CN102038953B - Composite for local anesthesia before ophthalmologic operation and preparation method and application thereof - Google Patents
Composite for local anesthesia before ophthalmologic operation and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a composite for local anesthesia before an ophthalmologic operation and a preparation method and application thereof. Relative to the total volume of the composite, the composite comprises 0.05-0.3w/v% of sodium hyaluronate and 1.0-4.0w/v% of local anesthetic.
Description
Technical field
The invention belongs to medical technical field, relate in particular to a kind of composition and method of making the same and purposes that is used for the preceding local surfaces anesthesia of ophthalmologic operation.
Background technology
External coat is except universal law and principle with surgery, because the dissection of eye, the particularity of structure elaborate and physiological function has made it to form professional very strong characteristics.Under normal conditions, human information by the vision transmission accounts for more than 80%, thereby the critical role of visual performance is self-evident.Clinically, many ophthalmics need could fully recover or avoid to worsen through operative treatment.The success or failure of operation are to quality of life of patient, mental status, and family and even society all have a significant effect.In recent years, the universal and development of microsurgery, the high-tech content of treatment technology is more and more, makes ophthalmologic operation meticulousr accurately.
For a long time, the local anaesthesia mode that intraocular surgery is commonly used has the anesthesia etc. down of anesthesia in RBA, the anesthesia of ball week, the Tenon ' s capsule, anterior chamber's anesthesia and bulbar conjunctiva.These methods have its security reliability; Yet also there are many potential dangers, possibly cause especially in the art that intraocular pressure raises and oculocardiac reflex occurs, for the patient who is associated with general disease; Increased in the art especially, the possibility of postoperative generation complication, moreover these methods all do not belong to painless operation.From 1993, Schuler successfully was applied to intraocular surgery with topical anesthesia, and the step of going forward side by side has been demonstrate,proved the feasibility that diabetes, hematopathy patient is adopted topical anesthesia row intraocular surgery.Subsequently, topical anesthesia technology is carried out rapidly in intraocular surgery.
The ophthalmologic operation topical anesthesia has lot of superiority, but owing to use general anaesthetic solution to carry out the preceding local anaesthesia of art, drug solution is easy to flow out at eye; Be difficult for stopping at eyeball surface; Problems such as cause drug absorption few, anaesthetic effect is shallow, and the persistent period is short are difficult to the anaesthetic effect of expection; Can cause patient's pain; The influence operation is carried out, if raising drug level and using dosage cause complication such as corneal edema again easily, the complication of ophthalmology local anaesthesia mainly occurs in to be used the anesthetis excessive concentration or surpass the medicine maximum dose.Cause the reason of poisoning: heavy dose of anesthetis mistake is annotated and is caused in the blood vessel and absorb too fastly, causes that blood drug level is too high to cause poisoning.Anesthetis also can be poisoned along optic nerve sheath entering intracranial in addition.Clinical manifestation is nervus centralis and cardiovascular system poisoning symptom.The lighter show as xerostomia, headache, dizziness, ear toot, hypertension, ballet's disease etc.Weight person can show as respiratory and circulatory failure, disturbance of consciousness, very causes death and dies.As: the tetracaine of high concentration can cause exfoliation of corneal epithelium.To absorb rapid drug toxicity bigger for tetracaine after corneal injury.
The new drug Akten of Akorn company of the U.S. special medicine manufacturer exploitation
TM(3.5% lidocaine hydrochloride cellulose gel) is a kind of lidocaine gel product of novel UD preservative free, room temperature storage, and can be used for any operated eye operation that needs local anesthesia.The local anaesthesia drug solution of domestic listing have " eye use tetracaine hydrochloride solution ", its component be tetracaine hydrochloride, sodium chloride, water for injection, system form use tetracaine hydrochloride solution.Yet these existing products can not be longer in the holdup time of tear film, thereby the bioavailability of the local anesthetic that makes wherein to be contained is lower.
Therefore, this area presses for provides a kind of new product that is used for the preceding local surfaces anesthesia of ophthalmologic operation, can prolong in the holdup time of tear film, thereby improve the local anaesthesia bioavailability of medicament.
Summary of the invention
The present invention aims to provide a kind of compositions that is used for the preceding local surfaces anesthesia of ophthalmologic operation.
Another object of the present invention provides the method for preparing of said composition.
