CN105749360A - Cornea protecting composition as well as preparation method and application thereof - Google Patents
Cornea protecting composition as well as preparation method and application thereof Download PDFInfo
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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Abstract
The invention discloses cornea protecting composition as well as a preparation method and an application thereof. Main components of the composition comprise a solid moisturizing and lubricating component, a liquid moisturizing and lubricating component, an osmoregulation component and water. The composition adopts double moisturizing and lubricating components including the solid moisturizing and lubricating component and the liquid moisturizing and lubricating component, so that the composition can be better spread and remained on the corneal surface and better protect the corneal epithelial layer, and damage caused by dryness to the cornea can be avoided. For a preparation process of the composition, a solution is not required to be heated to boiling, preparation operation is simpler, a preparation cycle is shorter than 48 h, cold storage is not needed during transportation and storage, and the transportation cost and use cost are reduced.
Description
Technical field
The present invention relates to ophthalmologic operation field of medical article technology, particularly relate to a kind of composition and method of making the same protecting cornea and application.
Background technology
When examination of eyes and ophthalmologic operation, corneal exposure, in the external world, loses the protection of tear, can sustain damage because of dry.Solution mostly clinical at present is to check and frequently using normal saline or commercially available viscoelastic agent in operation at anterior corneal surface.Shorter in the anterior corneal surface holdup time yet with normal saline, need to frequently use, this allows for operation and is interrupted, and makes troubles to clinician, and additionally normal saline uses and too much can make sufferer eye swelling, also brings discomfort to patient.And viscoelastic agent is due to comparatively thickness; poor at anterior corneal surface dispersibility; protective layer can not be quickly formed; need to wait for it to be uniformly dispersed; or again instillation viscoelastic agent time, have between the viscoelastic agent successively instiled interruption or bubble, it is impossible to play the effect of the cornea that adequately protects; also the visual field can be made unintelligible, make troubles to clinical manipulation.
Other is disclosed for protecting the product of cornea to there is also a lot of defect; such as a kind of viscoelastic agent for ophthalmic surgery disclosed in patent application that publication number is CN102225220A; it is that hyaluronate sodium and hypromellose are dissolved in phosphate buffer respectively; then mixing, filtration, sterilizing, subpackage form.Being injected in operation in postcorneal anterior chamber by this viscoelastic agent, play a supporting role, it is simple to operation technique, therefore viscosity and elasticity are desirable that higher, just can play the effect of supported anterior chamber, but the problem that viscosity higher position certainly exists bad dispersibility.Additionally, the main component hyaluronate sodium in this product needs to preserve under cryogenic, otherwise character is unstable, it may occur that rotten；Due to cannot high temperature sterilize, therefore clump count therein and endotoxin content cannot be controlled effectively, and for ophthalmologic operation, can increase the risk of infection.The preparation process of this product needs buffer is heated, moisture is had to evaporate, thus osmotic pressure will change, the addition of subsequent component (hyaluronate sodium), also the change of osmotic pressure can be caused, final utilization product in anterior chamber and environment seepage pressure reduction are not relatively big, at this moment can cause body tissue untoward reaction, such as swollen tissue or dehydration.
Publication number is the ophthalmic note dilution of a kind of improvement disclosed in the patent application of TWI290050, it is used in intraocular surgery process, it is used for reducing the drying condition injury to eye inner tissue, this note dilution mainly with hydroxypropyl methyl cellulose for viscosity and surface tension modifying agent, utilizes other inorganic salts for regulator.Similar with the viscoelastic agent for ophthalmic surgery in CN102225220A, this product is also used for inside eyeball, and viscosity and elasticity are desirable that higher, however it remains the problem of bad dispersibility.
Publication number is a kind of anterior corneal surface protective agent disclosed in the patent application of CN104083396, and this product is made up of hyaluronate sodium or chondroitin sulfate or chitosan and buffer.Wherein hyaluronate sodium, constituent of chitosan cost of material are higher；And unstable under product high temperature, transport and storage need cold preservation；The means reducing particle number, clump count and endotoxin content are made to be not used on these materials so that it is cleanliness factor is not readily reachable by operation with requiring.
Although prior art discloses the multiple product for eye containing moisturizing Lubrication Composition, but still not having a kind of product to meet the following conditions simultaneously: moisturizing greasy property is good, at anterior corneal surface good dispersion property, constitutive property is stable, and clump count, particle number, endotoxin content all easily reach operation with requiring.
