride 6,3g is also stirred, and makes it dissolving;
4. after treating the solution cooling of abovementioned steps, mix with the tetrandrine hydrochlorate, water for injection adds to 1000ml, and even mixing;
5. filter;
6. with 100 ℃ of flowing steam sterilizations 30 minutes;
7. packing, clear, the packing of inspection.
The study on the stability of Zhi Bei tetrandrine eye drop as stated above.The tetrandrine eye drop of preparation was placed under room temperature or the high temperature after 5 or 10 hours, observe outward appearance, PH and changes of contents, its result is as shown in table 4:
The stability test result of table 4 preparation under intensified condition
| 5h | 5h | 10h | 10h | ||
| Lot number | Condition | PH | Relative labelled amount % | PH | Relative labelled amount % |
| 1 | Room temperature | 4.86 | 99.95 | 4.90 | 99.60 |
| 2 | 4.90 | 100.30 | 4.89 | 99.51 | |
| 3 | 4.80 | 100.01 | 4.83 | 99.25 | |
| 1 | 80℃ | 4.80 | 100.13 | 4.90 | 98.83 |
| 2 | 4.92 | 97.45 | 4.78 | 100.51 | |
| 3 | 4.78 | 98.12 | 4.90 | 97.81 | |
| 1 | 90℃ | 4.84 | 100.11 | 4.86 | 97.83 |
| 2 | 4.89 | 101.79 | 4.80 | 99.25 | |
| 3 | 4.79 | 98.64 | 4.79 | 99.90 |
From result shown in the table 4, prove that Radix Stephaniae Tetrandrae first Chinese eye drop of the present invention does not all have significant change on outward appearance, pH value and content.
The application in the tetrandrine ophthalmic preparation of containing in preparation treatment ophthalmic diseases
One. experimental uveitic therapeutical effect:
Uveitis is a kind of common clinically autoimmune disease.Bring out the rabbit experiment uveitis with bovine serum albumin, tetrandrine (50mg/kgd, ip) and dexamethasone (5mg/kgd, ip) treatment 8d, can significantly reduce eye inflammation reaction, waterproof protein content, serum immune complex and peripheral T lymphocyte conversion ratio.Stop 4d after the administration, Dexamethasone group aqueous humor protein and serum immune complex raise once again.Though the tetrandrine group has rising, be evident as low than Dexamethasone group.Pathological examination finds that tetrandrine group venation inflammation is evident as gently than matched group.
The inflammation rank of each treated animal of table 5 (X ± SD)
| Group number | Group | The eye number | The inflammation rank | Suppression ratio % | F | P |
| 1 | Not medication | 12 | 3.75±0.75 | - | ||
| 2 | Dexamethasone | 12 | 1.08±0.51 | 71.2 | 36.21 | ＜0.001 |
| 3 | Tetrandrine | 12 | 1.42±0.51 | 62.1 |
Table 5 shows: tetrandrine does not relatively have significant difference to the inhibition and the dexamethasone of clinical inflammation feature.
The waterproof protein content of each treated animal of table 6 (X ± SD)
| Group number | Group | The eye number | The inflammation rank | Suppression ratio % | F | P |
| 1 | Normal control | 12 | 0.78±0.09 | - | ||
| 2 | Not medication | 12 | 14.33±1.21 | - | 91.18 | ＜0.01 |
| 3 | Dexamethasone | 12 | 4.43±1.64 | 73.8 | ||
| 4 | Tetrandrine | 12 | 5.95±1.63 | 61.8 |
Table 6 shows that the aqueous humor protein content of tetrandrine and dexamethasone does not have significant difference, all significantly is lower than the medication group, shows that tetrandrine has also obviously suppressed aqueous humor protein content and increased.
The result shows that tetrandrine suppresses experimental uveitis, and is also relevant with cell immune response with its inhibition body fluid except its antiinflammatory action, and do not cause knock-on after the drug withdrawal.Tetrandrine also significantly suppresses the Mus uveitis that endotoxin and IL-1-α cause by the noncompetitive mode.
Two. the effect of corneal inflammation:
Though cornea does not have blood vessel, immunoreactive various compositions such as immunoglobulin, complement, T cell, B cell etc. still are present in cornea, illustrate that cornea itself has normal immune system.Observe the effect of tetrandrine to the experimental herpes simplex keratitis of Mus by experiment, results suggest whole body powder application menispermine can be by modifying the development of host to immunity/inflammatory reaction adjusting Mus herpetic keratitis of virus.Further adopt the reverse transcription PCR method to detect the discovery normal cornea and do not express IL-1 β, TNF α mRNA, after viral infection is inflamed, then express the two.And it is infected but only express TNF α mRNA through the tetrandrine treatment person of not being inflamed.It is necessary that prompting local I L-1 β and TNF α expression of gene are that institute takes place keratitis, and tetrandrine is by suppressing the inflammatory reaction that IL-1 β generates cornea after the infection that alleviates the herpes simplex disease.
Three. to the inhibitory action of uveitis before experimental:
The preceding uveitis that crystalline protein causes mainly betides iris and corpus ciliare.Experiment shows that tetrandrine (50mg/kg) can significantly delay and suppress the inflammatory reaction of uveitis before the rabbit that crystalline protein causes, and prostaglandin E total amount in the reduction iris suppresses leukocytic oozing out, and the intraocular pressure that can not raise.Pathological examination finds that the inflammatory reaction of iris is obviously light than matched group, and local eye drip does not have obvious inhibitory action to the iris inflammation.Its anti-inflammatory mechanisms is main relevant with the calcium antagonism of tetrandrine.
