CN101234079A - Azithromycin ophthalmic gel preparation composition and preparation and application thereof - Google Patents
Azithromycin ophthalmic gel preparation composition and preparation and application thereof Download PDFInfo
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- CN101234079A CN101234079A CNA2008101015051A CN200810101505A CN101234079A CN 101234079 A CN101234079 A CN 101234079A CN A2008101015051 A CNA2008101015051 A CN A2008101015051A CN 200810101505 A CN200810101505 A CN 200810101505A CN 101234079 A CN101234079 A CN 101234079A
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Abstract
The invention discloses a novel composition of an ophthalmic Azithromycin gel preparation, a preparation method thereof and applications thereof. The researcher of the invention combines appropriate auxiliary materials with the combination of Azithromycin and citric acid to prepare the ophthalmic Azithromycin gel preparation; the combination of the Azithromycin and the citric acid in the invention can achieve better absorption of the Azithromycin, which resolves the problem that the Azithromycin is difficult to dissolve; meanwhile, the manufactured gel preparation can ensure that the drug have prolonged effects on lesion location to realize full absorption of the drug. The ophthalmic Azithromycin gel preparation of the invention has obvious pharmacological action and outstanding effects on treatment of such ophthalmic diseases as conjunctivitis, keratitis, trachoma, dacrocystitis, etc.
Description
Affiliated technical field
The invention belongs to medical technical field, be specifically related to a kind of azithromycin eye-gel preparation new compositions and its production and use.
Background technology
Ocular disease is a lot, mainly contains conjunctivitis, keratitis, the disease of ophthalmology aspects such as trachoma, dacryocystisis, glaucoma, cataract.Conjunctivitis is the commonly encountered diseases of ophthalmology, but its sickness rate is not determined at present as yet.Because most of conjunctiva directly contacts with extraneous, therefore be subjected to easily infectious in the surrounding (as antibacterial, virus, and chlamydia etc.) and the stimulation of non-infectious factor (wound, chemical substance and physical factor etc.), and the blood vessel of conjunctiva and lymphoid tissue are abundant, and self and extraneous antigen make its sensitization easily.Keratitis is meant that cornea tissue is inflamed, and the classical symptom that the patient can occur has that eyes are scorching hot, foreign body sensation is looked, easily sheds tears, had in twinge, mist and keep in dark place etc.Normal intact corneal epithelial cell is the best barrier of opposing foreign object invasion, when corneal epithelial cell sustains damage, as wound, wear contact lens, infected by microbes, courses of infection etc. for a long time, epithelial cell will wreck, and nature will cause the keratitis disease.Trachoma is a kind of common infectious eye disease, is a kind of chronic infection conjunctiva keratitis that is caused by the microorganism chlamydia trachomatis.Because of it forms hackly outward appearance on the palpebral conjunctiva surface, so the likeness in form sand grains is name trachoma.Trachoma infect cause keeping in dark place in various degree in early days, shed tears, itch, ophthalmic uncomfortable senses such as foreign body sensation, secretions increase, the conjunctiva palpebrae congestion of blood vessel, nipple hypertrophy, folliculus form, severe patient can be invaded cornea and corneal pannus is taken place.Dacryocystisis is to cause in obstruction of naso lacrimal duct, the lachrymal sac due to tear retention and the secondary bacterial infection because of reasons such as trachoma, sinusitis, tuberculosis.Common often shedding tears and blurred vision, eye burn feeling etc. with finger compressing lachrymal sac place, often has pus or mucus to be flowed out by lacrimal point.The lachrymal sac district red swelling of the skin of acute dacryocystitis, pain are suppurated after a few days and are worn out, and can leave over fistula.
Azithromycin (Azithromycin) is 15 yuan of ring macrolide antibiotics, and molecular weight is 748.99, and its chemical formula is C
38H
72N
2O
12, its chemical name is (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-and 13-[(2,6-dideoxy 3-C-methyl-3-O-methyl-α-L-nuclear-own pyrans glycosyl) oxygen]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-seven methyl isophthalic acid 1-[[3,4,6-three deoxidations-3-(dimethylamino)-β-D-wood-own pyrans glycosyl] oxygen]-1-oxa--6-azacyclo-pentadecane-15-ketone.Azithromycin can suppress multiple gram-positive cocci, mycoplasma, chlamydia and legionella pneumophilia, especially some important gram negative bacilli such as hemophilus influenza etc. had good antibacterial activity, azithromycin is commonly used to treat respiratory tract infection, skin soft-tissue infection and urogenital infections, and all obtains the good clinical curative effect.Test shows the azithromycin has a broad antifungal spectrum gram positive bacteria and gram negative bacteria are all had antibacterial action preferably.
