CN102697713A - Sodium hyaluronate eye drops and a preparation method thereof - Google Patents
Sodium hyaluronate eye drops and a preparation method thereof Download PDFInfo
- Publication number
- CN102697713A CN102697713A CN2012101953320A CN201210195332A CN102697713A CN 102697713 A CN102697713 A CN 102697713A CN 2012101953320 A CN2012101953320 A CN 2012101953320A CN 201210195332 A CN201210195332 A CN 201210195332A CN 102697713 A CN102697713 A CN 102697713A
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- CN
- China
- Prior art keywords
- sodium
- eye drops
- hyaluronic acid
- adds
- sodium hyaluronate
- Prior art date
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- 239000003889 eye drop Substances 0.000 title claims abstract description 85
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- 238000009603 uroscopy Methods 0.000 description 1
Abstract
The invention relates to the field of medicine and particularly relates to sodium hyaluronate eye drops and preparation method thereof. Every 100 ml of the sodium hyaluronate eye drops comprise the following components: 80 to 150 mg of sodium hyaluronate, 130 to 200 mg of boric acid, 10 to 20 mg of borax, 8 to 15 mg of edetate disodium, 80 to 160 mg of 6-amino caproic acid, 80 to 160 mg of mannitol, 600 to 800 mg of sodium chloride, 3 to 10 mg of benzalkonium chloride, and 8 to 15 mg of borneo camphor, wherein 100 ml of water for injection is added, and the pH value is regulated to 6.0 to 7.8. The eye drops provided by the invention can play the role of promoting healing of injuries of corneal epithelium, can prolong the break-up time remarkably and can better improve the symptoms of xerophthalmia. Meanwhile, the sodium hyaluronate eye drops have good stability at ambient temperature, and all figures are similar, which indicates that the preparation technology is steady and practicable; and if the eye drops are used within the available period, the indexes of HA-Na are all within the quality control range.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to sodium hyaluronate eye drops and preparation method thereof.
Background technology
Hyaluronic acid sodium has another name called hyaluronate sodium (sodiumHyaluronate; HA-Na) be the acid mucopolysaccharide macromole that makes by cockscomb extraction method or microbe fermentation method; The about 80-250 ten thousand of molecular weight, it is the straight chain macromole that the polymerization of disaccharidase unit constitutes by N-second phthalein glucosamine and D-Glucuronic acid sodium salt.Hyaluronic acid sodium is extensively to be present in the intravital biological active substances of people; Locate all to have distribution at vitreum, aqueous humor, skin, knuckle synovia, umbilical cord etc., play lubricated, water conservation, buffering, viscoelastic, repair in trauma, network is fixed and the regulating action of pair cell.
Hyaluronic acid sodium can be used for the filler of ophthalmologic operation, the therapeutic agent of osteoarthritis, and operating antitack agent, DEVELOPMENT PROSPECT is widely used.
Discover recently; On the eye cornea endotheliocyte, contain endogenous hyaluronic acid sodium and receptor thereof; And illustrate its physiological action, and hyaluronic acid sodium can promote the wound healing of corneal epithelial cell, the epithelial cell damage that the corneal sufferer is produced has the obvious treatment effect.In rabbit cornea epithelial damage model, iodine steam and the caused corneal epithelium of n-enanthol are stripped off, 0.1%HA-Na significantly dwindles wound surface, promotes corneal epithelial cell to extend.
Xerophthalmia is a kind of common ophthalmic diseases; Because the conjunctival epithelium infringement that local illness of eye or general disease cause and tear layer quality arranged and quantity unusual; Subjective symptom such as show as eye twinge, photophobia, foreign body sensation, dry sensation, shed tears; Objective determination demonstration fluorescein factory lacks and adds the Meng plays the part of rose-red stained positive, and breakup time of tear film (BUT) shortens, and lacrimal secretion reduces.
The oculopathy cause of disease is divided into: 1, dry syndrome (like the sjogren syndrome): owing to the general immunity disease causes that the whole body exocrine gland receives lymphocytic infiltration and causes the glandular secretion dysfunction; Show as lachrymal gland and salivary gland secretion and reduce, caused xerophthalmia scheorma and xerostomia.2, the outer xerophthalmia of dry syndrome: the tear downgrade or the hyposecretion that cause owing to reasons such as infection, operation, medicine or senile atrophies of lacrimal gland.3, the xerophthalmia that shortens of breakup time of tear film: when waiting some developed countries, many youngsters reduce number of winks for a long time in the face of picture and text datatron, computer display screen, TV or electronic game machine etc. American-European-Japanese; Cause breakup time of tear film to shorten easily; Lose protective effect, screen operation fatigue disease occurs looking, show as eyestrain conjunctiva, cornea; Eyes have twinge drying and foreign body sensation etc., are called modern xerophthalmia.
China is along with the foundation of the popularizing of TV, computer, information network; Students in middle and primary schools and adult use the number and the time of looking the screen operation obviously to increase; So that the sickness rate of modern xerophthalmia rises year by year, and the normal development and the adult eye of using that badly influence the teenager vision are healthy.