Table 9 clinical manifestation scoring
| Group | N | Clinical score | The P value |
| Normal group | 20 | 0 | |
| Not medication group | 20 | 3.0±0.6 | |
| The buffer solution group | 20 | 2.9±0.5 | |
| The sinomenine group | 20 | 2.2±0.4 | ＜0.05* |
* with do not treat and cushion the treatment mouse relatively
Table 10 histopathology result
| Group | n | Acidophilia's property | Total rod cell | Non-graininess rod cell |
| The normal raising | 15 | 53±53 | 373±106 | 53±53 |
| Untreated | 15 | 2185±1545 | 906±319 | 373±213 |
| Buffer solution | 15 | 1919±906 | 853±266 | 319±159 |
| Tetrandrine | 15 | 768±421 ++ | 693±53 + | 106±106 + |
* every mm
2The cell number meansigma methods (± SD)
Statistics goes up effective difference (P＜0.05) between+treatment group and untreated or the buffer solution treatment group
++(P＜0.01)
Experiment shows that tetrandrine can effectively suppress the inflammatory corneal injury that I-type herpes simplex virus brings out in the BALB/C mice.SWR/J rathole conjunctiva forms allergic conjunctivitis after ragweed pollen sensitization, its symptom and histopathology characteristic remarkable reduce after the tetrandrine treatment.The above results shows that tetrandrine is to the conjunctivitis therapeutical effect.
Four. the therapeutical effect of inflammation behind the ocular operation:
To 20 capable simple eye crystalline lens ultrasonic emulsification enucleation of experimental rabbit, be divided into 2 groups at random, matched group drips normal saline every day, and experimental group drips compound recipe tetrandrine eye drop.Postoperative different time detection technique aqueous humor protein content.Two groups of aqueous humor protein content of postoperative 3d no significant difference (p＞0.05) as a result, two groups of aqueous humor protein content of postoperative 7d and 14d have notable difference (p＜0.01).
Reach postoperative different time aqueous humor protein content (mg/ml) before the art
| Before the art | 3d | 7d | 14d | 30d | |
| Matched group | 0.21±0.18 | 2.34±0.48 | 1.97±0.35 | 0.59±0.18 | 0.28±0.15 |
| Experimental group | 0.21±0.18 | 2.27±0.28 | 1.23±0.43 | 0.29±0.19 | 0.26±0.11 |
Conclusion: tetrandrine can effectively suppress the inflammatory reaction of ultrasonic emulsification postoperative, alleviates aqueous humor protein content, promotes blood-aqueous barrier to recover.
Five. to the effect of anaphylaxis ophthalmic:
The experimental conjunctivitis of sinomenine (TDR) has therapeutical effect.
The SWR/J mice group is as follows: group one is the normal control group; Group two is sensitization but does not treat group; Group three is buffering saline solution (BS) the treatment group of sensitization; Group four is the TDR treatment group of sensitization.The back is passed through local nose for three groups and is contacted artemisiifolia with the conjunctiva mucosa, and allergen excites the conjunctiva modeling.Group three and group four are accepted BS and TDR treatment respectively.Pass judgment on the anaphylaxis conjunctivitis curative effect by clinical sign and histopathology scoring.The mRNA gene expression of polymerase chain reaction,PCR (PCR) technical Analysis conjunctiva interleukin 1 β (IL-1 β) and IL-5.All confirm to suffer from anaphylaxis conjunctivitis on the clinical and histology of the mice of all artemisiifolia modelings.By giving the inflammatory reaction that TDR has obviously suppressed conjunctiva.Histopathological analysis proof TDR has significantly alleviated oxyphil cell's infiltration of conjunctiva, and has significantly reduced the mastocyte number of complete threshing.Compare with not treatment group and BS treatment group, TDR treatment group mice conjunctiva IL-1 β and IL-5mRNA gene expression are significantly reduced.See Table, the result shows that TDR treatment conjunctivitis has potent clinical effect.
Experiment shows, can adjust the anaphylaxis conjunctivitis that ragweed pollen causes significantly to injection powder menispermine in the mouse peritoneum.
The scoring of table 7 clinical sign
| Group | n | Clinical score | The p value |
| The normal control group | 20 | 0 | |
| Not treatment group | 20 | 3.0±0.7 | p＜0.05 * |
| BS treatment group | 20 | 2.9±0.4 | |
| TDR treatment group | 20 | 2.4±0.4 |
Between TDR treatment group and the not treatment group mice (p＜0.05), on (p＜0.05) statistics significant difference is arranged between TDR treatment group and the BS treatment group mice.
Table 8 histopathology is * as a result
| Group | n | The oxyphil cell | The mastocyte sum | The mastocyte number of threshing |
| Normally | 15 | 53.3±53.3 | 373.1±106.6 | 53.3±53.3 |
| Not treatment | 15 | 2185.3±1545.7 | 906.1±319.8 | 373.1±213.2 |
| BS | 15 | 1918.8±906.1 | 852.8±266.5 | 319.8±159.9 |
| TDR | 15 | 768.0±421.0 + | 639.6±53.3 + | 1061.6±106.6 ++ |
* be worth: average cell number/mm
3(± SD)
On (p＜0.05 and p＜0.01) statistics significant difference is arranged between TDR treatment group and not treatment group or the BS treatment group mice.