A further object of the present invention provides the purposes of said composition.
In first aspect of the present invention, provide the preceding local anesthesia of a kind of ophthalmologic operation to use compositions, in the cumulative volume of compositions, described compositions contains hyaluronic acid sodium and the 1.0-4.0w/v% local anesthetic of 0.05-0.3w/v%.
In another preference, described compositions pH 4.0-7.5.
In another preference, described local anesthetic is selected from lidocaine hydrochloride, tetracaine hydrochloride or tropicamide.
In another preference, described local anesthetic is selected from any one medicine in lidocaine hydrochloride or the tetracaine hydrochloride.
In another preference, also contain sodium chloride, pH regulator agent and water for injection in the described compositions.
In another preference, said compositions contains the hyaluronic acid sodium of 0.1-0.2w/v%.
In another preference, said compositions contains the 2.0-4.0w/v% lidocaine hydrochloride or contains the 1.0w/v% tetracaine hydrochloride.
In second aspect of the present invention; A kind of aforesaid preparation of compositions method provided by the invention is provided; Said method comprises step: will contain the aqueous solution and the aqueous solution that contains local anesthetic of hyaluronic acid sodium, and obtain aforesaid compositions provided by the invention, in the cumulative volume of compositions; Described compositions contains hyaluronic acid sodium and the 1.0-4.0w/v% local anesthetic of 0.05-0.3w/v%.
In another preference, said method comprises step:
(1) hyaluronic acid sodium and water for injection are mixed, obtain containing the aqueous solution of hyaluronic acid sodium; Gross weight in the aqueous solution that contains hyaluronic acid sodium wherein contains hyaluronic acid sodium 0.3-0.5w/w%;
(2) local anesthetic and water for injection are mixed, obtain containing the aqueous solution of local anesthetic; Cumulative volume in the aqueous solution that contains local anesthetic wherein contains local anesthetic 2.0-8.0w/v%; With
Aqueous solution that (3) will contain hyaluronic acid sodium and the aqueous solution that contains local anesthetic obtain aforesaid compositions provided by the invention with the water for injection dilution.
In another preference, the water for injection temperature in the step (1) is 10-30 ℃.
In another preference, step (3) is with aqueous solution that contains hyaluronic acid sodium and the aqueous solution that contains local anesthetic, and 0.22 micron microvoid thin film aseptic filtration obtains aforesaid compositions provided by the invention with the water for injection dilution.
In the third aspect of the invention, a kind of purposes of aforesaid compositions provided by the invention is provided, be used as or be used to prepare the surperficial local anaesthesia preparation of the preceding local anesthesia of ophthalmologic operation.
In view of the above, the invention provides a kind of new product that is used for the preceding local surfaces anesthesia of ophthalmologic operation, can prolong, thereby improve the local anaesthesia bioavailability of medicament in the holdup time of tear film.
The specific embodiment
The inventor is surprised to find that through extensive and deep research the compositions that bioactive substance hyaluronic acid sodium and local anesthetic constitute can be used for the preceding local surfaces anesthesia of ophthalmologic operation.And will have the gel that similar bioactive carboxymethyl chitosan and local anesthetic be prepared into same medicine concentration and carry out the pharmacodynamics contrast test, find that hyaluronic acid sodium and local anesthetic pharmaceutical composition can obtain higher drug effect.
Particularly, compositions provided by the invention contains hyaluronic acid sodium and the 1.0-4.0w/v% local anesthetic of 0.05-0.3w/v% in the cumulative volume of compositions.
Hyaluronic acid sodium is a kind of biological active substances that extensively is present in application on human skin, synovium of joint liquid, umbilical cord, aqueous humor and vitreum; Have excellent biological compatibility and high bioactivity with human body ocular tissue; Its macromolecule RF makes it have high viscosity, high resiliency and special rheological charactristics; Effect with fixed cell, the higher viscous-elastic behaviour of local anaesthesia medicine ophthalmic solution of compatibility makes the surface that is trapped in of its ability long period with it, brings into play higher anaesthetic effect; Hyaluronic acid sodium and Interstitial cell, fibroblast film Watch glass acid sodium acceptor interaction are regulated cell function, thereby are quickened the endogenous repair process, promote the surgical wound reparation.Both reached and under the conventional medicine concentration conditions, had higher anaesthetic effect, simultaneously, retained in the repair process that the hyaluronic acid sodium on ocular tissue surface also can quicken surgical wound, for clinical ophthalmologic operation anesthesia provides better choice.