Summary of the invention
It is an object of the invention to for the technological deficiency existed in prior art; first aspect; thering is provided the compositions of a kind of protection cornea with good moisturizing lubrication and dispersion effect, it is mainly composed of solid moisturizing Lubrication Composition, liquid moisturizing Lubrication Composition, osmotic pressure modifying ingredients and water；Wherein, the content of each main component is: by weight/mass percentage composition 0.05%-10% solid moisturizing Lubrication Composition, 0.1%-55% liquid moisturizing Lubrication Composition, the water of 0.8%-1.4% osmotic pressure modifying ingredients and surplus.
Described solid moisturizing Lubrication Composition weight/mass percentage composition preferred 0.1%-5%, 1%-2%, 1%-3% or 1%-4%；Liquid moisturizing Lubrication Composition weight/mass percentage composition preferred 10%-45%, 10%-55%, 10%-25% or 10%-40%；Osmotic pressure modifying ingredients weight/mass percentage composition preferred 1%-1.2%, 0.83%-1%, 0.9%-1.4% or 1%-1.4%.That is, when solid moisturizing Lubrication Composition weight/mass percentage composition is selected from 0.1%-5%, liquid moisturizing Lubrication Composition weight/mass percentage composition can be 10%-45%, 10%-55%, 10%-25% or 10%-40%, and osmotic pressure modifying ingredients weight/mass percentage composition can be 1%-1.2%, 0.83%-1%, 0.9%-1.4% or 1%-1.4%；By that analogy.When liquid moisturizing Lubrication Composition weight/mass percentage composition is selected from 10%-45%, solid moisturizing Lubrication Composition weight/mass percentage composition can be 0.1%-5%, 1%-2%, 1%-3% or 1%-4%, and osmotic pressure modifying ingredients weight/mass percentage composition can be 1%-1.2%, 0.83%-1%, 0.9%-1.4% or 1%-1.4%；By that analogy.
Described solid moisturizing Lubrication Composition can be the combination of one or more in hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carrageenan and carbomer, it is preferable that one or more in hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and carbomer.
The available nominal viscosity of described hydroxypropyl methyl cellulose is one or more in 6,15,50,100,250,750,1500,4000,10000 and 15000mPa s, it is preferable that 15,50,100,250,750 and one or more in 1500mPa s；Described sodium carboxymethyl cellulose can be selected for high viscosity (the sodium carboxymethyl cellulose concentration range of viscosities when 1wt% is 1000-4500mPa s), medium viscosity (range of viscosities during sodium carboxymethyl cellulose concentration 2wt% is 300-3100mPa s) or low viscosity (during sodium carboxymethyl cellulose 2wt%, the range of viscosities of concentration is 25-100mPa s), it is preferable that medium viscosity or low viscosity；The available mean molecule quantity of described hydroxypropyl cellulose is one or more in 80000,95000,140000,370000,850000 and 1150000, it is preferable that one or more in 80000,95000,140000 and 370000；The preferred medical rank of described carrageenan；Described carbomer can be selected for carbomer 910, carbomer 934, Acritamer 940, Carbopol 941, it is preferable that carbomer 934 and Acritamer 940.
Described liquid moisturizing Lubrication Composition can be the combination of one or more in glycerol, PEG-4000, Polyethylene Glycol-300 and propylene glycol, it is preferable that at least one in glycerol, PEG-4000 and propylene glycol.
Described osmotic pressure modifying ingredients is that can to make described compositions osmotic pressure be the material of 295-305mOsmol/kg；
Described osmotic pressure modifying ingredients is selected from sodium chloride, potassium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate, zinc gluconate, one or more combination of lactic acid；
The material that the preferred final concentration (w/w) in the composition of described osmotic pressure modifying ingredients is following: sodium chloride (NaCl) 0.505%-0.710%, potassium chloride (KCl) 0%-0.021%, sodium dihydrogen phosphate (NaH2PO4) 0.052%-0.142%, potassium dihydrogen phosphate (KH2PO4) 0.027-0.166%, zinc gluconate 0-0.5% and lactic acid 0-0.01%.
Second aspect, it is provided that the method preparing above-mentioned composition, is dissolved in filtration sterilization after water dissolution by osmotic pressure modifying ingredients, obtains osmotic pressure and regulates solution；Adsorption treatment liquid moisturizing Lubrication Composition, obtains liquid moisturizing lubrication solution；Solid moisturizing Lubrication Composition is slowly added to one by one osmotic pressure and regulates in solution and dispersed one-tenth uniform solution, add liquid moisturizing lubrication solution, regulate infiltration with saturated nacl aqueous solution or normal saline and be depressed into 295-305mOsmol/kg, swelling overnight, filtration sterilization.