The oxyphil cell that histopathological analysis proof tetrandrine can reduce conjunctiva significantly infiltrates and cytomegalic quantity complete and threshing.Mice after the tetrandrine treatment, the gene expression of IL-1 β and IL-5mRNA has obvious downward modulation than the mice of buffer treatment.Treatment anaphylaxis ophthalmic
Six. intraocular pressure lowering treatment glaucoma and suppress cicatrization and glaucoma after the iatrotechnics:
Select body weight 2～3kg New Zealand white rabbit for use, the male and female dual-purpose.
1. tetrandrine is to the reduction effect of normal intraocular tension:
For examination 16 of animals (32 eyes), be divided into 4 groups at random, 8 eyes of 4 rabbits of 0.1% concentration group, 8 eyes of 0.2% concentration group, 8 eyes of 0.5% concentration group, 8 eyes of 1% concentration group.Experimental group is used 0.1%, 0.2%, 0.5%, 1% tetrandrine eye drop eye drip respectively, 0.5,1,2,4,8 hour mensuration intraocular pressure after (0 hour) and the administration before administration, and record intraocular pressure numerical value, the preceding intraocular pressure value of result and administration compares after the medication.
The result shows that 0.1% tetrandrine eye drop has reducing iop, reaches maximum drug effect after the medication about 2 hours, and significant difference has been analysed in credit by statistics.
The reduction intraocular pressure effect (n=8) of table 1 variable concentrations tetrandrine eye drop different time
| Concentration % | Intraocular pressure numerical value (x ± SD, mm Hg) | |||||
| 0h | 0.5h | 1h | 2h | 4h | 8h | |
| 0.1 | 12.64± 2.41 | 13.10± 2.21 | 11.32± 1.61 | 9.98±1.93 | 10.64± 2.04 | 11.82± 1.73 |
| 0.2 | 12.48± 1.51 | 13.82± 1.16 | 14.47± 0.59 | 12.93± 1.28 | 14.35± 2.37 | 13.93± 1.62 |
| 0.5 | 13.44± 1.93 | 14.00± 3.41 | 13.89± 2.26 | 13.83± 2.82 | 14.39± 2.62 | 13.94± 2.02 |
| 1 | 10.86± 3.17 | 11.69± 2.71 | 12.38± 2.62 | 13.25± 2.05 | 12.82± 2.06 | 12.04± 3.09 |
2. tetrandrine is to the reduction effect of experimental glaucoma (high intraocular pressure) intraocular pressure:
The preparation of high intraocular pressure animal model:
0.5% tetracaine eye liquid anesthetised animal, every eye extracts aqueous humor 0.1ml, injects 0.3% compound recipe carbomer solution 0.1ml subsequently.High Intraocular Pressure Model criterion: intraocular pressure＞22mmHg, persistent period＞1 week is for bringing out high intraocular pressure success.Measure intraocular pressure after the injection weekly 2 times, slit lamp is observed conjunctiva, cornea and iris inflammatory reaction down.
Grouping: 8 eyes of 4 rabbits of 0.1% concentration group, 8 eyes of 0.2% concentration group, 8 eyes of 0.5% concentration group, 8 eyes of 1% concentration group.Experimental group is used 0.1%, 0.2%, 0.5%, 1% tetrandrine eye drop eye drip respectively, 0.5,1,2,4,8 hour mensuration intraocular pressure after (0 hour) and the administration before administration, and record intraocular pressure numerical value, the preceding intraocular pressure value of result and administration compares after the medication.
The result shows that 0.1% tetrandrine eye drop has reducing iop to experimental high intraocular pressure, reaches maximum drug effect after the medication about 2 hours, and credit is analysed and had significant difference (P＜0.05) by statistics.
The reduction intraocular pressure effect (n=8) of variable concentrations tetrandrine eye drop different time
| Concentration % | Intraocular pressure numerical value (x ± SD, mm Hg) | |||||
| 0h | 0.5h | 1h | 2h | 4h | 8h | |
| 0.1 | 17.62± 2.81 | 18.16± 2.33 | 16.11± 1.69 | 14.44± 1.90 | 15.99± 2.11 | 16.82± 1.79 |
| 0.2 | 18.59± 1.91 | 18.68± 1.76 | 19.06± 0.99 | 17.89± 1.08 | 19.02± 2.16 | 18.93± 1.92 |
| 0.5 | 18.21± 1.83 | 19.75± 2.18 | 18.63± 2.26 | 18.50± 2.52 | 18.93± 2.67 | 18.49± 2.37 |
| 1 | 15.98± 2.07 | 16.96± 2.70 | 16.73± 2.60 | 16.91± 2.55 | 16.89± 2.14 | 17.04± 2.79 |
3. the tetrandrine eye drop suppresses the cicatrization behind the glaucoma operation
The preparation of animal model
Get 20 of experimental rabbits (40 eyes) conventional method and carry out micro-trabeculectomy, with 3% pentobarbital sodium (1mg/kg body weight) anterior auricular veins and ketamine (30mg/kg body weight) intramuscular injection, look into the optical fundus under the general anesthesia, measure intraocular pressure with tonometer, add and drip 1% tetracain hydrochloride 2 times, the trabeculectomy that the equal professional etiquette model of eyes is unified (routine is done subscleral sclerectomy, sews up conjunctival flap), right eye is experimental group (a tetrandrine eye drop), and 20 of left eyes are matched group (mitomycin group).With being soaked with the sponge block contact sclera bed of 3mm * 4mm of mitomycin of 0.2mg/ml and conjunctival flap following 5 minutes, remove sponge block, fully wash the mitomycin contact area with the 40-60ml normal saline immediately.All postoperatives drip uses the antibiotic eye dripping, and one day 3 times, week back drug withdrawal.