The treatment of xerophthalmia mainly is to dispel the cause of disease, improves symptom, and dripping with the artificial tears at eye is most common therapeutic method.External artificial tears has tens of kinds of kinds, generally by containing some inorganic salts and high molecular polymer and stimulating the medicine of lacrimal secretion to form.But most artificial tearss are unstable to the effect of treatment of dry eye, and the persistent period is short.Seeing from existing kind necessary exploitation is a kind of can be to person in middle and old age's xerophthalmia, particularly look the eye drop of the modern xerophthalmia stable curative effect that the screen operation brings out.Hyaluronic acid sodium is a kind of high viscoelastic, biomacromolecule that fabulous biocompatibility is arranged, and it obviously prolongs breakup time of tear film, and cornea, conjunctiva are had good protective action.In view of the external existing 0.1%HA-Na eye drop of counting company has gone through to go on the market, be used to treat all kinds xerophthalmia, its curative effect is superior to conventional artificial tears.Therefore, exploitation 0.1%HA-Na eye drop increases the means of treatment xerophthalmia, and it is very necessary protecting vast teenager vision health.
Because the definite curative effect of HA-Na eye drop on the treatment xerophthalmia successively is developed to the listing product with it in Japan and Britain.Japan Santen Pharmaceutical Co. Ltd. develops glass Fructus Tamarindi Indicae conjunctival epithelium infringement treatment eye drop; The 0.1%HA-Na 5ml of specification bacteriostatic agent; Reach 0.1% and the 0.3%HA-Na 0.4ml that do not contain antiseptic, trade name Hyalein0.1/Hyalein Mini 0.1,0.3.January nineteen ninety-five, formally sold June nineteen ninety-five by Japanese health ministry approval listing.The 0.1%HA-Na eye drop that Japan scientific research Co., Ltd. went on the market in Japan's approval in 2000 is identical with the former effect.The eye drop of the Japan's 0.1%HA-Nasml of Santen Pharmaceutical Co. Ltd. specification went through in 1996 in China's listing, the going on the market in China in 2000 of 0.3%HA-Na 0.4ml specification.
Britain Fermentech medical Ltd, manufacturer develops 0.1% sodium hyaluronate eye drops, and trade name Fermavisc goes on the market in Europe.
The kind of foreign treatment xerophthalmia listing has the artificial tears and increases the viscosity eye drop except sodium hyaluronate eye drops.Like Hypotears PF, Refresh, TearsPlus, Tears Naturale, Health Guard, Thera Tear, Bion Tears, ocucoat PF, Celluvisc etc., contain Na among the artificial tears usually
+, K
+Deng inorganic salt, thickening agents such as chondroitin sulfate.These artificial tearss have certain effect to the insufficient xerophthalmia patients of electrolyte in some tears, but to conjunctiva infringement patient's effect just too late sodium hyaluronate eye drops in clear and definite angle has been arranged.
Japan Santen Pharmaceutical Co. Ltd., gloomy Tian Long and etc. eyedrop (day flat 2-96515 of disclosure special permission of application; 1990) and glass acid eyedrop (day flat 2-164829 of disclosure special permission; 1990), be main component with glass acid and its esters, add inorganic salt and antibacterial and process drop.The aqueous pharmaceutical preparation of the pharmacy of thousand longevity and Shiseido Co., Ltd.'s application (day flat 4-69342 of disclosure special permission, 1992) with glass acid and its esters, adds inorganic salt and antibacterial and processes the aqueous drop.Cantoro applies for United States Patent (USP) (U.S.P5770628,1998), contains the hyaluronic acid sodium viscosity thickener among the artificial tears, is used to treat the eye stimulation that keratoconjunctivitis sicca and contact lens or environment cause.
Domestic patent application mainly contains application such as Pu Cong control ocular infection compound eye drops and preparation method thereof (number of patent application 9810222.1; Publication number CN1191723A); By the compound eye drops that promise ketone third generation antibiotics, hyaluronic acid sodium, sweetening agent, antiseptic and physiological buffer are formed, different with the kind treatment xerophthalmia of the present invention's exploitation.
Applications such as Ling Peixue contain eye drop of hyaluronic acid sodium and preparation method thereof (number of patent application 96116072 is authorized publication number CN1086590C), mainly treat various oculopathy such as xerophthalmia and various conjunctivitis keratitis.The patent protection content is different with the present invention.
Chinese invention patent (number of patent application 93111305; Authorize publication number 1045382) Runshu eye drops and manufacturing approach thereof are disclosed, mainly treat xerophthalmia, also can control sand holes, conjunctiva eyeball inflammation etc.; Because of it is the antibiotic eye drop that contains chloromycetin, obviously different with prescription of the present invention and function.
Chinese invention patent (application number: 03137663.0 applying date: 2003-06-19) disclose the Application of composite of hyaluronic acid sodium in the ophthalmic preparation; The composite interstitial substance that hyaluronic acid sodium that proposes and glycerol are formed; Add in the ophthalmic preparation, process the transparent eye drop of stable water solublity; Composite interstitial substance quantity is added in this invention in ophthalmic preparation be hyaluronic acid sodium 0.05% to 0.5% (g/ml), glycerol 0.1% to 2.5% (g/ml), and in the compound use of following ratio, i.e. hyaluronic acid sodium: glycerol is 1: 1 to 1: 4.Best working concentration scope is that hyaluronic acid sodium is 0.05% to 0.25%, and glycerol is 0.1% to 0.5%, and by hyaluronic acid sodium: glycerol is compound use in 1: 2 to 1: 4; Can in multiple ophthalmic preparation, add.
Hyaluronic acid sodium is a kind of macromole mucopolysaccharide, under some physics and chemical factor influence, causes molecular weight to reduce, at room temperature long preservation.Simultaneously, hyaluronic acid sodium is a kind of macromole mucopolysaccharide, also is beneficial to bacterial growth, is not non-returnable container, repeatedly drips with the back eye drop to be prone to contaminated long bacterium.
