CN107913246A - The medical composite for eye of local administration - Google Patents

The medical composite for eye of local administration Download PDF

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CN107913246A
CN107913246A CN201610883803.5A CN201610883803A CN107913246A CN 107913246 A CN107913246 A CN 107913246A CN 201610883803 A CN201610883803 A CN 201610883803A CN 107913246 A CN107913246 A CN 107913246A
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pharmaceutically acceptable
acid
sodium
etimicin
eye
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刘力
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Offer of the present invention prepare Etimicin and pharmaceutically-acceptable salts or its inclusion compound etc. prepare prevention or treatment people or mammal conjunctivitis, angular blepharitis, keratitis, sclerotitis, trachoma, sensitive bacterial infection eye disease, scheroma or xerophthalmia or dry eye syndrome local eye medicinal or pharmaceutical composition on application.Its eye-drops preparations, including eye drops or gel for eye use etc..Within the specific limits, medicine of the present invention has preferable security and validity.

Description

The medical composite for eye of local administration
Technical field
The present invention relates to pharmaceutical technology field, is specifically to provide prevention or treatment conjunctivitis, angular blepharitis, sand A kind of Etimicin part medical composite for eye and its system of eye, keratitis, scheroma or xerophthalmia or dry eye syndrome etc. Standby and purposes.
Background technology
Etimicin is the aminoglycoside medicaments of domestic-developed, and it is semi-synthetic water-soluble to be classified as forth generation in the world at present Property aminoglycoside antibiotics (document：Chaudhary M1,Kesava Naidu G,Kumar S,Payasi A.Comparative antibacterial activity of a novel semisynthetic antibiotic: etimicin sulphate and other aminoglycosides.World J Microbiol Biotechnol.2012Dec；28(12):3365-71.), its mechanism of action is to suppress the normal protein synthesis of sensitive bacteria, its Ear renal toxicity is low.Research institution of other countries does not find obvious toxicity to the sub-acute toxicity test of Etimicin yet.At present Intravenous drip Etimicin treats some infectious diseases, recommended dose of being grown up：For normal renal function urinary infection or complete The patient of the sexy dye of body, a 0.l~0.15g, 2 times a day, or a 0.2~0.3g, 1 times a day, it is diluted in 0.9% chlorination Sodium injection or 5% glucose injection l00ml or 250ml iv drip, when instillation 1 is small every time, the course for the treatment of is 5~10. Clinical studies show this product has a better effect following infection：Respiratory tract infection：Such as acute bronchitis, chronic bronchitis Acute attack, community's pulmonary infection etc.；Kidney and urogenital infections：Such as acute pyelonephritis, cystitis, chronic renal plevis Ephritis or chronic cystitis acute attack etc.；Skin soft tissue and other infection：Such as skin and soft tissue infection, wound, wound Infection and the infection of other sensitive bacterias with operation postpartum.
Etimicin is Formulations for systemic administration at present, and to easily lead to whole body flora unbalance or be also easy to produce drug-fast bacteria for Formulations for systemic administration. It is worth noting that, germ also constantly changes the drug resistance of aminoglycoside antibiotics, document also constantly reports such The drug resistance of medicine.163 plants of enterococcus that the detection such as Dan Zhiying is isolated from the sample of inpatient are to gentamicin and chain The height antibody-resistant bacterium (MICs >=2000mg/L) of mycin.It turns out that anti-109 plants of gentamicin height antibody-resistant bacterium (66.9%), anti-streptomycin height antibody-resistant bacterium 114 plants (69.9%).Total Test bacterial strain is to vancomycin sensitive.Prompting is faced Bed should use antibiotic with caution, select sensitive medicaments to be treated (document：Dan Zhiying, Wang Haiyi, Wu Hongfan, etc.；163 plants of intestines balls Bacterium is to high concentration aminoglycoside antibiotics resistance condition survey, Tianjin medicine, Tianjing Medical Journal, and 1997 10 phases of year；), Zheng for gentle Shi Wei peaks agar dilution detect gentamicin, amikacin, kanamycins, tobramycin, how Minimum inhibitory concentration for 6 kinds of medicines of meter Xing and neomycin to 37 plants of ESBL-producing E.colis, to aminoglycoside drug Resistant characterization and expression of drug resistance genes are studied, and detect 5 kinds of aminoglycoside drug modification genes with PCR methods, and use DNA sequencing is confirmed, it turns out that gentamicin, amikacin, kanamycins, tobramycin and Netilmicin are big to 37 plants Intestines angstrom uncommon bacterium MIC50, MIC90 are all higher than 256mg/L, its resistant rate is respectively 78.4%, 45.9%, 72.9%, 83.8% and 64.9%, and neomycin still has higher antibacterial activity (document：Zheng Weiping, Shi Weifeng；ESBLs-producing bacteria large intestine Angstrom uncommon bacterium studies aminoglycoside drug drug resistance and drug resistant gene, international laboratory medicine magazine, International Journal of Laboratory Medicine, 03 phase in 2009).
Infected keratitis is still global common diseases causing blindness so far, it is estimated that annual 5000000 people in the whole world occurs each The infected keratitis of type, about 20% blind person is blinded because of ocular infection.China is used as developing country, particularly exists Many rural areas, since people life environment is poor and the backwardness of health care consciousness, the incidence of infectious keratonosus Higher.China's luscitas caused by disease of cornea and the blind patient of eyes, occupy the 2nd of ophthalmology blinding disease by about 2,000,000 Position.Therefore, it is not only in the case where the drug-fast bacteria of Formulations for systemic administration constantly increases, develops new local anti-infective medicine reply and constantly increase Drug-fast bacteria or the control or treatment of disease be highly desirable and be worth.