Comprise the following steps:
1). weigh that osmotic pressure modifying ingredients is soluble in water is configured to saline solution (the preferably sodium chloride (NaCl) of final concentration of 0.505wt%-0.710wt% in the composition, the potassium chloride (KCl) of 0wt%-0.021wt%, the sodium dihydrogen phosphate (NaH of 0.052wt%-0.142wt%2PO4), the potassium dihydrogen phosphate (KH of 0.027wt%-0.166wt%2PO4), the zinc gluconate of 0wt%-0.5wt% and the lactic acid of 0wt%-0.01wt%), after crossing 0.22 μm of filter membrane, 121 DEG C of steam sterilization 30min, obtain osmotic pressure and regulate solution；
2). weigh at least one in liquid moisturizing Lubrication Composition, respectively with removing activated carbon after activated carbon adsorption, be mixed to get liquid moisturizing lubrication solution；Another preparation sodium chloride weight/mass percentage composition is the sodium chloride solution of 26.5wt%, 121 DEG C of steam sterilization 30min；
3). 65 ± 5 DEG C, solid moisturizing Lubrication Composition be slowly added to one by one under stirring condition osmotic pressure regulate in solution, treat the solid dispersed open form of moisturizing Lubrication Composition become uniform solution (if solid moisturizing Lubrication Composition more than one, after being then initially charged a kind of dispersed one-tenth uniform solution, add another kind again, after by that analogy), add step 2) the liquid moisturizing lubrication solution that obtains stirring 30min, regulate infiltration with the sodium chloride solution of 26.5wt% or normal saline and be depressed into 295-305mOsmol/kg, obtain solution A；
4). by step 3) solution A that obtains is at room temperature overnight swelling (> 12h) obtains solution B, crosses 0.8 μm, 0.5 μm, 0.3 μm filter membrane filter pressing successively；
5). by step 4) liquid after filter pressing is placed in steam sterilization pan 121 DEG C of steam sterilization 30min, stir after steam sterilization, obtain clear homogeneous viscous liquid；Sufficient standing, to bubble-free, namely obtains the compositions of described protection cornea.
The third aspect; the compositions protecting cornea that said method prepares is provided; viscosity is 350mPa s-500mPa s; endotoxin content < 0.5EU/mL; transmitance > 99%; the particle number that > the is 10 μm particle number less than 600, > 25 μm is less than 15.
Fourth aspect, it is provided that above-mentioned composition avoids the application in the medicine of bitot's patches in preparation, and described medicine is eye drop, irrigation or liniment.
Compared with prior art, the invention has the beneficial effects as follows:
The present invention protects the compositions of cornea to adopt dual moisturizing Lubrication Composition solid moisturizing Lubrication Composition and liquid moisturizing Lubrication Composition; by the group of two kinds of moisturizing Lubrication Composition kinds and content is joined; said composition is made to be more conducive to sprawling and being detained at anterior corneal surface; layer protective layer can be quickly formed at anterior corneal surface; bubble or section will not be produced when successively instiling; light transmittance is well beyond clinical demand; thus ensureing the definition of better moisturizing lubricity and visual area; protect corneal epithelium better, it is to avoid suffer damage because of dry.Said composition is by the regulation and control to osmotic pressure modifying ingredients, it is ensured that the osmotic pressure in final products is essentially identical with artificial tears, and for 295-305mOsmol/kg, (pH is: 6.5-7.5).In the compositions of the present invention, each constitutive property is stable, not by the impact of low temperature or high temperature, it is possible to by the inspection of the safety index such as aseptic, endotoxin, microgranule, safety has no side effect, and clinical patients can relieved use；Each component can participate in body metabolism and be carried over feces external, does not need other operations rinsed or remove, will not cause the discomfort of sufferer, untoward reaction；Low cost of raw materials, will not bring financial burden to sufferer, can by well-established greatly.Additionally, the preparation process of the present composition is without by solution heating extremely boiling, preparation manipulation is simpler, and manufacturing cycle, less than 48h, without cold preservation when transporting and store, reduces and transports and use cost.