Summary of the invention
For the stability that solves hyaluronic acid sodium and the technological deficiency that is prone to contaminated long bacterium, an object of the present invention is to provide a kind of sodium hyaluronate eye drops, this sodium hyaluronate eye drops has that bacteriostasis property is good, the characteristics of good stability.Another object of the present invention provides the method for preparing of above-mentioned sodium hyaluronate eye drops.
In order to realize first above-mentioned purpose, the technical scheme below the present invention has adopted:
Sodium hyaluronate eye drops, the every 100ml of this eye drop is made up of following component:
Hyaluronic acid sodium 80 ~ 150mg, boric acid 130 ~ 200mg,
Borax 10 ~ 20mg, disodium edetate 8 ~ 15mg,
6-aminocaprolc acid 80 ~ 160mg, mannitol 80 ~ 160mg,
Sodium chloride 600 ~ 800mg, benzalkonium chloride 3 ~ 10mg,
Borneolum Syntheticum 8 ~ 15mg, water for injection adds to 100ml, and adjusting pH is 6.0 ~ 7.8.
As preferably, the every 100ml of above-mentioned eye drop is made up of following component:
Hyaluronic acid sodium 90 ~ 120mg, boric acid 140 ~ 160mg,
Borax 12 ~ 14mg, disodium edetate 9 ~ 10mg,
6-aminocaprolc acid 90 ~ 110mg, mannitol 90 ~ 110mg,
Sodium chloride 650 ~ 750mg, benzalkonium chloride 4 ~ 6mg,
Borneolum Syntheticum 8 ~ 12mg, water for injection adds to 100ml.
As most preferably, the every 100ml of above-mentioned eye drop is made up of following component:
Hyaluronic acid sodium 100mg, boric acid 150mg,
Borax 12mg, disodium edetate 10mg,
6-aminocaprolc acid 100mg, mannitol 100mg,
Sodium chloride 700mg, benzalkonium chloride 5mg,
Borneolum Syntheticum 10mg, water for injection adds to 100ml.
In order to realize second above-mentioned purpose, the technical scheme below the present invention has adopted:
A kind of method for preparing above-mentioned sodium hyaluronate eye drops, this method comprises the steps:
1) water for injection of getting preparation cumulative volume 40% ~ 60% in advance is cooled to 50 ~ 60 ℃ and pours in the agitator, and accurately the weighing hyaluronic acid sodium under stirring state, adds hyaluronic acid sodium, is dipped to dissolving fully;
2) water for injection of getting preparation cumulative volume 20% ~ 40% is put in the stainless steel cask; With boric acid, Borax, disodium edetate, 6-aminocaprolc acid, mannitol, the accurate weighing of sodium chloride supplementary material; Add successively in the stainless steel cask, after the stirring and dissolving, pour in the Agitation Tank of cleaning-sterilizing;
3) benzalkonium chloride that accurately takes by weighing amount of preparation is put in the beaker, with the water for injection dissolving, and under agitation adds solution in the Agitation Tank;
4) Borneolum Syntheticum that accurately takes by weighing amount of preparation is put in the beaker, adopts the ethanol dissolving, and under agitation adds this solution in the Agitation Tank, stirs;
5) medicinal liquid carried out circulating filtration 8 ~ 12 minutes through 0.22 qualified μ m film tube filter of bubble point check, and it is subsequent use to make basal liquid after the inspection visible foreign matters is qualified;
6) adding above-mentioned basal liquid in hyaluronic acid sodium dissolving back is settled to capacity, stirs after 8 ~ 12 minutes, and through 0.22 μ m membrane filtration, intermediate detection hyaluronic acid sodium content, PH, osmotic pressure, visible foreign matters meet the requirements;
7) opened laminar flow car laminar flow in 20 ~ 40 minutes in advance, the vial of cleaning and sterilizing is put in the laminar flow car, medicinal liquid is packed in the vial after filtering, adds a cover, and is transferred to bottling department;
8) fill, tamponade, screw capping.
As preferably, dissolve with water for injection in the ratio of 0.2 ~ 0.4g benzalkonium chloride adding 100ml water for injection in the above-mentioned step 3).
As preferably, Borneolum Syntheticum adopts the dissolving of 95% medicinal alcohol in the above-mentioned step 4), and the ratio that adds the 100ml95% medicinal alcohol by the 3g Borneolum Syntheticum is dissolved.
The research effect of each component of sodium hyaluronate eye drops of the present invention is distinguished as follows:
One, hyaluronic acid sodium content
HA-Na has biology, the physical property that is similar to MGP and natural tears, is non-Newtonian fluid, under high-rate of shear; Shearing force diminishes, and viscosity reduces, under low shear rate; It is big that shearing force becomes, and viscosity increases, and is particularly suitable for the succedaneum as the artificial tears.To 12 patients (breakup time of tear film (BUT)≤10 second and low tear amount; Phenol red thread test≤15mm) with variable concentrations HA-Na eye drop (0,0.05,0.1 and 0.3%) with do not add HA-Na carry out randomized controlled trial for contrast; Before eye drip with behind the eye drip, survey BUT 5,15,30,60,120 and 180 minutes the time respectively; The result finds; 0.1 with 0.3%HA-Na eye drop equal significant prolongation tear membrane stability (p < 0.05) in all minutes, with 0 and the treatment of 0.05%HA-Na eye drop organize then that the person does not show any prolongation BUT.This result confirms to delay the preceding breakup time of tear film of cornea, needs 0.1%HA-Na concentration.