Eye under normal circumstances, a hyaluronic acid sodium formation skim that exists naturally is covered in the corneal endothelium surface.Animal and human corneal endothelial all have and the bonded position of hyaluronic acid sodium specificity, but the local anaesthesia medicine long period of containing hyaluronic acid sodium be attached to eyeball surface, it is lasting and effectively absorb to medicine to help ocular tissue, and its local anaesthesia effect is effectively strengthened.
Compositions provided by the invention is liquid condition, also contains the required isotonic agent-sodium chloride of an amount of preparation drug solution, pH regulator agent-sodium hydroxide and proper amount of water for injection.Their dosage oozes drug solution osmotic pressure and 0.9% sodium chloride of its preparation etc., and pH regulator is to pH 4.0-7.5, preferred pH 5.0-7.5, more preferably 6.0-7.5.
Compositions provided by the invention can adopt following step to prepare:
A. the hyaluronic acid sodium that takes by weighing recipe quantity is dissolved in an amount of, the cool water for injection and (is not higher than 30 ℃), and processing concentration expressed in percentage by weight is the hyaluronic acid sodium aqueous solution of 0.3-0.5%; Vibrate 1-3 every day, makes dissolving evenly;
B. the local anaesthesia medicine that takes by weighing recipe quantity in addition is dissolved in the proper amount of water for injection, and dissolving is even, and making its concentrated solution of processing is more than 2 times of whole liquor strength;
C. the solution that step a and step b is obtained respectively mixes and is diluted to about 90% of cumulative volume with water for injection, regulates pH value 5.0-7.5, and water for injection adds to recipe quantity; With
D.0.22 the microvoid thin film aseptic filtration of micron, packing get eye with hyaluronic acid sodium and local anaesthetics compositions finished product.
Compositions provided by the invention has high viscoelasticity; Effect with excellent biological compatibility and fixed cell; Be easy to combine the hyaluronic acid sodium specificity binding site of human corneal endothelial; Make the surface that is trapped in of local anaesthesia medicine ability long period, effectively absorption effectively strengthens its local anaesthesia effect to medicine is lasting to help ocular tissue.
Hyaluronic acid sodium and Interstitial cell, fibroblast film Watch glass acid sodium acceptor interaction are regulated cell function, retain in the repair process that the surperficial hyaluronic acid sodium of ocular tissue also can quicken surgical wound.
Compositions provided by the invention can adopt the eye drip administration, eliminates the feared state of mind of patient to injecting anesthetic, has reduced stimulation and the damage of injecting anesthetic to patient's eyeball, has strengthened patient's cooperation consciousness and the confidence that the patient performs the operation to completion; Widened the operation indication, the patient of hypertension, heart disease, disturbances of blood coagulation can accomplish intraocular surgery equally under topical anesthesia; Avoided injecting in the eye socket cause dangerous like complication such as infection in penetration injuries of eyeball, retrobulbar hemorrhage, optic nerve injury, the eye socket, oculomotor paralysis, diplopia; Alleviate the incidence rate of oculocardiac reflex, avoided edema that the bulbar conjunctiva infiltration anesthesia causes and hemorrhage; Avoid the use of the superior rectus draught line, reduce the ptotic generation of postoperative; Avoided the local anaesthetics mistake to inject blood vessel, optic nerve sheath or brain stem and occur one cross that sex consciousness is scattered and disappeared, amaurosis fugax is dim, maincenter suppresses even severe complications such as death; Simplify OP, shortened operating time, but patient's eyeball autonomic movement in the art; The patient can advise the patient to adjust the eye position according to the operation needs at any time; To obtain best surgical field of view and angle, the preoperative and postoperative intraocular pressure is more stable, does not block the dominating neural of sphincter pupillae; Big and the high resilience of pupil in the art, iris should not be deviate from injured.Eliminated the advanced glaucoma RBA and caused that tubular visual field disappears and the danger of Whiteout.
The above-mentioned characteristic that the present invention mentions, or the characteristic that embodiment mentions can combination in any.All characteristics that this case description is disclosed can with any composition forms and usefulness, each characteristic that is disclosed in the description can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, the characteristic that is disclosed to be merely the general example of equalization or similar features.
