CN102670493B - Lomefloxacin hydrochloride eye drops and preparation method and application thereof - Google Patents
Lomefloxacin hydrochloride eye drops and preparation method and application thereof Download PDFInfo
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- CN102670493B CN102670493B CN 201210159065 CN201210159065A CN102670493B CN 102670493 B CN102670493 B CN 102670493B CN 201210159065 CN201210159065 CN 201210159065 CN 201210159065 A CN201210159065 A CN 201210159065A CN 102670493 B CN102670493 B CN 102670493B
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Abstract
The invention discloses lomefloxacin hydrochloride eye drops and a preparation method and application thereof. The lomefloxacin accounts for 0.3% of the active components. The preparation also comprises a tackifier, a buffer salt system, a wetting agent, an isoosmotic adjusting agent, a pH adjusting agent and a bacteriostatic agent, and is suitable for treating the external eye infections such asacute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomiantis, dacryocystitis, keratitis, keratohelcosis and the like caused by sensitive pathogenic bacteria. The product is characterized in that: by adding the sodium hyaluronate with a tackifying effect and a moisturizing effect, the viscosity of the lomefloxacin hydrochloride eye drops is improved, the fluidics property thereof is changed, the residence time of the eye drops in the eyes is prolonged, the sufficient absorption of the medicine is ensured, the bioavailability is increased, the administration times are reduced, the compliance of a patient is improved, and an effective treatment effect is realized.
Description
Technical field
The present invention relates to a kind of opthalmological preparation of field of medicaments, be specifically related to prescription of a kind of lomefloxacin hydrochloride eye drop that can be used for treating outer eyes infection such as responsive cause a disease microbial acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomitis, dacryocystisis, keratitis and corneal ulcer etc. and preparation method thereof.
Background technology
Lomefloxacin (lomefloxacin) is third generation quinolones broad spectrum antibiotic, and its mechanism of action is for suppressing the DNA of bacteria helicase.Gram negative bacteria, positive bacteria and part anaerobe all there is antibacterial activity.Lomefloxacin hydrochloride (lomefloxacin Hydrochloric acid) is the hydrochlorate of lomefloxacin, and its capsule, tablet, eye drop, ear drop, injection etc. are arranged clinically, is used for the treatment of the microbial bacterial infection of various sensitivities.No matter antibacterial is in active phase or all can be killed effectively resting stage, external and clinical application effect shows that this medicine is a spectrum, efficient, safe antibiotics.
The lomefloxacin hydrochloride eye drop is used for the treatment of outer eye infection such as responsive cause a disease microbial acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomitis, dacryocystisis, keratitis and corneal ulcer etc. at present.Lomefloxacin hydrochloride eye drop treatment ocular infection is carried out more research abroad, obtained gratifying effect.Bibliographical information, because this medicine penetrance is good, during local application, preceding aqueous humor Chinese medicine concentration is higher, ocular infection diseases such as bacterial conjunctivitis, bacterial keratitis, chronic dacryocystitis, hordeolum, blepharitis are all had comparatively ideal therapeutic effect, and bacteria culture media MIC result of the test page or leaf shows that this medicine has stronger killing action to the several extremely greatly pathogenic bacterium of eye.
But because this preparation is the aqueous solution of lomefloxacin hydrochloride, viscosity is low excessively, most of fluid loss behind the eye drip, loss is serious, if nictation, then loss was more serious, bioavailability is low, in order to reach effective drug level, need multiple dosing, make that patient's compliance is low, influence therapeutic effect.
In addition, because lomefloxacin hydrochloride is mildly bitter flavor, make behind the eye drop behind the eye drip, medicinal liquid can flow in the nose by tear stains, thereby makes the bitter taste sense of medicine, and the patient is not felt well.
Defective at above-mentioned lomefloxacin hydrochloride eye drop, the present invention is by changing lomefloxacin hydrochloride eye drop fluidics character, increase the medicinal liquid viscosity, prolong medicinal liquid in the eye holdup time, medicine is fully absorbed, thereby improve bioavailability, reduce the medication number of times, reduce patient's sense of discomfort, improve patient's compliance, reach effective therapeutic effect.