Two, antibacterial
Sodium hyaluronate eye drops is by the sterile manner packing; In case open; Maybe be contaminated, HA-Na is worked as in the present invention's employing and benzalkonium chloride share, and significantly suppresses gram positive bacteria and fungi growth on the one hand; Also reduce the toxicity on BAK corneal epithelial surface in addition, the amount of antibacterial is lacked than external 0.1%.To contain with the sodium hyaluronate eye drops that does not contain benzalkonium chloride point-like corneal epithelium infringement patient is carried out double blind controling test, the result finds that no matter epithelium infringement and subjective symptoms improvement antibacterial are had or not, the both significantly improves, and both zero differences of side effect.And the eye drop that adds antibacterial is compared with not adding the person, significantly suppresses gram positive bacteria and fungi growth.
Carry out bacteriostatic test with paper disk method; Promptly draw the present invention with drug sensitive test paper; Be attached to respectively on the detection flat board that is mixed with staphylococcus aureus or Sarcina lutea; Put 37 ℃ of cultivations and observe inhibition zone after 24 hours, the result shows that this prescription has bacteriostasis to staphylococcus aureus and Sarcina lutea.With staphylococcus aureus, escherichia coli, Candida albicans and aspergillus niger is test organisms, is 10 with the bacterium number
6Be inoculated in respectively and carry out bacteriostatic test among the present invention, cultivated 7 days the inoculation back, detects the bacterium number of test organisms, and the result shows that the invention prescription all has certain bacteriostasis to gram positive bacteria, gram negative bacteria, candida mycoderma and fungus.
Three, osmotic pressure
The present invention adds sodium chloride and is adjusted to isosmotic solution.The general osmotic pressure of the tear of xerophthalmia patients is higher, and eye drop commonly used has hypotonic and grade is oozed.The present invention tests hypotonic and waits oozes prescription, adds the prescription of 0.55% sodium chloride, and osmotic pressure is obviously on the low side, and adds the prescription of 0.7% sodium chloride, oozes because of composition combineds effect such as borate buffer solution make it to wait.Selective chlorination sodium of the present invention is adjusted to isosmotic solution, and the osmotic pressure ratio is 0.9 ~ 1.1.
Four, pH value
Human tears film pH is about 7.4, and it is uncomfortable that too high (pH is greater than 9) or low excessively (pH is less than 5) can make eye produce.Therefore, confirm that eye drop pH is 6.0 ~ 7.8.It is 6.0 ~ 7.8 that the present invention adopts boric acid, Borax buffer agent to keep pH.Borate buffer solution and phosphate buffer are eye drop buffer system commonly used.Phosphate is the required nutrient substance of bacterial growth in the phosphate buffer; Hyaluronic acid sodium is a kind of macromole mucopolysaccharide, also is beneficial to bacterial growth, because of the present invention is not a non-returnable container; Repeatedly drip with the easy contaminated long bacterium of back eye drop, and borate buffer solution has certain bacteriostasis.
Five, stabilizing agent
Because HA-Na is prone to down degrade in light, heat, so the present invention adds disodium edetate and mannitol as stabilizing agent, can slow down the HA-Na molecular degradation, and disodium edetate and benzalkonium chloride there is collaborative bacteriostasis.
(1) disodium edetate: the present invention is a multiple agent type, in use is difficult to keep the eye drop aseptic condition, so added benzalkonium chloride as antibacterial.Compound antibacterial can be brought into play synergism, and benzalkonium chloride and disodium edetate are single to have stronger fungistatic effect with benzalkonium chloride, and hyaluronic acid sodium is a linear macromolecule, and disodium edetate plays Stabilization to hyaluronic acid sodium, can delay the hyaluronic acid sodium molecular degradation.The sample that will contain and not contain disodium edetate respectively places 60 ℃ of constant temperature, measures the HA-Na molecular weight after 10 days, and the former molecular weight retention rate is higher than the latter 12% as a result.
(2) mannitol: mannitol is auxiliary element commonly used in the eye drop, because of its for how hyaluronic acid sodium to be had Stabilization through based compound, this prescription interpolation mannitol 0.1% can delay the hyaluronic acid sodium molecular degradation.The sample that will contain and not contain mannitol respectively places 60 ℃ of constant temperature, measures the HA-Na molecular weight after 10 days, and the former molecular weight retention rate is higher than the latter 10% as a result.
Six, other
Eye drop of the present invention also adds a small amount of 6-aminocaprolc acid and Borneolum Syntheticum, has added a small amount of Borneolum Syntheticum, and Borneolum Syntheticum has the refreshment of having one's ideas straightened out, clearing away heat to alleviate pain function, makes eye drop that refrigerant comfortable sense arranged; 6-aminocaprolc acid has platelet protection and antiinflammatory action.
In sum, the present invention is owing to adopted above-mentioned prescription, and the damage of eye drop corneal epithelial has the healing of promotion effect, can obviously prolong breakup time of tear film, and dry eye symptoms is had a better role.Simultaneously, the present invention has good stable property in room temperature, and each batch data is close, and the expression stable preparation process is feasible.Use before the deadline, HA-Na each item index is all in the Quality Control scope.