Major advantage of the present invention is:
1, compositions provided by the invention can make the surface that is trapped in of local anaesthetics thing ability long period, and effectively absorption effectively strengthens its local anaesthesia effect to medicine is lasting to help ocular tissue.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example; Usually according to people such as normal condition such as Sambrook; Molecular cloning: lab guide (New York:Cold Spring Harbor Laboratory Press; 1989) condition described in, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
Only if definition separately, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any with the institute similar content of putting down in writing or the equalization method and material all can be applicable among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
Composition I
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 1.0 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.0g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 7.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and lidocaine hydrochloride composition I.
Embodiment 2
Composition I I
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 1.5 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 6.5 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and lidocaine hydrochloride composition I I.
Embodiment 3
Composition I II
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 2.0 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing tetracaine hydrochloride 10.0g, sodium chloride 7.4g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 5.5 with the 0.1M sodium hydroxide, water for injection adds to scale.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and tetracaine hydrochloride composition I II.
Embodiment 4
Composition I V
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 0.5 gram, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing tetracaine hydrochloride 10.0g, sodium chloride 7.4g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 5.0 with the 0.1M sodium hydroxide, water for injection adds to scale.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and tetracaine hydrochloride composition I V.
Embodiment 5
Compositions V
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 0.3 gram, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.0g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 7.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and lidocaine hydrochloride compositions V.
Embodiment 6
Compositions VI
A. under hundred grades of purification conditions, take by weighing hyaluronic acid sodium sterile product 3.5 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 7 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.0g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 7.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets hyaluronic acid sodium and lidocaine hydrochloride compositions VI.
The animal pharmacodynamics test
Embodiment 7
Purpose compares the composition I of this patent embodiment 1 preparation and the topical anesthesia intensity of 3.5% lidocaine hydrochloride cellulose gel.
Animal: 6 of rabbit
The composition I of medicine: embodiment 1 preparation; Make 3.5% lidocaine hydrochloride cellulose gel by oneself
Apparatus: 1 on shears, 2 in dropper, 6 of rabbit fixed bins, 2 of round end Glass rods.
Prepare 3.5% lidocaine hydrochloride cellulose gel:
A. under hundred grades of purification conditions; Take by weighing hydroxypropyl emthylcellulose 1.0 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection; About 0.3% hydroxypropyl emthylcellulose aqueous solution is processed concentration expressed in percentage by weight and is in sealing; Vibrate 1-3 every day, dissolved 3 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 7.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets 3.5% lidocaine hydrochloride cellulose gel.
Experimental technique:
1. get 1 of rabbit, put people rabbit fixed bin internal fixation.
With the round end Glass rod touch on two corneas, in, down, left and right 5 points, observe also record normal cornea reflection case (having or not in a moment).
3. with thumb and forefinger the left side palpebra inferior is pulled into cup-shaped, drip 3 of human sample I (push down nasolacrimal duct with middle finger in addition when splashing into. be absorbed in case medicinal liquid flows into nasolacrimal duct), make it retain 1min, let alone slime flux then.In right eyelid, splash into 3 of 3.5% lidocaine hydrochloride cellulose gels equally in addition.
4. after dripping medicine 10min, like preceding test corneal reflex.To stimulate power to try one's best the same at every turn, avoids injured corneas; Medicine should be consistent two time length that combine to stop in the membrane vesicle, and note making medicinal liquid fully contact cornea top; Stimulus object should reach cornea from the side, in case since the hands that animal is seen the experimenter in a moment promptly.After dripping medicine respectively behind the medicine, stimulate cornea in 10,30,40,50,60 minutes, observe, write down animal number of times in a moment, test corneal reflex.
Outcome record: testing time is a denominator, and in a moment number of times is a molecule, as tests five times, if any secondary in a moment, and record 2/5, and the like.
Table 1 is the order of reflection record in a moment
Table 2 is exempted from eye to the reflection case comparison in a moment of different local anaesthetics
The statistical disposition of experimental data: adopt the rank test method.
1. write down 6 groups of data of full laboratory, see experiment table 2.
2. obtain before the various medicines with medicine after two differences of number of times in a moment, be 5-0=5 like first group of difference of composition I
With before the two medicine medicines with medicine after difference by little to mixing queuing greatly, and write down their orders separately, see experiment table 2.