Summary of the invention
Learn character according to liquid fluid, at active component of the present invention, the present invention has the tackifier of adhesion-promoting effect and moisture-keeping function by adding, preferred glass acid sodium is selected suitable adjuvant simultaneously, improves the viscosity of lomefloxacin hydrochloride eye drop, its fluidics character is changed, prolong medicinal liquid in the eye holdup time, guarantee that medicine fully absorbs, improve bioavailability, reduce the medication number of times, reduce simultaneously zest greatly, improve patient's compliance, reach therapeutic effect effectively.
The object of the invention provides a kind of lomefloxacin hydrochloride eye drop
Another purpose of the present invention provides a kind of lomefloxacin hydrochloride eye drop preparation method.
A kind of lomefloxacin hydrochloride eye drop, it comprises, calculate by weight, 0.3-0.5% lomefloxacin or the husky star of hydrochloric acid Lip river magnesium as active component, 0.03-0.1% tackifier, 0.1-0.3% wetting agent, 0.01-0.03% buffer salt system, 0.4-0.7% osmotic pressure regulator, 0.01-0.03% antibacterial, 98.5-99% water for injection.
Also contain the PH regulator in the lomefloxacin hydrochloride eye drop of the present invention, it is sodium hydroxide test solution, regulates eye drop pH to 6.0.
Described tackifier is a kind of, two or more mixture in hyaluronic acid sodium, hydroxypropyl emthylcellulose, methylcellulose, carmethose, Na-alginate and the carbomer, special preferred glass acid sodium.
Described buffer comprises a kind of, two or more mixture in sodium dihydrogen phosphate-sodium hydrogen phosphate, boric acid-Borax, acetic acid-ammonium acetate, acetic acid-sodium-acetate buffer and the citrate buffer, special preferably phosphoric acid sodium dihydrogen-sodium hydrogen phosphate.
Described wetting agent is a kind of, two or more mixture in glycerol, Polyethylene Glycol and the poloxamer.
Described osmotic pressure regulator is a kind of, two or more mixture in sodium chloride, mannitol, sodium lactate and the glucose, preferred especially sodium chloride;
Antibacterial is a kind of, two or more mixture in benzalkonium bromide, benzalkonium chloride, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, butyl hydroxybenzoate, phenylpropanol, sorbitol and the thimerosal, preferred especially benzalkonium bromide.
The preferred lomefloxacin hydrochloride eye drop of the present invention, it is characterized in that lomefloxacin or lomefloxacin hydrochloride are 0.3%, hyaluronic acid sodium is 0.04%, sodium dihydrogen phosphate-sodium hydrogen phosphate is 0.02%, glycerol is 0.2%, and sodium chloride is 0.48%, and benzalkonium bromide is 0.02%, sodium hydroxide is an amount of, and surplus is water for injection.
The preparation method of lomefloxacin hydrochloride eye drop of the present invention is:
(1) with the tackifier of recipe quantity, preferred glass acid sodium is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) principal agent lomefloxacin or the lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the buffer salt system, osmotic pressure regulator, antibacterial, the wetting agent that add recipe quantity, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Maximum characteristics of the present invention are at active component of the present invention, selection is tackifier with ubiquitous acidic mucopolysaccharide hyaluronic acid sodium (Hyaluronan) in the organism, its aqueous solution has excellent biological compatibility, high viscosity elasticity, be a kind of non-Newton fluid characteristic and false plasticity, permeability, cooperate with more specific adjuvants simultaneously, mix with medicinal liquid, can improve the fluidics character of medicine, make eye drop have high viscosity elasticity, prolong the medicinal liquid eye holdup time, improve bioavailability, and by the comfort behind the lubrication increase eye drip, thereby reduced the medication number of times, improved patient's compliance, guaranteed effectively treatment.
Description of drawings
Fig. 1 tear medicine time graph
Fig. 2 aqueous humor pharmaceutical concentration-time curve
The specific embodiment
Further specify the present invention below by embodiment.The preparation method that it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention.