The specific embodiment
Embodiment 1
Sodium hyaluronate eye drops, every 100ml is made up of following component:
Hyaluronic acid sodium 100mg, boric acid 150mg,
Borax 12mg, disodium edetate 10mg,
6-aminocaprolc acid 100mg, mannitol 100mg,
Sodium chloride 700mg, benzalkonium chloride 5mg,
Borneolum Syntheticum 10mg, water for injection adds to 100ml.
The method for preparing of above-mentioned sodium hyaluronate eye drops comprises the steps:
1) water for injection of getting preparation cumulative volume 50% in advance is cooled to 50 ~ 60 ℃ and pours in the agitator, and accurately the weighing hyaluronic acid sodium under stirring state, adds hyaluronic acid sodium, is dipped to dissolving fully;
2) water for injection of getting preparation cumulative volume 30% is put in the stainless steel cask; With boric acid, Borax, disodium edetate, 6-aminocaprolc acid, mannitol, the accurate weighing of sodium chloride supplementary material; Add successively in the stainless steel cask, after the stirring and dissolving, pour in the Agitation Tank of cleaning-sterilizing;
3) benzalkonium chloride that accurately takes by weighing amount of preparation is put in the beaker, and the ratio that adds 100ml water for injection in the 0.3g benzalkonium chloride is dissolved with water for injection, and under agitation adds solution in the Agitation Tank;
4) Borneolum Syntheticum that accurately takes by weighing amount of preparation is put in the beaker, adds the ratio dissolving of 100ml95% medicinal alcohol in the 3g Borneolum Syntheticum, and under agitation adds this solution in the Agitation Tank, stirs;
5) medicinal liquid carried out circulating filtration 10 minutes through 0.22 qualified μ m film tube filter of bubble point check, and it is subsequent use to make basal liquid after the inspection visible foreign matters is qualified;
6) adding above-mentioned basal liquid in hyaluronic acid sodium dissolving back is settled to capacity, stirs after 10 minutes, and through 0.22 μ m membrane filtration, intermediate detection hyaluronic acid sodium content, PH, osmotic pressure, visible foreign matters meet the requirements;
7) opened laminar flow car laminar flow in 30 minutes in advance, the vial of cleaning and sterilizing is put in the laminar flow car, medicinal liquid is packed in the vial after filtering, adds a cover, and is transferred to bottling department;
8) fill, tamponade, screw capping.
Embodiment 2
Sodium hyaluronate eye drops, every 100ml is made up of following component:
Hyaluronic acid sodium 90mg, boric acid 110mg,
Borax 12mg, disodium edetate 10mg,
6-aminocaprolc acid 100mg, mannitol 90mg,
Sodium chloride 700mg, benzalkonium chloride 5mg,
Borneolum Syntheticum 10mg, water for injection adds to 100ml.
Method for preparing is shown in embodiment 1.
Embodiment 3
Sodium hyaluronate eye drops, every 100ml is made up of following component:
Hyaluronic acid sodium 140mg, boric acid 180mg,
Borax 18mg, disodium edetate 12mg,
6-aminocaprolc acid 150mg, mannitol 140mg,
Sodium chloride 650mg, benzalkonium chloride 5mg,
Borneolum Syntheticum 12mg, water for injection adds to 100ml.
Method for preparing is shown in embodiment 1.
Test Example 1 stability test
Sodium hyaluronate eye drops system is a main component with hyaluronic acid sodium (HA-Na), is aided with formations such as 6-aminocaprolc acid, sodium chloride, stabilizing agent and antibacterial.Because HA-Na is the biomacromolecule mucopolysaccharide; Some physics and conditions such as chemical factor such as high temperature, high light can make molecular degradation, so carry out stability test, in prescription, add stabilizing agent; Reduce the HA-Na molecular weight and molecular weight, to guarantee that eye drop is in quality control clearance.
Get sodium hyaluronate eye drops the packing of embodiment 1 preparation with commercially available sample.Observation item: outward appearance, pH, HA-Na content (mg/ml), molecular weight (ten thousand), intrinsic viscosity, osmotic pressure ratio.
One, accelerated test
1,40 ℃ of scholars 2 ℃, relative humidity RH75% scholar 5% (saturated NaCI solution)
2,40 ℃ of scholars 2 ℃, relative humidity RH75% scholar 5% (saturated NaCI solution)
Two, long term test, 25 ℃ of scholars are 2 ℃, and RH60% scholar 10%, place
2,25 ℃ of scholars 2 ℃, and RH60% scholar 10%
Three, conclusion
The three lot sample article that the embodiment of the invention 1 is produced are in 2 ℃ of 40 ℃ of scholars, and relative humidity RH75% scholar 5% (saturated NaCL solution) placed 6 months, and hyaluronic acid sodium (HA-Na) molar mass average decline 15% (still greater than 800,000) conform to quality requirements.In 2 ℃ of 25 scholars, RH60% scholar 10% (saturated NaN02 solution) placed 3 years, and the average conservation rate of HA-Na molecular weight and intrinsic viscosity is more than 90%, and outward appearance, pH, content, the equal no change of osmotic pressure conform to quality requirements.
The three lot sample article that the embodiment of the invention 1 is produced are in 2 ℃ of 40 ℃ of scholars, and relative humidity RH75% scholar 5% (saturated NaCL solution) placed 6 months, and hyaluronic acid sodium (HA-Na) molar mass average decline 15.6% (still greater than 800,000) conform to quality requirements.In 25 scholars 2, C, RH60% scholar 10% (saturated NaN02 solution) placed 1 year, and the average conservation rate of HA-Na molecular weight and intrinsic viscosity is 96%, and the HA-Na molecular weight is greater than 800,000, and outward appearance, pH, content, the equal no change of osmotic pressure conform to quality requirements.