Detailed description of the invention
The present invention propose a kind of in examination of eyes or ophthalmologic surgical procedures when there is a need to exposure angle film or bitot's patches for protecting the compositions of corneal epithelium.Said composition presses weight/mass percentage composition, including the water of the moisturizing Lubrication Composition of 0.15wt%-65wt%, 0.8wt%-1.4wt% osmotic pressure modifying ingredients and surplus.Moisturizing Lubrication Composition therein is made up of 0.05wt%-10wt% solid moisturizing Lubrication Composition and 0.1wt%-55wt% liquid moisturizing Lubrication Composition.
Solid moisturizing Lubrication Composition can be one or more in hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carrageenan and carbomer, and mixed proportion is not limit, it is preferred to hydroxypropyl methyl cellulose and one or both in carbomer.
Hydroxypropyl methyl cellulose is as the principle active component in the present composition, and one is provide suitable viscosity for compositions so that it is has adhesiveness, meets dispersibility required in operation process and holdup time requirement；Two is enough moistenings and lubrication, makes anterior corneal surface not and causes infringement because being exposed to extraneous dry；Three is safety, will not bring any potential safety hazard for patient.Sodium carboxymethyl cellulose has moisture retention, and its aqueous solution adheres to anterior corneal surface and forms protective layer.In the present composition, the content of sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose is directly connected to the viscosity of compositions, and then what have influence on is clinical applicability；Too high levels, then viscosity is big, and slowly, clinical manipulation is inconvenient in dispersion；Content is too low, then viscosity is low, it is impossible to meet the requirement of clinical operation holdup time.
In the present invention, hydroxypropyl methyl cellulose selects nominal viscosity to be the combination of one or more in 6,15,50,100,250,750,1500,4000,10000 and 15000mPa s, it is preferable that 15,50,100,250,750 and the combination of one or more in 1500mPa s；Sodium carboxymethyl cellulose can be selected for high viscosity (sodium carboxymethyl cellulose concentration range of viscosities when 1wt% is 1000-4500mPa s), medium viscosity (sodium carboxymethyl cellulose concentration range of viscosities when 2wt% is 300-3100mPa s) or low viscosity (sodium carboxymethyl cellulose concentration range of viscosities when 2wt% is 25-100mPa s) three kinds, it is preferable that medium viscosity or low viscosity；The mean molecule quantity of hydroxypropyl cellulose is the combination of one or more in 80000,95000,140000,370000,850000 and 1150000, it is preferable that the combination of one or more in 80000,95000,140000 and 370000.
Carrageenan aqueous solution has certain viscosity, can increase the viscosity of compositions itself, it may have stronger water-retaining property.Carbomer can adhere to anterior corneal surface, forms liquid reservoir at eyeball surface, to keep eye to moisten.Carbomer can increase in the adhesion of eyeball surface and retention time, it is approximately 2 hours in the holdup time of eye, can be selected for the combination of one or more in carbomer 910, carbomer 934, Acritamer 940 and Carbopol 941, it is preferable that carbomer 934 and Acritamer 940.
Liquid moisturizing Lubrication Composition can be one or more in glycerol, PEG-4000, Polyethylene Glycol-300 and propylene glycol, and mixed proportion is not limit, it is preferred to one or more in glycerol, PEG-4000 and propylene glycol.
What glycerol in the present composition, PEG-4000, Polyethylene Glycol-300 and propylene glycol rose is moisture-keeping function.Wherein glycerol viscosity is relatively big, and PEG-4000, Polyethylene Glycol-300 and propylene glycol viscosity are less, it is possible to group joins the common dispersibility regulating compositions and transparency.
Osmotic pressure modifying ingredients contains following material by final mass percentage composition in the composition: sodium chloride (NaCl) 0.505%-0.710%, potassium chloride (KCl) 0%-0.021%, sodium dihydrogen phosphate (NaH2PO4) 0.052%-0.142%, potassium dihydrogen phosphate (KH2PO4) 0.027-0.166%, zinc gluconate 0-0.5% and lactic acid 0-0.01%.
Water used in the present composition is water for injection, is distilled water or the water of distillation deionized water gained.