Azithromycin is unique semisynthetic 15 yuan of ring Macrolide antibiosis ropes, water insoluble, a large amount of pharmacology and clinical experimental study are found, azithromycin has significant therapeutic effect to the treatment ophthalmic diseases, especially more remarkable to the therapeutic effect of the ophthalmic diseases of conjunctivitis, keratitis, trachoma, dacryocystisis aspect, the many clinically diseases that are used for the treatment of the ophthalmology aspect with the form of solid preparation of azithromycin, because it is long that the solid preparation medicine reaches the highest blood drug level time, greatly reduce bioavailability of medicament, also reduced the therapeutic effect of medicine simultaneously.
Summary of the invention
Research worker of the present invention is passed through lot of experiments, combines with proper auxiliary materials after azithromycin is combined with citric acid, makes eye-gel preparation; The present invention better reaches the effect that azithromycin absorbs with azithromycin and citric acid binding energy, solved the not diffluent shortcoming of azithromycin, make gel preparation simultaneously, can make medicine reach the effect of abundant absorption action time lastingly at lesions position, discover that when the weight ratio of azithromycin and citric acid is 2: 1-6: eye-gel preparation of the present invention has good pharmacological action in the time of 1 through a large amount of animal experiments; Eye-gel preparation pharmacological action of the present invention is the most remarkable when the weight ratio of azithromycin and citric acid is 3.7: 1, has the disease of obvious treatment conjunctivitis, keratitis, trachoma, dacryocystisis ophthalmology aspect.
The object of the present invention is to provide a kind of new azithromycin gel composition for eyes.
The eye-gel preparation of making after the object of the present invention is to provide a kind of azithromycin and citric acid combining.
The object of the present invention is to provide the preparation method of azithromycin gel for eye use new compositions.
The present invention also aims to provide a kind of azithromycin gel for eye use new compositions preparation that is used for the treatment of conjunctivitis, keratitis, trachoma, dacryocystisis.
The present invention is achieved by the following technical solutions:
Gel for eye use new compositions of the present invention contains:
Azithromycin, citric acid, F407, glycerol, EDTA-2Na, benzalkonium bromide, crosslinked carbomer 980
The weight ratio of azithromycin and citric acid is 2 in the azithromycin gel for eye use new compositions of the present invention: 1-6: 1.
The weight ratio of azithromycin and citric acid is 3 in the azithromycin gel for eye use new compositions of the present invention: 1-4: 1.
The weight ratio of azithromycin and citric acid is 3.7: 1 in the azithromycin gel for eye use new compositions of the present invention.
Azithromycin gel for eye use new compositions of the present invention makes that each components contents scope is in the 100g preparation: the 0.5-4g azithromycin, 0.1-0.4g citric acid, 0.1-0.2g F407,1-3g glycerol, 0.01-0.03gEDTA-2Na, the 5-15mg benzalkonium bromide, the crosslinked carbomer 980 of 0.2-0.5g.
Azithromycin gel for eye use new compositions of the present invention makes that each components contents is in the 100g preparation: 1g azithromycin, 0.27g citric acid, 0.16g F407,1.6g glycerol, 0.02g EDTA-2Na, 10mg benzalkonium bromide, the crosslinked carbomer 980 of 0.35g.
Citric acid also can be a tartaric acid in the new compositions of the present invention, Aspartic Acid, hydrochloric acid, maleic acid, a kind of in the lactobionic acid.
EDTA-2Na can be EDTA also in the new compositions of the present invention, a kind of among the EDTA-CaNa.
Glycerol can be NaCl also in the new compositions of the present invention, a kind of in the glucose.
F407 can be F68 also in the new compositions of the present invention, a kind of among the F188.
Crosslinked carbomer 980 also can be a carbomer 934 in the new compositions of the present invention, hydroxypropyl methylcellulose, a kind of in the ethyl cellulose.