3. obtaining composition I sum of ranks is T=57 (being 7+8+9+10+11+12=57);
3.5% lidocaine hydrochloride cellulose gel sum of ranks is T=21 (being 1+2+3+4+5+6=21).
4. look for a little sum of ranks in two groups of sums of ranks, be T=21.
5. look into: two groups of rank test dividing value tables relatively
Work as n1=6, during n2=6, the P value is that 0.05 o'clock T value is 26, and the P value is that 0.01 o'clock fourth value is 23.
6. the result judges: because T=0.01 (23)＞T (21), so P＜0.01,
The result shows that the composition I of embodiment 1 preparation significantly is better than 3.5% lidocaine hydrochloride cellulose gel to the local anesthetic action of rabbit corneal.
Embodiment 8
Purpose: the composition I V that the comparison embodiment of the invention prepares and the topical anesthesia intensity of 1.0% tetracaine hydrochloride solution.
Animal: 6 of rabbit,
The composition I V of medicine: embodiment 4 preparations; Make 1.0% tetracaine hydrochloride solution by oneself
Apparatus: 1 on shears, 2 in dropper, 6 of rabbit fixed bins, 1 of round end Glass rod.
1.0% tetracaine hydrochloride solution of preparation:
A. under hundred grades of purification conditions, take by weighing tetracaine hydrochloride 10.0g, sodium chloride 7.4g is dissolved in (about 900 milliliters) in the proper amount of water for injection, and dissolving evenly.
B. regulate pH value to 5.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
C. with 0.22 micron filter membrane aseptic filtration, packing gets 1.0% tetracaine hydrochloride solution.
Experimental technique:
1. get 1 of rabbit, put people rabbit fixed bin internal fixation.
With the round end Glass rod touch on two corneas, in, down, left and right 5 points, observe also record normal cornea reflection case (having or not in a moment).
3. left eye drips people's composition I V3 and drips, and right eye splashes into 3 of 1.0% tetracaine hydrochloride solution.
4. after dripping medicine, stimulated rabbit cornea with Glass rod in 10,30,40,50,60 minutes respectively, observe, record animal number of times in a moment, test corneal reflex.
Outcome record: testing time is a denominator, and in a moment number of times is a molecule.Experimental data is seen table 3, table 4.
Table 3 is the order of reflection record in a moment
Table 4 is exempted from eye to the reflection case comparison in a moment of different local anaesthetics
The statistical disposition of experimental data: adopt the rank test method.
1. write down 6 groups of data of full laboratory, see experiment table 4.
2. obtain before the various medicines with medicine after two differences of number of times in a moment.
With before the two medicine medicines with medicine after difference by little to mixing queuing greatly, and write down their orders separately, see table 4.
4. obtaining embodiment 4 composition I V sums of ranks is T=57 (being 7+8+9+10+11+12=57);
1.0% tetracaine hydrochloride solution sum of ranks is T=21 (being 1+2+3+4+5+6=21).
5. look for a little sum of ranks in two groups of sums of ranks, be T=21.
6. look into: two groups of rank test dividing value tables relatively
Work as n1=6, during n2=6, the P value is that 0.05 o'clock T value is 26, and the P value is that 0.01 o'clock fourth value is 23.
7. the result judges: because T=0.01 (23)＞T (21), so P＜0.01,
The result shows that the composition I V of embodiment 4 preparations significantly is better than 1.0% tetracaine hydrochloride solution to the local anesthetic action of rabbit corneal.
Embodiment 9
Purpose compares the composition I I of this patent embodiment 2 preparations and the topical anesthesia intensity of 3.5% lidocaine hydrochloride chitosan gel.
Animal: 6 of rabbit
The composition I I of medicine: embodiment 2 preparations; Make 3.5% lidocaine hydrochloride chitosan gel by oneself
Apparatus: 1 on shears, 2 in dropper, 6 of rabbit fixed bins, 2 of round end Glass rods.
Prepare 3.5% lidocaine hydrochloride chitosan gel:
A. under hundred grades of purification conditions, take by weighing carboxymethyl chitosan 1.5 grams, put in 1000 milliliters of volumetric flasks, add (not being higher than 30 ℃) about 350 milliliters in the cool water for injection, sealing, vibrate 1-3 every day, dissolved 5 days.