The method preparing above-mentioned composition, comprises the following steps:
1). weigh the osmotic pressure modifying ingredients saline solution that is configured to soluble in water and (saline solution contains following material by weight/mass percentage composition: sodium chloride (NaCl) 0.505%-0.710%, potassium chloride (KCl) 0%-0.021%, sodium dihydrogen phosphate (NaH2PO4) 0.052%-0.142%, potassium dihydrogen phosphate (KH2PO4) 0.027-0.166%, zinc gluconate 0-0.5% and lactic acid 0-0.01%), after crossing 0.22 μm of filter membrane, 121 DEG C of steam sterilization 30min, obtain osmotic pressure and regulate solution；
2). cross film after weighing liquid moisturizing Lubrication Composition activated carbon adsorption, obtain liquid moisturizing lubrication solution (if liquid moisturizing Lubrication Composition has multiple, respectively with activated carbon adsorption every kind liquid moisturizing Lubrication Composition, after removing activated carbon, it is mixed to get liquid moisturizing lubrication solution)；Preparation sodium chloride weight/mass percentage composition is the sodium chloride solution of 26.5wt%, 121 DEG C of steam sterilization 30min；
3). while stirring solid moisturizing Lubrication Composition is slowly added to one by one osmotic pressure under 65 ± 5 DEG C of conditions and regulates in solution, treat solid moisturizing Lubrication Composition be uniformly dispersed formation uniform solution (if solid moisturizing Lubrication Composition more than one, after being then initially charged a kind of dispersed one-tenth uniform solution, add another kind again, after by that analogy), add step 2) the liquid moisturizing lubrication solution that obtains, stirring 30min, take the average osmotic pressure of a small amount of test, by formula step 2) sodium chloride solution that obtains or normal saline regulate infiltration and be depressed into 295-305mOsmol/kg, pH is: 6.5-7.5, obtain solution A；
4). by step 3) solution A that obtains is at room temperature overnight swelling (> 12h) obtains solution B, crosses 0.8 μm, 0.5 μm, 0.3 μm filter membrane filter pressing successively；
5). by step 4) filter after liquid be placed in steam sterilization pan 121 DEG C of steam sterilization 30min; stirring after steam sterilization, obtain clear homogeneous viscous liquid, sufficient standing is to bubble-free; fill, to the container after sterilizing, namely obtains the present invention and protects the compositions of cornea；The viscosity of test compositions is 350mPa s-500mPa s, if composition viscosity is not within the scope of this, then needs again to prepare.
Below in conjunction with specific embodiment, further illustrate present disclosure, and the present invention is further elaborated, but these embodiments limit the invention absolutely not.
In following embodiment, method therefor is conventional method if no special instructions.
Embodiment 1-10, preparation protection cornea compositions
The compositions of embodiment of the present invention 1-10 protection cornea and the formula of comparative example are such as shown in table 1-2.Comparative example 1 is the product prepared according to the method in CN102225220A, comparative example 2 is the product prepared according to the method in TWI290050B, comparative example 3 and 4 is the product prepared according to the method in CN104083396A, the product that comparative example 5 and 6 is the formula according to the present invention and method prepares, is only that solid moisturizing Lubrication Composition is not in the numerical range of the present invention.
Table 1 embodiment 1-5 protects the compositions of cornea and the formula (in the compositions of every 1000g protection cornea the quality of each component) of comparative example 1-3
Table 2 embodiment 6-10 protects the compositions of cornea and the formula (in the compositions of every 1000g protection cornea the grams of each component) of comparative example 4-6
Test one, particular product performance parameters detection
The performance parameter of the protection compositions of cornea, the product of comparative example 1-6 and listing like product CORNEAPROTECT prepared by embodiment 1-10 detects, and result is in Table 3 and table 4.Commercialized product CORNEAPROTECT, purchased from Beijing and Bang Site development in science and technology company limited, this product is made up of hydroxypropyl methyl cellulose (HPMC), sodium chloride, potassium chloride, calcium chloride, lactic acid and water for injection.
The performance parameter of the compositions of the protection cornea of table 3 embodiment 1-10
The product of table 4 comparative example 1-6 and the performance parameter of CORNEAPROTECT
It is with reference to " GBT16886.10-2005 BiologicalEvaluationofMedicalDevice " the 10th part that ocular injury in table 3 and table 4 is scored: stimulate the carrying out with the B.3 eye irritant test defined in the Appendix B in delayed hypersensitivity test to evaluate.Detailed score system is in Table 5.
Table 5 ocular injury score system
The testing result of performance parameter in contrast table 3 and 4, can be seen that the compositions comparing embodiment 1-10, the product of comparative example 1-6 and commercialized product CORNEAPROTECT viscosity are not that too higher position is too low, endotoxin content and transmitance can not meet clinical needs simultaneously, particle number is also too high, illustrate that the compositions of the present invention is joined by strict group on formula composition and content and screened, the strict control of preparation technology, just makes indices be superior to comparative example and commercialized product.