The treatment of tetrandrine eye drop is organized in used after operation 0.1% tetrandrine eye drop eye drip, every day 4 times, medication 14d.
In postoperative 1d, 7d, 2wk, 3wk, January, February, the observation eye hyperemia down of regular slit lamp microscope in March, filtration bubble, anterior chamber's depth etc.Measure intraocular pressure with tonometer.Filter bubble: filter the bubble typing and press the Kronfeld method, the I type is small vesicle type; The II type is for filling the air platypelloid type; The III type is for lacking as type; The IV type is a coated.I II type is functional filtration bubble, and III, IV type are that non-functional filters bubble.Get respectively in postoperative February, March filter mouthful near a sclera undertissue place 2% pentanedial liquid, do tissue pathology checking.
The result
1. the intraocular pressure situation sees Table 1.
Table 1 experimental group and matched group intraocular pressure be (mmHg) relatively
| Group | Intraocular Pressure Values (x ± s) | |||
| Before the art | Postoperative 7d | Postoperative 2 months | Postoperative 3 months | |
| The tetrandrine group | 12.88±2.86 | 8.46±1.91 | 9.66±2.04 | 11.25±2.57 |
| The mitomycin group | 12.88±2.86 | 11.03±2.36 | 12.31±2.57 | 12.69±2.98 |
Through the t check, notable difference (P＜0.05) is arranged all between experimental group and matched group
2. filter the bubble situation and see Table 2.
Table 2 experimental group and matched group filter the bubble form relatively
| Observing time | Total eye number (only) | The tetrandrine group | Total eye number (only) | Silk splits the syphilis group | ||
| Functional | Non-functional | Functional | Non-functional | |||
| 7 days | 20 | 20 | 0 | 20 | 20 | 0 |
| 2 months | 14 | 14 | 0 | 14 | 12 | 2 |
| 3 months | 8 | 6 | 2 | 8 | 5 | 3 |
| Add up to | 18(90％) | 2(10％) | 15(75％) | 5(25％) | ||
The result shows that experimental group and matched group filter the bubble morphological differences significance (P＜0.05) is arranged
3. other eye manifestation: postoperative 1d, conjunctival congestion is in various degree all arranged, experimental group has 2 routine corneal edemas, and 6d disappears, and matched group filters bubble and leaks 4 examples, ocular hypotension maculopathy 3 examples.
4. histopathology performance: experimental group pathology end sees that obvious paralysed trace forms, and shows as the slight hypertrophy of squamous epithelial cancer, goes up subcutaneous volume chronic inflammatory cell and soaks into, and does not see the connective tissue collagenzation; Matched group pathological section paralysis trace forms, proliferation of fibrous tissue, obviously collagenzation.
Conclusion
1. 0.1% tetrandrine eye drop has the effect of remarkable reduction normal intra-ocular tension.
2. 0.1% tetrandrine eye drop has remarkable reduction intraocular pressure, thereby has the effect of treatment glaucoma.
3. 0.1% tetrandrine eye drop filters the cicatrization of bubble and other filtration surgery after having remarkable inhibition glaucoma operation, thereby has the glaucomatous effect of further treatment.
Seven. the cataract of turning white after the inhibition forms:
To outer lens extraction of 48 capable simple eye capsules of experimental rabbit and implantation of artificial lens.Be divided into A group matched group, B group postoperative eyedrops of dexamethasone every day 4 times, C group postoperative before the art at random with compound recipe tetrandrine eye drop (0.1% tetrandrine, the % tarivid) eye drip, every day 4 times and D group postoperative subconjunctival injection tetrandrine 5mg, administration time is 7 days.The postoperative different time detects aqueous cell number, the protein content of respectively organizing the art eye, the muddy weight in wet base of record posterior lens capsule film.
The result:
One, aqueous cell number (table 1)
The outer lens extraction postoperative different time aqueous cell density (n=12) of capsule
| Group | Aqueous cell density is (individual/mm 2)( x±s) | |||
| 1d | 3d | 1w | 2w | |
| A | 600.80±136.82 | 325.93±86.11 | 295.11±92.01 | 62.01±21.01 |
| B | 418.63±144.03 | 151.98±64..1 | 127.99±38..5 | 37.09±20.87 |
| C | 459.02±19.91 | 174.86±98.91 | 159.01±93.11 | 31.96±17.11 |
| D | 543.12±152.10 | 251.06±49.02 | 229.89±68.14 | 42.97±20.09 |
The outer lens extraction postoperative different time aqueous humor protein concentration (n=12) of table 2 capsule
| Group | Aqueous humor protein concentration (g/L) (x ± s) | |||
| 1d | 3d | 1w | 2w | |
| A | 20.29±3.69 | 19.69±3.22 | 12.40±3.19 | 5.87±2.06 |
| B | 16.90±3.86 | 16.98±3.01 | 9.36±1.67 | 4.16±1.11 |
| C | 16.52±4.89 | 16.51±2.31 | 8.99±2.37 | 3.60±1.51 |
| D | 19.29±3.68 | 17.51±2.61 | 11.09±3.49 | 4.59±1.65 |
Aqueous cell number, the protein content of 4 groups of lens extraction postoperative different time except that postoperative 14d capsule, and the muddy equal significance of weight in wet base difference (P＜0.05) of posterior lens capsule film.Wherein B and C group postoperative different time aqueous cell number, protein content all are lower than A group, difference significance (P＜0.05); The degree and the weight in wet base of B, C and D group postoperative different time posterior lens capsule film muddiness all are lower than A group, difference significance (P＜0.05).