B. under hundred grades of purification conditions, take by weighing lidocaine hydrochloride 35.g, sodium chloride 1.5g is dissolved in (about 100 milliliters) in the proper amount of water for injection, and dissolving evenly.
C. be diluted to about 900 milliliters with B solution adding A solution mixing and with water for injection, after the vibration evenly, regulate pH value to 7.0 with the 0.1M sodium hydroxide, water for injection adds to 1000 milliliters.
D. with 0.22 micron filter membrane aseptic filtration, packing gets 3.5% lidocaine hydrochloride carboxymethyl chitosan gel.
Experimental technique:
1. get 1 of rabbit, put people rabbit fixed bin internal fixation.
With the round end Glass rod touch on two corneas, in, down, left and right 5 points, observe also record normal cornea reflection case (having or not in a moment).
3. left eye drips 3 of sample II, and right eye splashes into 3 of 3.5% lidocaine hydrochloride chitosan gels.
4. after dripping medicine 10min, after dripping medicine, stimulated cornea in 10,30,40,50,60 minutes respectively, the observed and recorded animal is number of times in a moment, test corneal reflex.
Outcome record: testing time is a denominator, and in a moment number of times is a molecule.
Table 5 is the order of reflection record in a moment
Table 6 is exempted from eye to the reflection case comparison in a moment of different local anaesthetics
The statistical disposition of experimental data: adopt the rank test method.
1. write down 6 groups of data of full laboratory, see experiment table 6.
2. obtain before the various medicines with medicine after two differences of number of times in a moment, be 5-0=5 like first group of difference of composition I I
With before the two medicine medicines with medicine after difference by little to mixing queuing greatly, and write down their orders separately, see experiment table 2.
3. obtaining composition I I sum of ranks is T=51;
3.5% lidocaine hydrochloride chitosan gel sum of ranks is T=53.
4. look for a little sum of ranks in two groups of sums of ranks, be T=25.
5. look into: two groups of rank test dividing value tables relatively
Work as n1=6, during n2=6, the P value is that 0.05 o'clock T value is 26, and the P value is that 0.01 o'clock fourth value is 23.
6. the result judges: because T=0.05 (26)＞T (25), so P＜0.05,
The result shows that the composition I I of embodiment 2 preparations is better than lidocaine hydrochloride chitosan gel (P＜0.05) to the anesthetic action on rabbit cornea surface.
Embodiment 10
Purpose divides two groups to experimentize, and compares the composition I and the compositions V of this patent embodiment preparation respectively; The topical anesthesia intensity of composition I and compositions VI.
Animal: 12 of rabbit
Test composition I, the compositions V of 1 group of medicine: embodiment preparation
Test composition I, the compositions VI of 2 groups of medicine: embodiment preparations
Apparatus: 1 on shears, 12 in dropper, 12 of rabbit fixed bins, 4 of round end Glass rods.
Experimental technique:
1. get rabbit, put people rabbit fixed bin internal fixation respectively.
Successively with the round end Glass rod touch on two corneas, in, down, left and right 5 points, observe also record normal cornea reflection case (having or not in a moment).
3. one group of left eye drips 3 of sample I, and right eye drips 3 of sample V.Another is organized in kind left eye and drips 3 of people's composition I, and right eye splashes into 3 of compositions VI.
4. stimulate cornea in 10,30,40,50,60 minutes respectively at dripping medicine, observe animal number of times in a moment.
Outcome record: testing time is a denominator, and in a moment number of times is a molecule.
Table 7 is the order of reflection record in a moment
Table 8 is the order of reflection record in a moment
Interpretation of result: from the present embodiment experimental result; The concentration of hyaluronic acid sodium has tangible influence to the anaesthetic effect of compositions in the compositions; This maybe be because hyaluronic acid sodium concentration be low excessively, and the local anaesthesia medicine can not fully combine with the local anaesthesia medicine, thereby has influenced the hyaluronic acid sodium receptors bind of pharmaceutical composition with the eye surface; Be unfavorable for drug absorption, make its anaesthetic effect descend; Along with hyaluronic acid sodium concentration increases, anaesthetic effect strengthens, and when hyaluronic acid sodium concentration acquired a certain degree, its viscosity also increased thereupon, and drug releasing rate is reduced, thereby influences its anesthesia speed.