CORNEAPROTECT is the product of corneal protection in unique a special Rhizoma Atractylodis Macrocephalae on domestic market.CORNEAPROTECT and the present composition are distinctive in that this product is without liquid moisturizing Lubrication Composition.From data in table; the present composition because making the performances such as its moisturizing greasy property having, surface tension, anterior corneal surface adhesive force all be more suitable for the protection of anterior corneal surface containing liquid moisturizing Lubrication Composition, and its dispersibility and transparency are also superior to un-added product.
Additionally the present composition is because of containing liquid moisturizing Lubrication Composition and strict preparation technology so that the present composition is better than existing like product in transmitance and microgranule index.In this test, commercialized product group observed paranormal discharge of eye, it is possible to be because microgranule more caused by.To sum up comparing, the compositions of the present invention is more applicable for the moisturizing lubrication maintaining corneal epithelium in clinical operation room ophthalmologic operation and ophthalmologic examination, thus playing the effect of protection cornea.
Test two, corneal protection test
In order to verify that the present invention protects the use effectiveness of the compositions of cornea, choosing embodiment 1-10, comparative example 1-6 and commercialized product CORNEAPROTECT and carry out following corneal protection test, wherein comparative example and commercialized product are as the comparison of the embodiment of the present invention.Concrete test method is as follows:
Selecting healthy adult regular grade New Zealand white rabbit, male and female are not limit, body weight 2.5-3.0Kg.Raising temperature: 20-26 DEG C；Relative humidity: 40-70%；Illumination: 15-20Lx；Feed complete granular rabbit feed, freely drink water.
Laboratory animal is with 2wt% Nembutal sodium solution through ear vein injecting anesthetic, and lateral position is fixed on operating-table, keeps anterior corneal surface level.Respectively using the embodiment group compositions of embodiment 1-10 (use), comparative example group (using the compositions of comparative example 1-6), negative control group (normal saline), the blank group (not using any material) of positive controls (commercialized product CORNEAPROTECT) sample drip 3 as corneal protection agent and drop on animal corneal, and make it that cornea is completely covered.The coverage condition on basis of microscopic observation sample corneal surface.Corneal protection agent liquid level thinks when occurring breaking that covering was lost efficacy.Record from the time dripped when breaking with corneal protection agent to its liquid level, as the holdup time of corneal protection agent.Observing simultaneously and drip by the reflective situation of liquid level within 2 seconds after corneal protection agent, evaluate the smoothness of corneal protection agent liquid level with this, uses three grades of stagings, 0 grade be smooth, and 1 is partly smooth, and 2 is unsmooth.Test is investigated sample and is dispersed to the time of smooth liquid level at anterior corneal surface, disperse more fast more will not make troubles to clinical manipulation.For the product of the compositions of embodiment 1-6 and comparative example 1-5, result of the test is as shown in table 6, and the result of other embodiments and embodiment 1-6 is as good as.
The corneal protection effect of each experimental group corneal protection agent of table 6
| Experimental group | Holdup time | Smoothness | Jitter time |
| Blank group | - | - | - |
| Negative control group | 20” | 0 | 1” |
| Positive controls | 16’01”08 | 0 | 10” |
| Embodiment 1 | 15’28”13 | 0 | 3” |
| Embodiment 2 | 14’06”19 | 0 | 2” |
| Embodiment 3 | 15’06”44 | 0 | 2” |
| Embodiment 4 | 15’09”04 | 0 | 3” |
| Embodiment 5 | 17’06”18 | 0 | 4” |
| Embodiment 6 | 10’36”06 | 0 | 3” |
| Comparative example 1 | 20’17”56 | 2 | 51” |
| Comparative example 2 | 23’03”19 | 2 | 55” |
| Comparative example 3 | 28’48”56 | 2 | 48” |
| Comparative example 4 | 18’39”56 | 1 | 37” |
| Comparative example 5 | 31’29”56 | 2 | 59” |
Result in table 6 can be seen that; normal saline can scatter rapidly at anterior corneal surface; but the holdup time is very of short duration; comparative example 1 and comparative example 2 holdup time as ophthalmically acceptable viscoelastic agent are longer, but rate of dispersion is relatively slow, and it was experimentally observed that the cornea area that a same sample covers is less; need to follow-up drip again; have tomography between the liquid level that during dropping, two samples are formed again, also have bubble and occur, it is impossible to fully cover cornea and play a protective role.Sample provided by the present invention, mostly just can form the smooth liquid level got a clear view in 5 seconds, dispersion is very rapid, and the holdup time is all at 10-20 minute, it is possible to meet the requirement of examination of eyes and ophthalmologic operation.Visible, at dispersibility with on the holdup time, the compositions of the present invention can be taken into account, and is therefore better than existing product.After overall merit, the compositions of the present invention is the prioritizing selection of clinical manipulation.