Tetrandrine can effectively suppress the formation of lagophthalmos lens extraction postoperative posterior lens capsule film muddiness, and the cataract of turning white after the inhibition forms.
Eight. suppress retina vitreous body proliferative lesion:
Experiment material:
The tetrandrine eye drop:
Laboratory animal: select body weight 2～3kg New Zealand white rabbit for use, the male and female dual-purpose.
Experimental cell: adopt through former being commissioned to train and foster exempt from the conjunctiva fibroblast and carry out drug study with the rabbit conjunctiva fibroblast in the 3rd generation.
Main experimental apparatus: 96 porocyte culture plates (GBCO, enzyme immunoassay (EIA) instrument (BAKMAN).
Experimental technique and result:
(1) rabbit conjunctiva isolated test
The culture fluid preparation:
Complete culture solution: DMEM cultivates stock solution, contains 150mIL
-1Calf serum, 30mgL
-1, L-glutamine, penicillin 100 * 10
3UL
-1, streptomycin 100mgL
-1
Keep liquid: DMEM cultivates stock solution, contains 20mIL
-1Calf serum, 30mgL
-1, L-glutamine, penicillin 100 * 10
3UL
-1, streptomycin 100mgL
-1
Assay method:
1.MTT enzyme reaction colorimetric method for determining Tet is to exempting from the effect of conjunctiva fibroblast (RCF) inhibition of proliferation;
The 3rd generation RCF is inoculated in the 96 porocyte culture plates (100 * 10
3Individual hole ', the 200ul hole), 37 ℃, 50mIL CO
2After cultivating 24h, abandon original fluid add contain 100,80,20,5,1.25,0.3125mgL
-1Per 6 holes of the culture fluid 200ul of tetrandrine eye drop are a concentration group, and no medicine culture fluid is a matched group, totally 6 groups.37 ℃, 50mlL
-1CO
2, discarding inoculation liquid behind the 48h, every hole adds fresh liquid 100ul and MTT10ul mixing, the CO of keeping
2Abandon liquid behind the 4-6h in the incubator, add DMSO100ul vibration 10-15min, with microplate reader (A=490nm) photometry density λ value, cell inhibitory rate behind the calculating variable concentrations drug effect.Cell inhibitory rate=(control group A value-experimental group A value)/control group A value * 100%.A value between each group of statistical method relatively adopts one factor analysis of variance.The results are shown in Table 1
Table 1 tetrandrine eye drop is to the fibroblastic inhibitory action of rabbit conjunctiva (n=6)
| Concentration mgL -1 | MTT colourimetric number x ± SD | Suppression ratio % |
| 0 | 0.7182±0.0725 | |
| 0.3125 | 0.6672±0.0340 | 7.10 |
| 1.25 | 0.6418±0.0580 | 10.64 |
| 5 | 0.4998±0.0364 | 30.41 |
| 20 | 0.2864±0.0451 | 60.12 |
| 80 | 0.1510±0.0567 | 78.98 |
| 100 | 0.1102±0.0391 | 84.66 |
P＜0.05
Remember that with tetrandrine content concentration is at 0.3125-100mgL in the culture fluid
-1In the scope, along with the increase of drug level, the MTT colourimetric number descends, and the suppression ratio of RCF growth is risen, and shows dose-effect relationship.Compare with matched group, all there were significant differences in this concentration range for the tetrandrine group.
2. the inhibitory action of pair cell after relatively tetrandrine eye drop, dexamethasone are used with mtt assay
With culture fluid drug dilution is become required concentration: matched group does not add any medicine, and tetrandrine eye drop group contains 5mgL
-1Tetrandrine, dexamethasone (Dex) group contains Dex 200mgL
-1, per 4 holes are a concentration group, method is the same.The results are shown in Table 2
Table 2 tetrandrine eye drop is to the effect (n=6) of rabbit conjunctiva fibroblast proliferation
| MTT colourimetric number x ± SD | Suppression ratio % | |
| Matched group | 0.7693±0.0772 | |
| The tetrandrine eye drop | 0.4914±0.0389 | 36.12 |
| Dexamethasone | 0.4791±0.0354 | 37.72 |
The result shows that tetrandrine and dexamethasone all have inhibitory action P＜0.01 to fibroblasts proliferation.
(2) zoopery
The preparation of rabbit proliferative vitreoretinopathy model:
For 50 of rabbits of examination at the descending three cuts formula of 3% pentobarbital sodium general anesthesia vitrectomy.Excision middle body vitreous body gradually near the retina of ambitus, strengthens captivation then earlier, and retina is picked up, and stings into the retinal hole of 3PD size with cutting head.After sewing up three imports, under the indirect ophthalmoscope, away from ceasma and in the middle of ceasma excessive condensation retina and choroid.After turning white, every some condensation continues to continue 20 seconds.Every eye is condensation 8 points altogether, make to touch the back animal and be equally divided into 2 groups at random, tetrandrine eye drop treatment group and matched group.
Administrated method and observation index:
Treatment group postoperative is with tetrandrine eye drop eye drip every day 4 times, medication 7 days.Matched group equivalent normal saline eye drip, every day 4 times, totally 7 days.Mydriasis is checked the optical fundus every day in the postoperative 7 days, after 7 days weekly mydriasis check optical fundus and vitreous body situation, a situation arises to understand RD and PVR, observed for 6 weeks altogether.
Proliferative vitreoretinopathy is divided into 5 grades.