Test Example 2 sodium hyaluronate eye drops pharmacology, toxicological study
The sodium hyaluronate eye drops pharmacology of the embodiment of the invention 1 preparation, toxicological study prove through the experiment of pharmacological room of Shanghai Institute of Pharmaceutical Industry: these article splash in the lagophthalmos; Every day 5 times; Continuous 14 days; Observe cornea, conjunctival reaction, the result shows that corneal transparency, conjunctiva do not have that congestion and edema, iris are normal, no epiphora, conjunctiva palpebrae and bulbar conjunctiva smear do not have inflammatory cell it is thus clear that.So these article are to lagophthalmos nonirritant, safety non-toxic.
The safety testing of Test Example 3 sodium hyaluronate eye drops
The present invention is with 0.5% hyaluronic acid sodium (HA-Na) eye drop and do not contain HA-Na contrast eye drop respectively to lagophthalmos eye drip l time per hour, and every day 13 times, each 1, continuous 7 days eye drips carry out a toxicity test.With 0.3% and 0.5% sodium hyaluronate eye drops, and do not contain HA-Na contrast eye drop lagophthalmos is per hour dripped 1 time, every day 8 times, each 1, continuous 4 all eye drips carry out a toxicity test.The result shows that the histopathologic examination of scintilltion observation, the number of times of twinkling mensuration, crystalline lens observation, examination of ocular fundus and eyeball does not all show eye irritation and eye infringement property in the sort of sodium hyaluronate eye drops pro-eye irritation observation, the anterior chamber.Sensitization test (STT) shows to guinea pig skin, and HA-Na does not have sensitization.
0.3% sodium hyaluronate eye drops is to male rabbit (KBL:JW) per hour 1 time; Every day 8 times; Continuous 26 all eye drips; The result shows that this eye drop does not have zest and infringement property to lagophthalmos, and eyeball histopathologic examination and Electronic Speculum cornea are checked also no change, and general state observation in addition, body weight determination, food ration mensuration, uroscopy, hematological examination, blood chemical examination, dissection inspection, organ weight measure and the variation relevant with the 0.3%HA-Na eye drop all do not seen by histopathologic examination.
Above result shows that the 0.1%HA-Na eye drop has extremely high safety.
In rabbit cornea epithelial damage model pharmacological testing, using concentration is that 0.1% sodium hyaluronate eye drops can make the wound surface of peeling off below 24 hours obviously dwindle.Show that 0.1%HA-Na can promote corneal wound healing.
The preceding tear membrane stability of artificial tears's substituting agent corneal that contains hyaluronic acid sodium 0.1% has desirable influence.
0.1% sodium hyaluronate eye drops alleviate serious xerophthalmia objective with subjective symptom on all show tangible clinical effectiveness.
Above result shows that the damage of 0.1%HA-Na eye drop corneal epithelial has the healing of promotion effect, can obviously prolong breakup time of tear film, and dry eye symptoms is had a better role.Three batches of above stability of sample tests of these article show that these article have good stable property in room temperature, and each batch data is close, and the expression stable preparation process is feasible.Use before the deadline, HA-Na each item index is all in the Quality Control scope.As long as preparation technology carries out according to the quality control standard, just can guarantee the qualified of every lot sample article.
The test of Test Example 4 quality research work
It is 90.0% ~ 110.0% of labelled amount that these article contain hyaluronic acid sodium.
1 character: these article are the little thick liquid of achromatism and clarity.
2 differentiate: the main component of these article is a hyaluronic acid sodium, gets these article lml, adds Borax sulphuric acid test solution 5ml, and through heating hydrolysis, the cooling back adds a small amount of carbazole dehydrated alcohol test solution, shakes up, and puts in the boiling water bath and heats, and it is red that solution should show.
These article of getting lml adds 2 ~ 3 of 5% chloro-hexadecane yl pyridines, and vibration generates white flocculent deposit.
These article of getting lml, the discrimination test that shines sodium salt carries out, and flame shows foresythia.
These article have also added 6-aminocaprolc acid, Borneolum Syntheticum, and according to thin layer chromatography, through steps such as point sample, expansion, colour developings, the result shows in the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
3 inspections:
3.1PH value: it is an amount of according to pH value algoscopy mensuration to get these article, and pH value is 6.0 ~ 7.8.
3.2 osmotic pressure: it is an amount of according to osmotic pressure molar density algoscopy mensuration to get these article, and osmotic pressure is than between 0.9 ~ 1.1.
3.3 intrinsic viscosity and molecular weight: get these article solution 5ml, add 0.9% sodium chloride solution standardize solution and become 10ml, as need testing solution; Using capillary tube E internal diameter is the Ubbelohde viscometer of 0.6 ~ 0.7mm; Measure according to viscosimetry, obtain intrinsic viscosity (n), by formula (n)=0.036M
0.78, obtain mean molecule quantity M.Molecular weight is not less than 800,000.
3.4 limit test of microbe: owing to added antibacterial in these article, according to the membrane-filter procedure inspection, up to specification.
3.5 other: these article meet pertinent regulations under the eye drop item.
4 assays: contain hyaluronic acid sodium in these article, indicate its content with Glucuronic acid lactone.