Benzalkonium bromide can be a benzalkonium chloride in the new compositions of the present invention, Buddhist nun's platinum, a kind of in the thimerosal.Eye-gel preparation preparation method of the present invention:
(1) take by weighing glycerol and EDTA-2Na and add in the water for injection, the dissolving back adds benzalkonium bromide, obtains solution A; Take by weighing crosslinked carbomer 980 and put into solution A and dissolve, refrigerator was placed 8-24 hour, substrate B;
(2) take by weighing azithromycin and citric acid, add in the water for injection and stirred 1-3 hour, fully dissolving, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add F407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6-7, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5-6.5, pressure sterilizing 0.5-1 hour then, substrate B mixed with solution C, and the NaOH of reuse 2mol/L regulates PH to 6-7, added injection water adjusting stirring and promptly got the azithromycin gel for eye use.
Research worker of the present invention is made eye-gel preparation with azithromycin and citric acid, can effectively improve the therapeutical effect of medicine in focus, prolong drug is in the retention time of lesions position simultaneously, make medicine can give full play to drug effect, azithromycin combined with citric acid also effectively solved the not diffluent shortcoming of azithromycin, drug bioavailability is improved greatly, give full play to the therapeutic effect of medicine.
Preparation stabilization Journal of Sex Research of the present invention
Whether more stable for the eye-gel preparation that makes after investigating azithromycin and citric acid combining, research worker of the present invention is investigated the stability test of azithromycin gel for eye use, and the result is as follows:
1. experimental condition
Accelerated test: 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%, the time is 6 months.
Long term test: under the condition that temperature is 6 ℃ ± 2 ℃.
2. investigation project
According to Chinese Pharmacopoeia version in 2005 two appendix XIX C crude drug and pharmaceutical preparation stability test guideline, the investigation project of determining the stability test of eye-gel preparation of the present invention is visible foreign matters, content, related substance.
3. investigation method and result
3.1 accelerated test
Get eye-gel preparation of the present invention, press commercially available back, in (25 ℃ ± 2 ℃ of constant temperature, relative humidity 60% ± 10%) placed six months under the condition, each sampling once detected by above-mentioned investigation project, and compares with 0 month result duration of test the 1st, 2,3 and 6 months.
Conclusion: result of the test shows that eye-gel preparation of the present invention has carried out quickening test in 6 months by commercially available back, and the character of eye-gel preparation of the present invention, visible foreign matters, content, pH value and related substance do not have significant change substantially, the results are shown in Table 1.
Table 1 azithromycin gel for eye use accelerated test result
| Lot number | Time (moon) | Visible foreign matters | Related substance (%) | Content (%) |
| Eye-gel preparation of the present invention | 0 1 2 3 6 | Up to specification up to specification | Up to specification up to specification | 99.97 99.95 99.94 99.21 98.98 |
3.2 long term test
Get eye-gel preparation of the present invention, press commercially available back, place under 6 ℃ ± 2 ℃ condition, each sampling once detected by above-mentioned investigation project, and compares with 0 month result duration of test the 3rd, 6,9,12,18,24 and 36 months.
Conclusion: result of the test shows, has carried out long-term 12 months stability test by commercially available back, and the visible foreign matters of eye-gel preparation of the present invention, content and related substance do not have significant change substantially, the results are shown in Table 2.
Table 2 azithromycin gel for eye use long term test is investigated the result
| Lot number | Time (moon) | Visible foreign matters | Related substance (%) | Content (%) |
| Eye-gel preparation of the present invention | 0 3 6 9 12 | Up to specification up to specification | Up to specification up to specification | 99.97 99.91 99.60 99.37 99.12 |
Eye-gel preparation of the present invention is pressed commercially available back, through 6 months accelerated tests and 12 months long-term stable experiments, compares with 0 month result of the test, and every investigation index has no significant change, and having good stability of eye-gel preparation of the present invention is described.