The above is merely preferred embodiment of the present invention; Be not in order to limit essence technology contents scope of the present invention; Essence technology contents of the present invention is broadly to be defined in the claim scope of application, and if any technological entity or method that other people accomplish are defined identical with the claim scope of application; Also or a kind of change of equivalence, all will be regarded as and be covered by among this claim scope.
Claims (9)
1. compositions is used in the preceding local anesthesia of ophthalmologic operation, it is characterized in that in the cumulative volume of compositions, described compositions contains hyaluronic acid sodium and the 1.0-4.0w/v% local anesthetic of 0.05-0.3w/v%;
Also contain sodium chloride, pH regulator agent and water for injection in the described compositions; Solution osmotic pressure and 0.9% sodium chloride etc. ooze.
2. compositions as claimed in claim 1 is characterized in that, described compositions pH 4.0-7.5.
3. compositions as claimed in claim 1 is characterized in that described local anesthetic is selected from lidocaine hydrochloride, tetracaine hydrochloride or tropicamide.
4. compositions as claimed in claim 1 is characterized in that said compositions contains the hyaluronic acid sodium of 0.1-0.2w/v%.
5. compositions as claimed in claim 1 is characterized in that, said compositions contains the 2.0-4.0w/v% lidocaine hydrochloride or contains the 1.0w/v% tetracaine hydrochloride.
6. preparation of compositions method as claimed in claim 1; It is characterized in that; Said method comprises step: will contain the aqueous solution and the aqueous solution that contains local anesthetic of hyaluronic acid sodium, and obtain compositions as claimed in claim 1, in the cumulative volume of compositions; Described compositions contains hyaluronic acid sodium and the 1.0-4.0w/v% local anesthetic of 0.05-0.3w/v%;
Also contain sodium chloride, pH regulator agent and water for injection in the described compositions; Solution osmotic pressure and 0.9% sodium chloride etc. ooze.
7. method for preparing as claimed in claim 6 is characterized in that, said method comprises step:
(1) hyaluronic acid sodium and water for injection are mixed, obtain containing the aqueous solution of hyaluronic acid sodium; Gross weight in the aqueous solution that contains hyaluronic acid sodium wherein contains hyaluronic acid sodium 0.3-0.5w/w%;
(2) local anesthetic and water for injection are mixed, obtain containing the aqueous solution of local anesthetic; Cumulative volume in the aqueous solution that contains local anesthetic wherein contains local anesthetic 2.0-8.0w/v%;
Aqueous solution that (3) will contain hyaluronic acid sodium and the aqueous solution that contains local anesthetic obtain compositions as claimed in claim 1 with the water for injection dilution.
8. method for preparing as claimed in claim 7 is characterized in that, the water for injection temperature in the step (1) is 10-30 ℃.
9. the purposes of a compositions as claimed in claim 1 is characterized in that, is used as or is used to prepare the surperficial local anaesthesia preparation of the preceding local anesthesia of ophthalmologic operation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101971399A CN102038953B (en) | 2009-10-14 | 2009-10-14 | Composite for local anesthesia before ophthalmologic operation and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101971399A CN102038953B (en) | 2009-10-14 | 2009-10-14 | Composite for local anesthesia before ophthalmologic operation and preparation method and application thereof |
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| CN102038953B true CN102038953B (en) | 2012-07-18 |
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| CN102949755B (en) * | 2011-08-16 | 2015-04-08 | 上海建华精细生物制品有限公司 | Local anesthetic drug-containing medical cavitary speculum lubricating gel preparation method and application |
| CN102580104A (en) * | 2012-02-14 | 2012-07-18 | 上海昊海生物科技股份有限公司 | Narcotic drug composition for examining or curing cavities and preparation method of narcotic drug |
| US9463201B2 (en) * | 2014-10-19 | 2016-10-11 | M.G. Therapeutics Ltd | Compositions and methods for the treatment of meibomian gland dysfunction |
| CN112022799A (en) * | 2020-09-16 | 2020-12-04 | 上海昊海生物科技股份有限公司 | High-permeability local anesthetic gel and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251979A (en) * | 1997-03-18 | 2000-05-03 | 麦尔斯·A·加林 | Controlled release of pharmaceuticals in antiterior chamber of eye |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251979A (en) * | 1997-03-18 | 2000-05-03 | 麦尔斯·A·加林 | Controlled release of pharmaceuticals in antiterior chamber of eye |
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