4.1 principle: hyaluronic acid sodium is the linear polymeric polysaccharide that forms with D-Glucuronic acid sodium salt and N one acetylglucosamine disaccharidase unit polymerization (sloughing two parts of water).In boiling water, the hyaluronic acid sodium sample is resolved into glucuronic acid by concentrated sulphuric acid, is combined into bright-coloured rose with carbazole, and the depth of color and the proportional relation of glucuronic acid content.In like manner, Glucuronic acid lactone is hydrolyzed into glucuronic acid by concentrated sulphuric acid in boiling water, is combined into bright-coloured rose with carbazole, and the depth of color and the proportional relation of glucuronic acid content.So by Glucuronic acid lactone content multiply by 2.278 and extension rate can know hyaluronic acid sodium content in the sample.
Annotate: the D-Glucuronic acid sodium salt molecular weight is 216.1, the glucosamine molecular weight is 221.2, molecular weight water is 18, cruel molecular weight is 176.06 in the glucuronic acid.
5, the mensuration of sample
The aseptic methodology checking of Test Example 5 sodium hyaluronate eye drops
Owing to except containing the main component hyaluronic acid sodium, also added antibacterial in these article; And these article are not disposable use; Do not belong to " intraocular injection solution, ophthalmic intercalating agent and the ophthalmic preparation that supplies operation, wound, cornea perforating wound to use "; With reference to ophthalmic preparation (Chinese Pharmacopoeia two appendix IG in 2005), these article should carry out limit test of microbe.
1 experiment purpose:
The three lot sample article (1201,1202,1203) that keep sample for a long time carry out limit test of microbe by the quality standard of revision.
2 experimental techniques:
According to membrane-filter procedure (Chinese Pharmacopoeia two appendix XIH in 2005) inspection, produce ormal weight (every kind of culture medium inoculated 2, every lml) from 2 test samples at least, directly or be inoculated in after handling in sulfur ethanol broth and the improvement Martin culture medium.Cultivated 7 days, bacteria growing must not be arranged.If bacteria growing is arranged, should get 2 times of amount test samples again, retrial in accordance with the law respectively, each pipe all must not have bacteria growing.
3 experimental procedures: the sterile working prevents microbial contamination
3.1 membrane-filter procedure method validation:
3.1.1 preparation THIOGLYCOLLIC ACID salt fluid culture medium, nutrient agar, improvement Martin culture medium and improvement Martin agar culture medium, pH7.0 sodium chloride one peptone buffer solution, packing, sterilization (115 ℃, 30 minutes).
3.1.2 sterilizations such as filter (the 0.45pm filter membrane is housed), tweezers.
3.1.3 test organisms is staphylococcus aureus and Candida albicans, cultivates respectively, dilutes, counts.
3.1.4 2 of sample thiefs, mixing through the membrane filter of aperture 0.45pm is housed, is used an amount of pH7.0 then.Sodium chloride one peptone buffer solution divides the flushing filter membrane three times, adds 10 ~ 100 test organismss the last time in the flushing liquor, filters.
3.1.5 filter membrane is taken out, adds respectively in THIOGLYCOLLIC ACID salt fluid culture medium, the improvement Martin culture medium.
3.1.6 the positive control pipe inserts respectively in equivalent test organisms to sulfur ethanol broth, the improvement Martin culture medium.The negative control pipe adds pH7.0 sodium chloride one peptone buffer solution.
3.1.7 the antibacterial culturing parent tube is put 33 ℃, the fungal culture parent tube is put 25 ℃.
3.1.8 observed 5 days.
3.1.9 experimental result:
3.2 sample limit test of microbe
3.2.1 operating procedure is with above-mentioned " method validation " each step down, difference is: flushing liquor does not add test organisms, and the result to observe the positive control pipe be 48 hours, other pipes are seven days.
3.2.2 experimental result:
The microbial limit of the three lot sample article that 4 conclusions chronic keep sample is up to specification.
Claims (6)
1. sodium hyaluronate eye drops is characterized in that the every 100ml of this eye drop is made up of following component:
Hyaluronic acid sodium 80 ~ 150mg, boric acid 130 ~ 200mg,
Borax 10 ~ 20mg, disodium edetate 8 ~ 15mg,
6-aminocaprolc acid 80 ~ 160mg, mannitol 80 ~ 160mg,
Sodium chloride 600 ~ 800mg, benzalkonium chloride 3 ~ 10mg,
Borneolum Syntheticum 8 ~ 15mg, water for injection adds to 100ml, and adjusting pH is 6.0 ~ 7.8.
2. sodium hyaluronate eye drops according to claim 1 is characterized in that the every 100ml of this eye drop is made up of following component:
Hyaluronic acid sodium 90 ~ 120mg, boric acid 140 ~ 160mg,
Borax 12 ~ 14mg, disodium edetate 9 ~ 10mg,
6-aminocaprolc acid 90 ~ 110mg, mannitol 90 ~ 110mg,
Sodium chloride 650 ~ 750mg, benzalkonium chloride 4 ~ 6mg,
Borneolum Syntheticum 8 ~ 12mg, water for injection adds to 100ml.
3. sodium hyaluronate eye drops according to claim 1 is characterized in that the every 100ml of this eye drop is made up of following component:
Hyaluronic acid sodium 100mg, boric acid 150mg,
Borax 12mg, disodium edetate 10mg,
6-aminocaprolc acid 100mg, mannitol 100mg,
Sodium chloride 700mg, benzalkonium chloride 5mg,
Borneolum Syntheticum 10mg, water for injection adds to 100ml.