The specific embodiment
Embodiment 1
Azithromycin: citric acid=5: 1
(1) take by weighing 1g glycerol and 0.01g EDTA-2Na and add in the water for injection, the dissolving back adds the 5mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.2g and put into solution A and dissolve, refrigerator was placed 8 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.1g citric acid, add in the water for injection and stirred 1 hour, fully dissolving, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.1g F407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 2
Azithromycin: citric acid=1: 1
(1) take by weighing 3g glycerol and 0.03g EDTA-2Na and add in the water for injection, the dissolving back adds the 15mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.5g and put into solution A and dissolve, refrigerator was placed 24 hours, substrate B;
(2) take by weighing 0.4g azithromycin and 0.4g citric acid, add in the water for injection and stirred 3 hours, fully dissolving, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.2g F407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 7, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6.5, pressure sterilizing is 1 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 7, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 3
Azithromycin: citric acid=2: 1
(1) take by weighing 1.5g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 10mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.3g and put into solution A and dissolve, refrigerator was placed 12 hours, substrate B;
(2) take by weighing 1g azithromycin and 0.5g citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.15g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.5 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.5, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 4
Azithromycin: citric acid=3: 1
(1) take by weighing 2g glycerol and 0.03g EDTA-2Na and add in the water for injection, the dissolving back adds the 8mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.4g and put into solution A and dissolve, refrigerator was placed 16 hours, substrate B;
(2) take by weighing 1.5g azithromycin and 0.5g citric acid, add in the water for injection and stirred 1.5 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.2g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.3 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 1 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.3, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 5
Azithromycin: citric acid=3.7: 1
(1) take by weighing 1.6g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 10mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.35g and put into solution A and dissolve, refrigerator was placed 12 hours, substrate B;
(2) take by weighing 1g azithromycin and 0.27g citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.16g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.3 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.3, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 6
Azithromycin: citric acid=4: 1
(1) take by weighing 2.5g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 12mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.45g and put into solution A and dissolve, refrigerator was placed 21 hours, substrate B;
(2) take by weighing 1.4 azithromycins and 0.35 citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.2g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.3 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.5, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 7
Azithromycin: citric acid=6: 1
(1) take by weighing 1.6g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 10mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.35g and put into solution A and dissolve, refrigerator was placed 24 hours, substrate B;
(2) take by weighing 1.62g azithromycin and 0.27g citric acid, add in the water for injection and stirred 1 hour, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.16g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.3 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 1 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.5, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 8
Azithromycin: citric acid=7: 1
(1) take by weighing 1.75g glycerol and 0.01g EDTA-2Na and add in the water for injection, the dissolving back adds the 12mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.25g and put into solution A and dissolve, refrigerator was placed 20 hours, substrate B;
(2) take by weighing 1.4g azithromycin and 0.2g citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.12g F407 and stirring and dissolving then, the NaOH adjusting PH to 6 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.5, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 9
Azithromycin: citric acid=8: 1
(1) take by weighing 2.5g glycerol and 0.03g EDTA-2Na and add in the water for injection, the dissolving back adds the 8mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.35g and put into solution A and dissolve, refrigerator was placed 18 hours, substrate B;
(2) take by weighing 2.4g azithromycin and 0.3g citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.15g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.2 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.3, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 10
Azithromycin: citric acid=9: 1
(1) take by weighing 1.6g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 10mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.35g and put into solution A and dissolve, refrigerator was placed 18 hours, substrate B;
(2) take by weighing 3.6g azithromycin and 0.4g citric acid, add in the water for injection and stirred 2 hours, dissolving fully, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add 0.16g F407 and stirring and dissolving then, the NaOH adjusting PH to 6.3 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 6, pressure sterilizing is 1 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.3, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 11
(1) take by weighing 1g glucose and 0.01g EDTA and add in the water for injection, the dissolving back adds the 6mg benzalkonium chloride, obtains solution A; Take by weighing the crosslinked carbomer 934 of 0.2g and put into solution A and dissolve, refrigerator was placed 8 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.2g tartaric acid, add in the water for injection and stirred 2 hours, fully dissolving, obtain azithromycin-tartaric acid saturated solution, in saturated solution, add water for injection, add 0.1g F68 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.8, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 12
(1) take by weighing 1g NaCl and 0.02g EDTA-CaNa and add in the water for injection, the dissolving back adds 5mg Buddhist nun's platinum, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.3g and put into solution A and dissolve, refrigerator was placed 8 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.3g Aspartic Acid, add in the water for injection and stirred 1 hour, dissolving fully, obtain azithromycin-Aspartic Acid saturated solution, in saturated solution, add water for injection, add 0.1g F188 and stirring and dissolving then, the NaOH adjusting PH to 6 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.7, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.2, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 13
(1) take by weighing 1g glycerol and 0.01g EDTA and add in the water for injection, the dissolving back adds the 9mg thimerosal, obtains solution A; Take by weighing the crosslinked carbomer 934 of 0.2g and put into solution A and dissolve, refrigerator was placed 8 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.4g hydrochloric acid, add in the water for injection and stirred 1 hour, fully dissolving, obtain azithromycin-hydrochloric acid saturated solution, in saturated solution, add water for injection, add 0.1gF407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6.3, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 14
(1) take by weighing 1g glycerol and 0.02g EDTA-2Na and add in the water for injection, the dissolving back adds the 7mg benzalkonium bromide, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.25g and put into solution A and dissolve, refrigerator was placed 10 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.5g maleic acid, add in the water for injection and stirred 1 hour, fully dissolving, obtain azithromycin-maleic acid saturated solution, in saturated solution, add water for injection, add 0.1g F407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Embodiment 15
(1) take by weighing 1g glucose and 0.01g EDTA and add in the water for injection, the dissolving back adds the 6mg benzalkonium chloride, obtains solution A; Take by weighing the crosslinked carbomer 980 of 0.25g and put into solution A and dissolve, refrigerator was placed 11 hours, substrate B;
(2) take by weighing 0.5g azithromycin and 0.45g lactobionic acid, add in the water for injection and stirred 1 hour, dissolving fully, obtain azithromycin-lactobionic acid saturated solution, in saturated solution, add water for injection, add 0.1g F407 and stirring and dissolving then, the NaOH adjusting PH to 6 with 2mol/L gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5, pressure sterilizing is 0.5 hour then, and substrate B mixes with solution C, and the NaOH of reuse 2mol/L regulates PH to 6, adds injection water adjusting stirring and promptly gets 100g azithromycin gel for eye use.