Embodiment 1
Prescription:
Its preparation method is:
(1) hyaluronic acid sodium with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the sodium dihydrogen phosphate-sodium hydrogen phosphate buffer of adding recipe quantity, sodium chloride, benzalkonium bromide, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Embodiment 2
Prescription:
Its preparation method is:
(1) hyaluronic acid sodium with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the sodium dihydrogen phosphate-sodium hydrogen phosphate of adding recipe quantity, sodium chloride, benzalkonium bromide, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Embodiment 3
Prescription:
Its preparation method is:
(1) hyaluronic acid sodium with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the sodium dihydrogen phosphate-sodium hydrogen phosphate of adding recipe quantity, sodium chloride, benzalkonium chloride, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Comparative Examples 1
Prescription:
Its preparation method is:
The principal agent lomefloxacin hydrochloride of recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the phosphate sodium dihydrogen buffer solution of adding recipe quantity, sodium chloride, benzalkonium chloride, glycerol, after mixing, regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Comparative Examples 2
Prescription:
Its preparation method is:
(1) hydroxypropyl emthylcellulose with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the boric acid of adding recipe quantity, Borax, sodium chloride, benzalkonium chloride, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Comparative Examples 3
Prescription:
Its preparation method is:
(1) hydroxyl third methylcellulose with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the sodium dihydrogen phosphate/sodium hydrogen phosphate of adding recipe quantity, sodium chloride, benzalkonium chloride, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add the full dose of injecting water, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
Comparative research
One, stability relatively
Get embodiment 1~4 and Comparative Examples 1~3 assembly side and commercially available product, commercially available back is in 40 ℃, placed 6 months under relative humidity 65% condition, take a sample respectively 1st month, 2 months, 3 months, 6 the end of month and once to detect, and compare with 0 month result, result of the test sees Table 1.
Table 1 lomefloxacin hydrochloride eye drop enforcement group and matched group accelerated stability are investigated the result
Two, irritation test relatively
Get the embodiment of the invention, Comparative Examples and blank adjuvant, observe behind the animal eyes contact test sample irritant reaction situation to conjunctiva, cornea and iris.
(cornea does not have muddiness, and conjunctiva does not have hyperemia, edema and secretions, the pupil circle to get 21 of the undamaged healthy rabbits of examination of eyes, both sides etc. are big, and light reflex is good), be divided into 7 groups at random by body weight, 3/group, the 1st group of left eye made own control to normal saline, and right eye is given blank adjuvant eye drop.The 2nd~7 group of left eye also made own control to normal saline, and right eye is given embodiment 1~3 and Comparative Examples 1~3.Respectively with medicine liquid droplet in tame lagophthalmos conjunctival sac, the compressing nasolacrimal duct and made the passive closure of eyes about 5~10 seconds.4 times/day, each 1~2 (about 50ul), eye drip is 14 days continuously, before each administration and after the last administration 1,2,4,24,48 and 72 hours, directly perusal or observe cornea with magnifier, iris, whether conjunctiva has zest, and zest marked, dye with 2% fluorescein sodium in good time, whether observe each position has painted, the result carries out irritant reaction scoring by table 1, with the cornea of each of each rabbit observing time, the irritant reaction score value addition of iris and conjunctiva gets total mark, with one group integration summation divided by number of animals, namely get last mean scores, and compare with left eye.Then, press the evaluation criterion judgement sample to eye irritation.When the stimulus intensity of cornea, iris, conjunctiva is inconsistent, should make evaluation respectively.All observations finish the back and put to death rabbit, and the clip eyes reach goes up palpebra inferior, and perusal has or not ANOMALOUS VARIATIONS such as redness, and are fixing in 10% formalin then, paraffin embedding, and section, histopathological examination is carried out in HF dyeing.
Eye irritant reaction score value standard
The eye irritation evaluation criterion
Score value | 0-3 | 4-8 | 9-12 | 13-16 |
Estimate | Nonirritant | Slight zest | The moderate zest | The intensity zest |
Zest the results are shown in Table 2.
Table 2 levofloxacin eye drop irritation test result
By stability study as can be known, all up to specification to the embodiment of the invention and Comparative Examples outward appearance, content, pH, related substance, but embodiment group viscosity is big and stable, and the determination data of total related substance shows that the embodiment group is being better than Comparative Examples in varying degrees.
By animal eye irritation test result as can be known, Comparative Examples 1,2,3 has slight zest, and embodiment 1,2,3, blank adjuvant and normal saline are all non-stimulated, and lomefloxacin hydrochloride eye drop nonirritant provided by the present invention is described.