The present composition is by quickly forming one layer of clear protective layer in visual area at exposure anterior corneal surface, and it is longer in the holdup time of anterior corneal surface, will be free from bubble or forms tomography.In clinical operation and ophthalmologic examination, the application of this compositions makes clinical doctor operate more convenient, normal saline need not be dripped again frequently, sprawl at anterior corneal surface also without at the wait viscoelastic agent class articles for use that expend time in, because visual area becomes apparent from so that operation is more smooth in operation and checking process；On the other hand, this compositions is with low cost, and preparation is simple, can be accepted by vast sufferer, adds its moisturizing lubrication and thinks well, can have the performance identical with natural tear, make user more comfortable；Because in preparation, indices controls strict, this compositions is used to avoid the appearance of complication of user eye swelling and tissue inflammation.
The above is only the preferred embodiment of the present invention, it should be pointed out that, for those skilled in the art, under the premise without departing from the principles of the invention, can also making some improvements and modifications, these improvements and modifications also should be regarded as present disclosure.
Claims (10)
1. protecting a compositions for cornea, it is mainly composed of solid moisturizing Lubrication Composition, liquid moisturizing Lubrication Composition, osmotic pressure modifying ingredients and water；Wherein, the content of each main component is: by weight/mass percentage composition 0.05%-10% solid moisturizing Lubrication Composition, 0.1%-55% liquid moisturizing Lubrication Composition, the water of 0.8%-1.4% osmotic pressure modifying ingredients and surplus.
2. the compositions of protection cornea according to claim 1, it is characterised in that: described solid moisturizing Lubrication Composition weight/mass percentage composition preferred 0.1%-5%, 1%-2%, 1%-3% or 1%-4%；Liquid moisturizing Lubrication Composition weight/mass percentage composition preferred 10%-45%, 10%-55%, 10%-25% or 10%-40%；Osmotic pressure modifying ingredients weight/mass percentage composition preferred 1%-1.2%, 0.83%-1%, 0.9%-1.4% or 1%-1.4%.
3. the compositions of protection cornea according to claim 1 and 2; it is characterized in that: described solid moisturizing Lubrication Composition can be the combination of one or more in hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carrageenan and carbomer, it is preferable that one or more in hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and carbomer.
4. the compositions of protection cornea according to claim 3; it is characterized in that: the available nominal viscosity of described hydroxypropyl methyl cellulose is one or more in 6,15,50,100,250,750,1500,4000,10000 and 15000mPa s, it is preferable that 15,50,100,250,750 and one or more in 1500mPa s；Described sodium carboxymethyl cellulose can be selected for high viscosity (the sodium carboxymethyl cellulose concentration range of viscosities when 1wt% is 1000-4500mPa s), medium viscosity (range of viscosities during sodium carboxymethyl cellulose concentration 2wt% is 300-3100mPa s) or low viscosity (during sodium carboxymethyl cellulose 2wt%, the range of viscosities of concentration is 25-100mPa s), it is preferable that medium viscosity or low viscosity；The available mean molecule quantity of described hydroxypropyl cellulose is one or more in 80000,95000,140000,370000,850000 and 1150000, it is preferable that one or more in 80000,95000,140000 and 370000；The preferred medical rank of described carrageenan；Described carbomer can be selected for carbomer 910, carbomer 934, Acritamer 940, Carbopol 941, it is preferable that carbomer 934 and Acritamer 940.
5. the compositions according to the arbitrary described protection cornea of claim 1-4; it is characterized in that: described liquid moisturizing Lubrication Composition can be the combination of one or more in glycerol, PEG-4000, Polyethylene Glycol-300 and propylene glycol, it is preferable that at least one in glycerol, PEG-4000 and propylene glycol.
6. the compositions according to the arbitrary described protection cornea of claim 1-5, it is characterised in that:
Described osmotic pressure modifying ingredients is that can to make described compositions osmotic pressure be the material of 295-305mOsmol/kg；
Described osmotic pressure modifying ingredients is selected from sodium chloride, potassium chloride, sodium dihydrogen phosphate, potassium dihydrogen phosphate, zinc gluconate, one or more combination of lactic acid；
The material that the preferred final concentration (w/w) in the composition of described osmotic pressure modifying ingredients is following: sodium chloride (NaCl) 0.505%-0.710%, potassium chloride (KCl) 0%-0.021%, sodium dihydrogen phosphate (NaH2PO4) 0.052%-0.142%, potassium dihydrogen phosphate (KH2PO4) 0.027-0.166%, zinc gluconate 0-0.5% and lactic acid 0-0.01%.