0 grade: the optical fundus is normal, and vitreous body can have very thin band;
The I level: the vitreous body band reaches medullary ray, does not have obvious tractive sign;
The II level: strap pulls causes medullary ray and obviously raises, or the limitation detachment of retina is arranged;
The III level: medullary ray breaks away from fully;
The IV level: total detachment of retina, or be funnel-form.
II-IV level accumulative total then is the incidence rate of detachment of retina (RD).
Statistical method:
Experimental result data adopts medical statistics program (POMS) to carry out statistical procedures.
The result:
In the 1st week of postoperative, anterior chamber and vitreous chamber are vaporific muddiness, and the 2nd week of postoperative, refractive media was clear gradually along with absorbing from blood.
When testing end to the 6th week, the treatment group has 25, and matched group has 25.PVR and traction property RD appear in 23 eyes (92%) in 25 eyes of matched group, wherein the funnel-form total detachment appears in 15 eyes, 25 eyes of treatment group have 10 eyes (40.0%) PVR and traction property RD to occur, and wherein the funnel-form total detachment appears in 1 eye, and above result all confirms through pathologic finding.Two groups of comparing differences have significance (P＜0.01)
A situation arises sees Table 3 for each phase RD.
A situation arises for table 3 detachment of retina
| Group | Classification | Time (w) | |||||
| 1 | 2 | 3 | 4 | 5 | 6 | ||
| Matched group (n=25) | 0 | 9 | 3 | 2 | 0 | 0 | 0 |
| I | 16 | 13 | 8 | 7 | 5 | 2 | |
| II | 0 | 7 | 6 | 3 | 3 | 3 | |
| III | 0 | 2 | 7 | 8 | 5 | 5 | |
| IV | 0 | 0 | 2 | 7 | 3 | 2 | |
| Treatment group (n=25) | 0 | 12 | 8 | 4 | 4 | 3 | 2 |
| I | 13 | 15 | 15 | 12 | 14 | 14 | |
| II | 0 | 1 | 5 | 5 | 4 | 4 | |
| III | 0 | 1 | 1 | 3 | 3 | 4 | |
| IV | 0 | 0 | 0 | 1 | 1 | 1 | |
Matched group postoperative 1w, 25 eyes retinas do not have disengaging, and 9 eyes have RD in the time of 14 days, and RD appears in 23 eyes during to 42 days.Because vitreous hemorrhage, 2 weeks of postoperative are smudgy with interior optical fundus.Along with vitreous hemorrhage alleviates, propagation bar rope and propagation film before and after visible gradually vitreous chamber has, the propagation film rises from otch, reaches posterior retina, occurs the shallow disengaging of retina in early days, late period occurs funnel-shaped detachment of retina.Tetrandrine eye drop treatment group postoperative 1w, 25 eyes retinas do not have disengaging, and 2 eyes have retina partly to break away from during 2w, and RD appears in 9 eyes during to 42 days.Other 16 eyes RD occurs in the end in 6 weeks, also otch is seen at the end has fiber to breed into people's vitreous body.
Conclusion:
The tetrandrine eye drop has certain preventive and therapeutic effect to experimental proliferative vitreoretinopathy.
Compound recipe tetrandrine eye drop irritation test.
1. test objective; Observe the animal eyes contact and tried the irritant reaction situation that produced behind the thing.
2. animal: rabbit, 10, body weight 2～3kg.
3. tried thing: tetrandrine eye drop, excipient.
4. test method: will be tried thing and splash into or be coated in the branch hole conjunctival sac, dosage 0.1ml, opposite side do the excipient contrast.Every day 4 times, continuous 7 days, give tried thing after, with hands with passive closed 5～10 seconds of animal eyelid.The local response situation tried behind the thing 6,24,48,72 hours to 14 days given in record.
5. the result judges and estimates: by table 11,12 each animal is contacted the irritant reaction score value addition of cornea, iris and conjunctiva afterwards with trying thing, be the total mark that this is tried the thing irritant reaction.The irritant reaction total mark of each animal subject with divided by number of animals, be the last score value that this is tried the thing eye irritation.According to said method try to achieve respectively, stimulate score value for the eye tried behind the thing 6,24,72 hours to 14 days, and be as the criterion, press table 11,12 standards, judge the eye irritation degree of trying thing with highest score.
Table 11 an irritant reaction scoring
| The eye irritant reaction | Score value |
| The corneal opacity (being as the criterion) with the finest and close position | |
| Do not have muddy | 0 |
| Be dispersed in or the diffusivity muddiness, iris is high-visible | 1 |
| Translucent areas is easily differentiated, and iris is smudgy | 2 |
| The canescence translucent areas occurs, the iris details is unclear, and the pupil size reluctantly as seen | 3 |
| Cornea is opaque, because muddy, iris is beyond recognition. | 4 |
| Iris is normal | 0 |
| Gauffer is obviously deepened, and mild hyperaemia is arranged around hyperemia, swelling, the cornea, | 1 |
| Pupil still responds to light, | |
| Hemorrhage, as seen necrosis of naked eyes are to light reactionless (or wherein a kind of pathological reaction occurring) | 2 |
| Conjunctiva | |
| A, hyperemia (referring to palpebral conjunctiva, bulbar conjunctiva position) | |
| Blood vessel is normal | 0 |
| The congestion of blood vessel is cerise | 1 |
| The congestion of blood vessel is peony, and blood vessel is difficult for differentiating | 2 |
| Diffusivity hyperemia is aubergine | 3 |
| B, edema | |
| No edema | 0 |
| Slight edema (comprising instant embrane) | 1 |
| Obviously edema is turned up with the part conjunctiva | 2 |
| Edema causes the nearly semi-closed of a face | 3 |
| Edema to eye face surpasses semi-closed | 4 |
| C, secretions | |
| No secretions | 0 |
| A small amount of secretions | 1 |
| Secretions makes eyelid and eyelashes are moist or adhesion | 2 |
| Secretions makes the moist or adhesion in whole eye district | 3 |
| Total mark | 16 |
Table 12 a stimulation evaluation criterion
| Integration | |
| Nonirritant | 0-3 |
| Slight zest | 4-8 |
| The moderate zest | 9-12 |
| The intensity zest | 13-16 |
6. result of the test: tetrandrine rabbit eye irritation result of the test sees Table 13.