Three, pharmacokinetic study
Describe the preparation sample with embodiment 1-3 and Comparative Examples 1-3, investigated its lagophthalmos anterior chamber pharmaco-kinetic processes of being in separately respectively, result of the test is seen Fig. 1-Fig. 2.
Conclusion: lomefloxacin hydrochloride eye drop provided by the present invention has good stability, to the eye nonirritant, make eye drop have high viscosity elasticity, can prolong the medicinal liquid eye holdup time, improve bioavailability, and by the comfort behind the lubrication increase eye drip, thereby the medication number of times reduced, improve patient's compliance, guarantee effectively treatment.
Claims (1)
1. a lomefloxacin hydrochloride eye drop is calculated by weight, and it contains:
Lomefloxacin hydrochloride 3.32g
Hyaluronic acid sodium 1.00g
Sodium dihydrogen phosphate-sodium hydrogen phosphate 0.20g
Benzalkonium bromide 0.20g
Glycerol 2.00g
Sodium chloride 6.80g
Water for injection is to 1000ml,
Its preparation method is:
(1) hyaluronic acid sodium with recipe quantity is scattered in an amount of 40 ℃~55 ℃ waters for injection, makes swelling, makes clear solution;
(2) the principal agent lomefloxacin hydrochloride with recipe quantity is dissolved in an amount of 60 ℃~70 ℃ waters for injection, the mixed solution of the sodium dihydrogen phosphate-sodium hydrogen phosphate of adding recipe quantity, sodium chloride, benzalkonium bromide, glycerol, after mixing, change over to again in (1), regulate pH to 6.0 with the 0.1mol/L sodium hydroxide solution, add to the full amount of water for injection, with 0.22 μ m filtering with microporous membrane, sterile packaged namely after the passed examination.
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CN104491876A (en) * | 2014-12-23 | 2015-04-08 | 中国药科大学 | Sodium hyaluronate-containing epinastine eye drops and preparation method thereof |
CN105476954B (en) * | 2015-11-30 | 2018-06-15 | 湖北兴华制药有限公司 | A kind of lomefloxacin hydrochloride injection and preparation method |
CN109833294B (en) * | 2019-04-19 | 2020-06-09 | 江苏远恒药业有限公司 | Lomefloxacin hydrochloride eye drops and preparation process thereof |
CN111700912B (en) * | 2020-06-03 | 2022-04-19 | 青岛海尔生物科技有限公司 | Eye drops suitable for limbal stem cell deficiency and preparation |
CN115337263B (en) * | 2022-08-09 | 2023-10-03 | 江苏汉晨药业有限公司 | Lomefloxacin hydrochloride eye drops |
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CN1483478A (en) * | 2003-08-02 | 2004-03-24 | 无锡杰西医药科技有限公司 | Eye preparation formula adapted for therapentic medicine |
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CN1895253A (en) * | 2005-07-11 | 2007-01-17 | 张宏业 | Lomesaline hydrochloride eye drops and preparation thereof |
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Patent Citations (4)
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CN1459291A (en) * | 2003-05-28 | 2003-12-03 | 凌沛学 | Eyedrops containing low molecular weight heparin, and its prepn. method |
CN1488404A (en) * | 2003-06-19 | 2004-04-14 | 刘继东 | Compounding use of sodium hyaluronate for eye preparation |
CN1483478A (en) * | 2003-08-02 | 2004-03-24 | 无锡杰西医药科技有限公司 | Eye preparation formula adapted for therapentic medicine |
CN1895253A (en) * | 2005-07-11 | 2007-01-17 | 张宏业 | Lomesaline hydrochloride eye drops and preparation thereof |
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Address after: 750002 the Ningxia Hui Autonomous Region street, Jinfeng District, Yinchuan City Fu Ning Lane No. 57 Patentee after: Ningxia Kang Ya pharmaceutical Limited by Share Ltd Address before: 750002 No. 6 road, hi tech Industrial Development Zone, the Ningxia Hui Autonomous Region, Yinchuan Patentee before: Kangya Pharmaceutical Industry Co., Ltd., Ningxia |