4. a method for preparing any described sodium hyaluronate eye drops of claims of claim 1 ~ 3 is characterized in that this method comprises the steps:
1) water for injection of getting preparation cumulative volume 40% ~ 60% in advance is cooled to 50 ~ 60 ℃ and pours in the agitator, and accurately the weighing hyaluronic acid sodium under stirring state, adds hyaluronic acid sodium, is dipped to dissolving fully;
2) water for injection of getting preparation cumulative volume 20% ~ 40% is put in the stainless steel cask; With boric acid, Borax, disodium edetate, 6-aminocaprolc acid, mannitol, the accurate weighing of sodium chloride supplementary material; Add successively in the stainless steel cask, after the stirring and dissolving, pour in the Agitation Tank of cleaning-sterilizing;
3) benzalkonium chloride that accurately takes by weighing amount of preparation is put in the beaker, with the water for injection dissolving, and under agitation adds solution in the Agitation Tank;
4) Borneolum Syntheticum that accurately takes by weighing amount of preparation is put in the beaker, adopts the ethanol dissolving, and under agitation adds this solution in the Agitation Tank, stirs;
5) medicinal liquid carried out circulating filtration 8 ~ 12 minutes through 0.22 qualified μ m film tube filter of bubble point check, and it is subsequent use to make basal liquid after the inspection visible foreign matters is qualified;
6) adding above-mentioned basal liquid in hyaluronic acid sodium dissolving back is settled to capacity, stirs after 8 ~ 12 minutes, and through 0.22 μ m membrane filtration, intermediate detection hyaluronic acid sodium content, PH, osmotic pressure, visible foreign matters meet the requirements;
7) opened laminar flow car laminar flow in 20 ~ 40 minutes in advance, the vial of cleaning and sterilizing is put in the laminar flow car, medicinal liquid is packed in the vial after filtering, adds a cover, and is transferred to bottling department;
8) fill, tamponade, screw capping.
5. the method for preparing of sodium hyaluronate eye drops according to claim 4 is characterized in that: dissolve with water for injection in the ratio of 0.2 ~ 0.4g benzalkonium chloride adding 100ml water for injection in the step 3).
6. the method for preparing of sodium hyaluronate eye drops according to claim 4 is characterized in that: Borneolum Syntheticum adopts the dissolving of 95% medicinal alcohol in the step 4), and the ratio that adds the 100ml95% medicinal alcohol by the 3g Borneolum Syntheticum is dissolved.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106668322A (en) * | 2017-01-19 | 2017-05-17 | 蚌埠丰原医药科技发展有限公司 | Eye drops containing traditional Chinese medicine extract and preparation method thereof |
| CN107164454A (en) * | 2017-07-03 | 2017-09-15 | 中国大冢制药有限公司 | Benza microbial limit tests |
| CN109528550A (en) * | 2018-12-27 | 2019-03-29 | 江苏海伦隐形眼镜有限公司 | A kind of dissolving method of sodium hyaluronate for solution preparation |
| CN111588693A (en) * | 2020-06-18 | 2020-08-28 | 广州瑞尔医药科技有限公司 | Cromolyn sodium eye drops and preparation method thereof |
| ES2886723A1 (en) * | 2021-07-23 | 2021-12-20 | Fundacion Para El Fomento De La Investig Sanitaria Y Biomedica De La Comunidad Valenciana Fisabio | COMPOSITION BASED ON THE ANTIOXIDANT ACTIVITY OF THE ENZYME SUPEROXIDE DISMUTASE AND ITS APPLICATION IN EYE DISEASES (Machine-translation by Google Translate, not legally binding) |
| CN115252543A (en) * | 2022-07-22 | 2022-11-01 | 苏州弘森药业股份有限公司 | Preparation method of single-dose sodium hyaluronate eye drops |
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| CN106668322A (en) * | 2017-01-19 | 2017-05-17 | 蚌埠丰原医药科技发展有限公司 | Eye drops containing traditional Chinese medicine extract and preparation method thereof |
| CN107164454A (en) * | 2017-07-03 | 2017-09-15 | 中国大冢制药有限公司 | Benza microbial limit tests |
| CN109528550A (en) * | 2018-12-27 | 2019-03-29 | 江苏海伦隐形眼镜有限公司 | A kind of dissolving method of sodium hyaluronate for solution preparation |
| CN111588693A (en) * | 2020-06-18 | 2020-08-28 | 广州瑞尔医药科技有限公司 | Cromolyn sodium eye drops and preparation method thereof |
| ES2886723A1 (en) * | 2021-07-23 | 2021-12-20 | Fundacion Para El Fomento De La Investig Sanitaria Y Biomedica De La Comunidad Valenciana Fisabio | COMPOSITION BASED ON THE ANTIOXIDANT ACTIVITY OF THE ENZYME SUPEROXIDE DISMUTASE AND ITS APPLICATION IN EYE DISEASES (Machine-translation by Google Translate, not legally binding) |
| WO2023002088A1 (en) * | 2021-07-23 | 2023-01-26 | Fundación para el Fomento de la investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO) | Composition based on the antioxidant activity of the enzyme superoxide dismutase and application thereof in eye diseases |
| CN115252543A (en) * | 2022-07-22 | 2022-11-01 | 苏州弘森药业股份有限公司 | Preparation method of single-dose sodium hyaluronate eye drops |
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