Azithromycin and the research of citric acid proportioning test
Azithromycin is made preparation (adopting ratio and preparation method in the specific embodiment of the invention to make) with pharmaceutic adjuvant combine salify with citric acid after, can make the medicine in the gel composition for eyes preparation of the present invention reach better absorption.This experimentation personnel are at this marked feature, in research process, azithromycin and citric acid have been carried out the weight proportion experimentation, experimental result shows that the drug absorption effect is best when azithromycin and citric acid during in the certain proportion scope, and pharmacological action is the most obvious.
In order to prove that fully azithromycin and citric acid can access ideal pharmacological action at best ratio range, this experimentation personnel have carried out following pharmacodynamic experiment.
6 age in week 140 of Kunming mouses, male and female half and half, except that the normal control group, pentobarbital sodium (40mg/kg body weight) anesthesia will be injected in the mouse peritoneal, be " # " shape with aseptic No. 1 syringe needle and scratch every mice cornea of left eye, normal control group drop 5 μ l normal saline are in anterior corneal surface, all the other mice drop 5 μ l herpes simplex virus I-types (HSV-I) were massaged eyelid 30 seconds simultaneously in anterior corneal surface.The mice of corneal infection HSV-I was pressed male and female half and half in back 24 hours in infection, every group 10, set up the normal control group separately, the gel for eye use group of the present invention that model control group, azithromycin and citric acid different proportion are made, normal control group and model group are not given any medicine and solvent, the cornea fluorescence staining, with fluorescein sodium dyeing, observe the painted situation of lesions position in infect the back the 3rd day, 5 days, 7 days, 9 days and 12 days at the crack microscopically, by following standard scoring:
0 minute: corneal stroma was Clear ﹠ Transparent, non-coloring;
1 minute: corneal stroma was muddy slightly, punctate lesion number＜10, and color range is in the cornea area 1/4;
2 minutes: corneal stroma moderate muddiness, the short dendroid focus of punctate lesion 10-20 or appearance, color range is cornea area 1/4-1/2;
3 minutes: corneal stroma severe muddiness, punctate lesion were counted 10-20 or dendroid, map shape focus are occurred, but still can judge the position of pupil edge, the 1/2-3/4 that color range is the cornea area;
4 minutes: corneal stroma was muddy fully, loses the rear portion feature, intensive dendroid or map shape focus in blocks occurred, and color range is that the cornea area is more than 3/4.
The HSV-I of this experiment can successfully infect Kunming mouse, behind the cornea virus inoculation the 3rd day, and fluorescein sodium shows that point-like, short dendroid focus can appear in cornea; And the trend that As time goes on increases the weight of is arranged, after the 8th day, the state of an illness tends towards stability.Behind the eye-gel preparation drug treatment of the present invention, fluorescein sodium dyeing shows that azithromycin and citric acid weight ratio are 2 in the eye-gel preparation of the present invention: 1-6: 1 o'clock, keratopathy had the trend that alleviates; When azithromycin and citric acid weight ratio are 3: 1-4: in the time of 1, the trend that keratopathy alleviates clearly; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect, see table 3 for details.