Table 13 tetrandrine eye drop adds lagophthalmos irritation test appraisal result
| 6h | 24h | 48h | 72h | 4d | 5d | 6d | 7d | |||||||||
| Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | |
| Total mark | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 3 | 0 | 6 | 1 | 0 | 0 |
| Average mark | 0.2 | 0 | 0 | 0 | 0 | 0 | 0.1 | 0 | 0.1 | 0 | 0.3 | 0 | 0.6 | 0.1 | 0 | 0 |
| 8d | 9d | 10d | 11d | 12d | 13d | 14d | ||||||||
| Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | Preparation | Contrast | |
| Total mark | 0 | 0 | 1 | 0 | 2 | 1 | 3 | 0 | 4 | 1 | 3 | 1 | 1 | 0 |
| Average mark | 0 | 0 | 0.1 | 0 | 0.2 | 0.1 | 0.3 | 0 | 0.4 | 0.1 | 0.3 | 0.1 | 0.1 | 0 |
7. conclusion: above-mentioned experimental result as seen, irritation test integration＜3, the tetrandrine eye drop nonirritant that provides.
Claims (10)
1. ophthalmic preparation that contains tetrandrine is characterized in that the weight percent content of each raw material components of said preparation is:
Tetrandrine: Radix stephaniae tetrandrae ground caustic 0.001-2%,
Combination with medication: the levofloxacin hydrochloride 0-5% in the anti-microbial type,
Excipient: water for injection 93-99.999g.
2. the ophthalmic preparation that contains tetrandrine according to claim 1 is characterized in that the excipient in the tetrandrine eye ointment is lanoline 0-20%, and liquid paraffin 0-20% and vaseline add to 1000g.
3. the ophthalmic preparation that contains tetrandrine according to claim 1 is characterized in that tetrandrine type gel-type eye ointment adds substrate: ethyl cellulose sodium 0.1-10%.
4. the ophthalmic preparation that contains tetrandrine according to claim 1 is characterized in that containing in the collyrium of water for injection and also contains:
The complexing of metal ion agent: disodium edetate 0-5%,
Osmotic pressure regulator: sodium chloride 0-10%,
Cosolvent: hydrochloric acid 0.1-2mol/L 0.05-50ml,
Thickening agent: hydroxy methocel 0-5%,
Keatolytics: Borneolum Syntheticum 0-5%,
Antioxidant: sodium pyrosulfite 0-5%.
5. according to claim 1 or the 3 described ophthalmic preparations that contain tetrandrine, it is characterized in that containing in the gel-type eye ointment of thickening agent hydroxy methocel 0-5% and also contain:
The complexing of metal ion agent: disodium edetate 0-5%,
Osmotic pressure regulator: sodium chloride 0-10%,
Cosolvent: hydrochloric acid 0.1-2mol/L 0.05-50ml,
Keatolytics: Borneolum Syntheticum 0-5%,
Antioxidant: sodium pyrosulfite 0-5%.
6. the ophthalmic preparation that contains tetrandrine according to claim 1 is characterized in that combination with medication is the erythromycin in the anti-microbial type, or kanamycin, or gentamycin, or amikacin, or tobramycin, or Sisomicin, or netilmicin, or micronomicin, or isepamicin, or astromicin, or etimicin, or spectinomycin, or neomycin, or paromomycin, or tetracycline, or doxycycline, or minocycline, or sulphacetamide, or norfloxacin, or ofloxacin, or enoxacin, or ciprofloxacin, or lomefloxacin, or pefloxacin, or Lu's Flucloxacillin, or sparfloxacin, or fleroxacin, or moxifloxacin, or rifampicin, or metronidazole, or tinidazole, or cefoperazone, or the acyclovir of antiviral apoplexy due to endogenous wind, or ganciclovir, or valaciclovir, or ribavirin; Or the dexamethasone phosphate in the hormones, or fluorometholone powder, or hydrocortisone, or methyl meticortelone, or betamethasone, fluocinolone acetonide, or beclometasone, or halcinonide, or fluticasone; Or the vitamin B in the vitamins
1, or vitamin B
2, or vitamin B
6, or vitamin B
12Or vitamin C, or nicotiamide, or folic acid; Or the indomethacin of anti-inflammatory agent apoplexy due to endogenous wind, or ibuprofen, or meloxicam, or piroxicam, or diclofenac sodium, or acetaminophen, or nimesulide; Or the chlorphenamine in the antiallergic class medicine, or diphenhydramine, or tripelennamine, or levocabastine, or astemizole, or loratadine, or cetirizine, or terfenadine, or sodium cromoglicate, or zaprinast, or tranilast; Or the husky dynamics amine of immunomodulating apoplexy due to endogenous wind, or ciclosporin A, or the Radix Tripterygii Wilfordii total glycosides, or tacrolimus, or leflunomide, or cyclophosphamide, or methotrexate; Or the aminoacid in the nutrient drug; Or the nicotinic acid of microcirculation improvement apoplexy due to endogenous wind, or Inositol Hexanicotinate, or vinpocetine; Or the Herba Erigerontis in the middle pharmaceutically active ingredient, or puerarin, or ligustrazine, or garlicin, or berberine, or Radix Isatidis, or fibrauretin, or houttuynine sodium bisulfite, or punching is even, or Radix Sophorae Flavescentis total alkaloids.