7. the method preparing the compositions protecting cornea described in any one of claim 1-6, it is characterised in that osmotic pressure modifying ingredients is dissolved in filtration sterilization after water dissolution, obtains osmotic pressure and regulates solution；Adsorption treatment liquid moisturizing Lubrication Composition, obtains liquid moisturizing lubrication solution；Solid moisturizing Lubrication Composition is slowly added to one by one osmotic pressure and regulates in solution and dispersed one-tenth uniform solution, add liquid moisturizing lubrication solution, regulate infiltration with saturated nacl aqueous solution or normal saline and be depressed into 295-305mOsmol/kg, swelling overnight, filtration sterilization.
8. method according to claim 7, it is characterised in that comprise the following steps:
1). weigh that osmotic pressure modifying ingredients is soluble in water is configured to saline solution (the preferably sodium chloride (NaCl) of final concentration of 0.505wt%-0.710wt% in the composition, the potassium chloride (KCl) of 0wt%-0.021wt%, the sodium dihydrogen phosphate (NaH of 0.052wt%-0.142wt%2PO4), the potassium dihydrogen phosphate (KH of 0.027wt%-0.166wt%2PO4), the zinc gluconate of 0wt%-0.5wt% and the lactic acid of 0wt%-0.01wt%), after crossing 0.22 μm of filter membrane, 121 DEG C of steam sterilization 30min, obtain osmotic pressure and regulate solution；
2). weigh at least one in liquid moisturizing Lubrication Composition, respectively with removing activated carbon after activated carbon adsorption, be mixed to get liquid moisturizing lubrication solution；Another preparation sodium chloride weight/mass percentage composition is the sodium chloride solution of 26.5wt%, 121 DEG C of steam sterilization 30min；
3). 65 ± 5 DEG C, solid moisturizing Lubrication Composition be slowly added to one by one under stirring condition osmotic pressure regulate in solution, treat the solid dispersed open form of moisturizing Lubrication Composition become uniform solution (if solid moisturizing Lubrication Composition more than one, after being then initially charged a kind of dispersed one-tenth uniform solution, add another kind again, after by that analogy), add step 2) the liquid moisturizing lubrication solution that obtains stirring 30min, regulate infiltration with the sodium chloride solution of 26.5wt% or normal saline and be depressed into 295-305mOsmol/kg, obtain solution A；
4). by step 3) solution A that obtains is at room temperature overnight swelling (> 12h) obtains solution B, crosses 0.8 μm, 0.5 μm, 0.3 μm filter membrane filter pressing successively；
5). by step 4) liquid after filter pressing is placed in steam sterilization pan 121 DEG C of steam sterilization 30min, stir after steam sterilization, obtain clear homogeneous viscous liquid；Sufficient standing, to bubble-free, namely obtains the compositions of described protection cornea.
9. the compositions protecting cornea that a method described in claim 7 or 8 prepares; it is characterized in that; viscosity is 350mPa s-500mPa s; endotoxin content < 0.5EU/mL; transmitance > 99%; the particle number that > the is 10 μm particle number less than 600, > 25 μm is less than 15.
10. the compositions of the arbitrary described protection cornea of claim 1-7 avoids the application in the medicine of bitot's patches in preparation, and described medicine is eye drop, irrigation or liniment.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107158452A (en) * | 2017-05-05 | 2017-09-15 | 山东赛克赛斯生物科技有限公司 | A kind of bone surface of a wound hemostatic composition and its preparation method and application |
| CN112076152A (en) * | 2020-09-23 | 2020-12-15 | 江苏地韵医疗科技有限公司 | Ophthalmic composition, preparation method and application thereof |
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| CN107158452A (en) * | 2017-05-05 | 2017-09-15 | 山东赛克赛斯生物科技有限公司 | A kind of bone surface of a wound hemostatic composition and its preparation method and application |
| CN107158452B (en) * | 2017-05-05 | 2020-05-01 | 赛克赛斯生物科技股份有限公司 | Bone wound hemostatic composition and preparation method and application thereof |
| CN112076152A (en) * | 2020-09-23 | 2020-12-15 | 江苏地韵医疗科技有限公司 | Ophthalmic composition, preparation method and application thereof |
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