The influence of table 3 pair experimental mice I herpes simplex virus type keratitis extent of disease
Result of the test shows, when azithromycin and citric acid weight ratio are 3: 1-4: in the time of 1, pharmacological action is remarkable; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect.
Pharmacological testing research
1. eye irritant test
Get large ear rabbit male female half and half, body weight 2.5kg ± 0.09kg, medicine of the present invention (adopting ratio and preparation method in the specific embodiment of the invention to make) is splashed into 1 of large ear rabbit left side ophthalmic, make passive closed 10 seconds of eye immediately, every day 1 time, continuous use 3 days, after the medication 6 hours, 24 hours, 48 hours, the 4th day, the 7th day, observer's rabbit conjunctival, the cornea situation, the right side eye is for observing matched group, and by " disinfection technology standard " eye irritant test standard, it is 0 that medicine of the present invention stimulates 24 hours integrations of degree to the large ear rabbit eye, true border ophthalmic is non-stimulated, and result of the test and scoring see Table 4.
Table 4 eye irritant test result and grade form
| Group | Observed scoring in 24 hours | Observed scoring in 48 hours | Observed scoring in 4 days | Observed scoring in 7 days | ||||
| Blank group gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: gel for eye use (Zitromax of the present invention citric acid=1: 1) citric acid=3.7: 1) | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 | 0 0 0 0 |
| Plain: gel for eye use of the present invention citric acid=2: 1), (azithromycin: gel for eye use of the present invention citric acid=3: 1), (azithromycin: gel for eye use of the present invention citric acid=4: 1), (azithromycin: gel for eye use of the present invention citric acid=5: 1), (azithromycin: gel for eye use of the present invention citric acid=6: 1), (azithromycin: gel for eye use of the present invention citric acid=7: 1), (azithromycin: citric acid=8: 1) | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 | 0 0 0 0 0 0 |
| Gel for eye use of the present invention (azithromycin: citric acid=9: 1) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
2. eye-gel preparation of the present invention is to the influence of rabbit infective conjunctivitis
Get 60 of rabbit, male and female half and half, be divided into blank group, model group and eye-gel preparation group of the present invention (adopting ratio and preparation method in the specific embodiment of the invention to make) at random, every group 5, with the rabbit conjunctival sac antibacterial culturing of drawing materials, bacterium inspection feminine gender experimentizes, after smearing palpebral conjunctiva 10 times with aseptic cotton carrier, draw the scar of 5mm * 6mm "+" at upper tarsal conjunctiva with the aseptic operation knife back, the degree of depth is broken and be not advisable thoroughly (not hindering tarsus) with epithelial layer, change carry eyelid eyelid pulled into cup-shaped after, in conjunctival sac, splash into bacterium liquid (golden Portugal bacterium 5 * 10
9Cfu/ml) 4 (about 0.2ml) keeps resetting after 30 seconds.After 24 hours, draw materials and do the bacterium inspection, choosing is infected the conjunctivitis winner and is used for experiment, drips the medicine treatment, each (being equivalent to 0.05ml) every day 3 times, inflammatory activity for three days on end.Adopt non-parametric ranked data statistics Ridit analytic process to carry out statistical procedures, the results are shown in Table 5,6.
Table 5 curative effect judging standard
| Pupil | Normally | Dwindle |
Every detection index meter 0,1,2,3 minute;
Table 6 gel for eye use of the present invention is to the observation of curative effect of rabbit infective conjunctivitis
| Group | Conjunctive disorder scoring in the 3rd day after the medication |
| Blank group model group gel for eye use of the present invention (azithromycin: citric acid=3.7: 1) gel for eye use of the present invention (azithromycin: citric acid=1: 1) gel for eye use of the present invention (azithromycin: citric acid=2: 1) gel for eye use of the present invention (azithromycin: citric acid=3: 1) gel for eye use of the present invention (azithromycin: citric acid=4: 1) gel for eye use of the present invention (azithromycin: citric acid=5: 1) gel for eye use of the present invention (azithromycin: citric acid=6: 1) gel for eye use of the present invention (azithromycin: citric acid=7: 1) gel for eye use of the present invention (azithromycin: citric acid=8: 1) | 0 3 0 2 1 0 0 1 1 2 2 |
| Gel for eye use of the present invention (azithromycin: citric acid=9: 1) | 2 |
Result of the test shows that eye-gel preparation pharmacological action of the present invention is remarkable; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect.