7. according to claim 4 or the 5 described ophthalmic preparations that contain tetrandrine, it is characterized in that antioxidant is a sodium sulfite, or sodium thiosulfate, or methionine (methionine), or thiourea, or butylated hydroxyarisol (BHA), or Butylated Hydroxytoluene (BHT), or nor-pair of hydrogen guaiaretic acid (CDGA), or tocopherol or gallate esters; Osmotic pressure regulator is a boric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, glucose; Thickening agent is a methylcellulose, or ethyl cellulose, or hydroxyethyl-cellulose, or propyl methocel, or hydroxypropyl emthylcellulose, or carboxymethyl cellulose, or hydroxypropyl cellulose, or above-mentioned sodium salt, or hyaluronic acid sodium, or carbomer; Keatolytics is a Mentholum; The 0.1-0.5% that is weight percentage of sodium pyrosulfite wherein; The 0.1-0.5% that sodium thiosulfate is weight percentage; Methylcellulose in the thickening agent, concentration range 0.1-1%; The hyprolose concentration range is 0.5-1.0%.
8. the ophthalmic preparation that contains tetrandrine according to claim 1 is characterized in that tetrandrine is a hydrochloric acid acid tetrandrine; The sulfate powder menispermine; Or nitric acid tetrandrine; Or phosphoric acid tetrandrine; Or acetic acid tetrandrine; Or carbonic acid tetrandrine; Or tartaric acid tetrandrine; Or hydrobromic acid tetrandrine; Or succinic acid tetrandrine.
9. the ophthalmic preparation that contains tetrandrine according to claim 1, it is characterized in that combination with medication belongs to the non-antibiotic time-like, add with antibacterial hibitane 0-5%, or bromination benzene first hydroxylamine 0.004-0.02%, or phenylmercuric nitrate 0.002-0.05%, or phenylmercuric acetate 0.005-0.02, with 1/2 water 40-50 ℃ dissolving, or three glass container of packing into after the neoprene tertiary alcohol 0.25-0.5% heating for dissolving, or thimerosal 0.01-0.02% dissolving, or mercuric oxycyanide 0.01-0.02%, or the oxybenzene first, second, third, butyl ester 0.03-0.1%, or phenethanol 0.25-0.5%, or sorbic acid 0.01-0.2%, or sorbic acid, or parabens, or bromination benzalkonium, or domiphen bromide, or phenylmercuric nitrate, or thimerosal, or benzoic acid, or phenethanol.
10. application in the ophthalmic preparation that contains tetrandrine of preparation treatment ophthalmic diseases is characterized in that:
A. to experimental uveitic therapeutical effect, tetrandrine suppresses experimental uveitis, except its antiinflammatory action, also relevant with cell immune response with its inhibition body fluid, and do not cause knock-on after the drug withdrawal, tetrandrine also significantly suppresses the Mus uveitis that endotoxin and IL-1-α cause by the noncompetitive mode;
B. the effect of corneal inflammation, whole body powder application menispermine can be regulated the development of Mus herpetic keratitis to immunity/inflammatory reaction of virus by modifying the host, and tetrandrine is by suppressing the inflammatory reaction that IL-1 β generates cornea after the infection that alleviates the herpes simplex disease;
C. to the inhibitory action of uveitis before experimental, tetrandrine can significantly delay and suppress the inflammatory reaction of uveitis before the rabbit that crystalline protein causes, reduce prostaglandin E total amount in the iris, suppress leukocytic oozing out, and the intraocular pressure that can not raise, its anti-inflammatory mechanisms is main relevant with the calcium antagonism of tetrandrine;
D. the therapeutical effect of inflammation behind the ocular operation, tetrandrine can effectively suppress the inflammatory reaction of ultrasonic emulsification postoperative, alleviates aqueous humor protein content, promotes blood-aqueous barrier to recover;
E. to the effect of anaphylaxis ophthalmic, sinomenine has obviously suppressed the inflammatory reaction of conjunctiva, the oxyphil cell who has significantly alleviated conjunctiva is soaked into, and significantly reduced the mastocyte number of complete threshing, can adjust the anaphylaxis conjunctivitis that ragweed pollen causes significantly, the oxyphil cell who reduces conjunctiva significantly infiltrates and cytomegalic quantity complete and threshing, treatment anaphylaxis ophthalmic;
F. intraocular pressure lowering treatment glaucoma and suppress cicatrization and glaucoma after the iatrotechnics, 0.1% tetrandrine eye drop has the effect of remarkable reduction normal intra-ocular tension, 0.1% tetrandrine eye drop has remarkable reduction intraocular pressure, thereby has the effect of treatment glaucoma, 0.1% tetrandrine eye drop filters the cicatrization of bubble and other filtration surgery after having remarkable inhibition glaucoma operation, thereby has the glaucomatous effect of further treatment;
G. the cataract of turning white after suppressing forms, and tetrandrine can effectively suppress the formation of lagophthalmos lens extraction postoperative posterior lens capsule film muddiness, and the cataract of turning white after the inhibition forms;
H. suppress retina vitreous body proliferative lesion, the tetrandrine eye drop has certain preventive and therapeutic effect to experimental proliferative vitreoretinopathy.
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