3. gel for eye use of the present invention is to the influence of rabbit chronic conjunctivitis
Get 60 of rabbit, male and female half and half, be divided into blank group, model group and eye-gel preparation group of the present invention (adopting ratio and preparation method in the specific embodiment of the invention to make) at random, every group 5, behind tame rabbit anesthesia, under bulbar conjunctiva elongation limbus of sclera 2mm place row bulbar conjunctiva, sunken cord, the end of a thread does not expose, drip the medicine treatment after 24 hours, every day 3 times, continuous 2 weeks.By torch bore hole and the fluorescent staining slit lamp examination day by day of 2-3 people's double-blind method, curative effect judging standard the results are shown in Table 7 with infectious conjunctivitis.
Table 7 gel for eye use of the present invention is to the observation of curative effect of rabbit chronic conjunctivitis
| Group | 2 all conjunctive disorder scorings after the medication |
| Blank group model group gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: citric acid=5: 1) citric acid=4: 1) citric acid=3: 1) citric acid=2: 1) citric acid=1: 1) citric acid=3.7: 1) | 0 3 0 2 1 0 0 0 |
| Gel for eye use of the present invention (azithromycin: citric acid: 6: 1) gel for eye use of the present invention (azithromycin: gel for eye use of the present invention (azithromycin: citric acid=8: 1) citric acid=7: 1) | 1 2 2 |
| Gel for eye use of the present invention (azithromycin: citric acid=9: 1) | 2 |
Result of the test shows that eye-gel preparation pharmacological action of the present invention is remarkable; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect.
4. bacteriostatic test
The eye-gel preparation of the present invention (adopting ratio and preparation method in the specific embodiment of the invention to make) that azithromycin and citric acid different proportion are made joins in the agar culture medium that has melted, pour into into different plating mediums, establish simultaneously do not add medicinal liquid and contain penicillin, streptomycin plating medium each one, make antibacterial normal growth matched group and positive drug matched group respectively.The flat board of inoculation test bacterium liquid put in 37 ℃ of incubators cultivated 24 hours, the growing state of each bacterial strain of observed and recorded in the culture medium that eye-gel preparation of the present invention is made the results are shown in Table 8.
Table 8 gel for eye use bacteriostatic test of the present invention is observed
| Group | Staphylococcus aureus | Bacillus pyocyaneus | Escherichia coli | B family streptococcus | Klebsiella pneumoniae |
| Bacterium blank group penicillin streptomycin gel for eye use of the present invention (azithromycin: citric acid=3.7: 1) gel for eye use of the present invention (azithromycin: citric acid=1: 1) gel for eye use of the present invention (azithromycin: citric acid=2: 1) gel for eye use of the present invention (azithromycin: citric acid=3: 1) gel for eye use of the present invention (azithromycin: citric acid=4: 1) gel for eye use of the present invention (azithromycin: citric acid=5: 1) gel for eye use of the present invention (azithromycin: citric acid=6: 1) gel for eye use of the present invention (azithromycin: citric acid=7: 1) gel for eye use of the present invention (azithromycin: citric acid=8: 1) | + - - - - - - - - - - - | + - - - - - - - - - - - | + - - - - - - - - - - - | + - - - - - - - - - - - | + - - - - - - - - - - - |
| Gel for eye use of the present invention (azithromycin: citric acid=9: 1) | - | - | - | - | - |
Result of the test shows that eye-gel preparation pharmacological action of the present invention is remarkable; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect.
5. antiinflammatory test
Get 110 of Kunming mouses, 18-22g cuts off auris dextra hair on every side, is divided into 11 groups at random, azithromycin of the present invention and citric acid different proportion eye-gel preparation group (adopting ratio and preparation method in the specific embodiment of the invention to make) and matched group, 10 every group.Drawing 25 μ l with micropipettor is subjected to reagent to be applied to auris dextra auricle both sides, except the blank group, three times on the one, successive administration 5 days, in the last administration after 30 minutes, be applied to auris dextra auricle both sides with 25 μ l dimethylbenzene, dislocation is put to death after 15 minutes, with the card punch of 6mm the punching of mice ears same area is drawn materials, precision is weighed respectively, as swelling degree index, the difference of comparative drug group and group of solvents the results are shown in Table 9 with two ear weight differences.
Table 9 gel for eye use antiinflammatory of the present invention experimental observation
| Group | Left side ear auricle heavy (mg) | Auris dextra auricle heavy (mg) |
| Blank group gel for eye use of the present invention (azithromycin: citric acid=3.7: 1) gel for eye use of the present invention (azithromycin: citric acid=1: 1) gel for eye use of the present invention (azithromycin: citric acid=2: 1) gel for eye use of the present invention (azithromycin: citric acid=3: 1) gel for eye use of the present invention (azithromycin: citric acid=4: 1) gel for eye use of the present invention (azithromycin: citric acid=5: 1) gel for eye use of the present invention (azithromycin: citric acid=6: 1) gel for eye use of the present invention (azithromycin: citric acid=7: 1) gel for eye use of the present invention (azithromycin: citric acid=8: 1) | 10.12±1.15 10.60±1.23 10.98±0.14 10.68±0.13 10.64±0.10 10.62±0.13 10.64±0.10 10.65±0.13 10.78±0.15 10.88±0.14 | 24.32±2.17 12.54±0.09 17.94±0.11 14.62±0.09 13.60±0.08 13.58±0.09 14.61±0.07 14.62±0.09 16.75±0.13 17.85±0.10 |
| Gel for eye use of the present invention (azithromycin: citric acid=9: 1) | 10.95±0.13 | 18.90±0.14 |
Result of the test shows that eye-gel preparation pharmacological action of the present invention is remarkable; When azithromycin and citric acid weight ratio are 3.7: 1, reach best therapeutic effect.
Claims (10)
1. an azithromycin eye-gel preparation new compositions is characterized in that said composition contains azithromycin and citric acid.
2. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 1 is characterized in that said composition also contains F407, glycerol, EDTA-2Na, benzalkonium bromide, crosslinked carbomer 980.
3. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2 is characterized in that the weight ratio of azithromycin and citric acid is 2 in the said composition: 1-6: 1.
4. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2 is characterized in that the weight ratio of azithromycin and citric acid is 3 in the said composition: 1-4: 1.
5. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2 is characterized in that the weight ratio of azithromycin and citric acid is 3.7: 1 in the said composition.
6. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2, it is characterized in that said composition makes that each components contents scope is in the 100g eye-gel preparation: the 0.5-4g azithromycin, 0.1-0.4g citric acid, 0.1-0.2g F407,1-3g glycerol, 0.01-0.03g EDTA-2Na, 5-15mg benzalkonium bromide, the crosslinked carbomer 980 of 0.2-0.5g.
7. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2, it is characterized in that said composition makes that each components contents is in the 100g eye-gel preparation: the 1g azithromycin, 0.27g citric acid, 0.16gF407,1.6g glycerol, 0.02g EDTA-2Na, 10mg benzalkonium bromide, the crosslinked carbomer 980 of 0.35g.
8. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2, its preparation method specifically comprises following step:
(1) take by weighing glycerol and EDTA-2Na and add in the water for injection, the dissolving back adds benzalkonium bromide, obtains solution A; Take by weighing crosslinked carbomer 980 and put into solution A and dissolve, refrigerator was placed 8-24 hour, substrate B;
(2) take by weighing azithromycin and citric acid, add in the water for injection and stirred 1-3 hour, fully dissolving, obtain azithromycin-citric acid saturated solution, in saturated solution, add water for injection, add F407 and stirring and dissolving then, NaOH with 2mol/L regulates PH to 6-7, gets solution C;
(3) substrate B is used the NaOH of 2mol/L regulate PH to 5.5-6.5, pressure sterilizing 0.5-1 hour then, substrate B mixed with solution C, and the NaOH of reuse 2mol/L regulates PH to 6-7, added injection water adjusting stirring and promptly got the azithromycin gel for eye use.
9. the preparation method of a kind of azithromycin eye-gel preparation as claimed in claim 8 is characterized in that azithromycin and citric acid and water for injection dissolved stirring time are 2 hours.
10. a kind of azithromycin eye-gel preparation new compositions as claimed in claim 2 is characterized in that said composition is mainly used in the disease of treatment conjunctivitis, keratitis, dacryocystisis, trachoma ophthalmology aspect.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100031556A1 (en) * | 2021-12-16 | 2023-06-16 | Claudio Bandini | ULTRASOUND GEL |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202100031556A1 (en) * | 2021-12-16 | 2023-06-16 | Claudio Bandini | ULTRASOUND GEL |
| WO2023111973A1 (en) * | 2021-12-16 | 2023-06-22 | Bandini Claudio | Ultrasound gel |
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