Ophthalmic infection disease further includes many, and harm is not shallow, for example, conjunctivitis be conjunctival tissue extraneous and body from The effect of body factor and the general designation of inflammatory reaction occurred.Although conjunctivitis is not serious to eyesight influence in itself, work as it When inflammation involves cornea or causes complication, the infringement of eyesight can be caused.Conjunctivitis has foreign body sensation, burn feeling, itches, photophobia, stream Tear.Important sign has conjunctival congestion, oedema, exudate, nipple hyperplasia, folliculus, pseudomembrane, true film, granuloma, lymphoglandulae auriculares anteriores Enlargement etc..Trachoma and complication account for the 3% of the inpairment of vision cause of disease.Lacrimal Passage Block is the common disease and frequently-occurring disease of ophthalmology, Obstruction of lacrimal passage often results in excessive tear, can develop into acute and chronic dacryocystitis, and excessive tear is hindered beauty to the dipping of face with tear in itself, given Patient causes body and psychological discomfort, and dacryocystitis can spread into eyeball and socket of the eye as the focus of infection of eye, cause bad Consequence, and frequently as intraocular surgery contraindication (Liu Shuan, Tao Hai, Wang Wei, the epidemiological study of Lacrimal Passage Block into Exhibition, international ophthalmology magazine, 2,008 8 (1)).
Xerophthalmia is a kind of tear and ocular one kind disease caused by many factors, including ocular malaise symptoms, eyesight become Change and tear film is unstable and (or) the damage of ocular, and have potential ocular surface injury and visual disorder, with tear osmotic pressure Rise and ocular inflammatory reaction.The common sympton of xerophthalmia mainly has：Eyes are dry and astringent, foreign body sensation, pain burning heat sensation, tired, eye are itched, Sticky secretion, photophobia, severe patient affect vision, and make troubles to work and life.
In recent years, with the aging of population, increasingly aggravating for environmental pollution and largely using for various display screens, do The quantity of eye patient is in obvious increase trend.Dry eyes are as a kind of common disease at present, it has also become global pandemic disease, both at home and abroad Epidemiological investigation shows that the incidence of dry eyes is up to 7.8%~22.1%~33.7%, women illness rate apparently higher than Male, and its illness rate is in rising trend with the growth at age.According to statistics, there are dry eye patients in the U.S. more than 50,000,000, merely from Population calculates, thus it is speculated that Chinese dry eye patients are more than 300,000,000.The common sympton of xerophthalmia mainly has：Eyes are dry and astringent, foreign body sensation, pain Burning heat sensation, tired, eye are itched, sticky secretion, photophobia, severe patient affect vision, and are made troubles to work and life.Majority is dry Eye patient goes to a doctor repeatedly, and mood is urgent, and complaint dry eyes shape influences its quality of life；Half patient feels that dry eye disorders make its vision Quality is decreased obviously, and produces pessimistic idea, it is believed that can do by myself blind because of dry eyes some day.The diagnosis and treatment work of xerophthalmia is more next More be taken seriously [document 1：Du Xianghong, Liang Qingfeng, Du Xianghong, Liang Qingfeng；Dry eye patients mental handicape Progress, Chinese Journal of Ophthalmology, Chinese Journal of Ophthalmology, 2,016 52 (3)；Document 2：Yang Yong It is bright, Ma Linkun, Yong-Ming Yang Lin-Kun Ma；The Advance of Epidemiological Research of dry eyes, international ophthalmology magazine, INTERNATIONAL JOURNAL OF OPHTHALMOLOGY, 2,010 10 (10)；].
One medicine may show different effects and toxic reaction after different way of administration or medicine-feeding part administration, It is effective with a kind of method of administration, but another method of administration is invalid or poor effect, or different pharmaceutical is in different way of administration Toxicity be different, this is very common in materia medica, and at present, the gatifloxacin of oral or intravenous administration and Moses are husky Magnitude can be clearly used for ophthalmology disease treatment (document 1, Chen Zuji, gatifloxacin ophthalmology application study be in progress, eye Optometry magazine, Chinese Journal of Optometry ＆Ophthalmology, 2006,8 (6):400-402；Document 2nd, Chen Zuji；The new fluoroquinolone antibacterial agent Moxifloxacin of broad-spectrum high efficacy and its application in ophthalmology, ophthalmology research, Chinese Ophthalmic Research, 06 phase in 2005:656-659；), however, cefalexin, cefadroxil can only It is oral can not drug administration by injection or poor effect, Ceftriaxone Sodium, cefminox sodium etc. can only drug administration by injection can not be administered orally or Oral nearly unavailable, the topical treatment such as sodium cromoglycate eye-drop or spray conjunctivitis or allergy or asthma etc. are effective, are World's situation of selling well common medicine, but oral tablet easy to carry or capsule are valueless；More typically but to be generally known Example perhaps also has：The intravenous injection toxicity of the spectinomycin hydrochloride of aminoglycoside is far above toxicity during its intramuscular injection, Cause the medicine can not therapeutic dose upper vein be administered and can only intramuscular injection.However, at present open source literature do not report according to for Whether meter Xing is enough to be used in treatment or toxicity of clinical efficacy or local administration of ophthalmology disease etc., Etimicin Sulfate at present with Drug administration by injection mode treats the infectious diseases of whole body, does not there is the report of topical therapy, unknown its curative effect and local toxicity Reaction, also it is unknown its different dose profiles the effect of or the toxicity such as adverse reaction or retina or cornea or irritation etc., It can not be administered from intravenous injection and speculate that local administration has the toxic action of eye more to toxic reaction power of eye etc., medicine Sample and complexity.Eyes are the windows of human body soul, also one of most important organ of animal, and cornea of eyes etc. is non-to medicine Often sensitive, once the exposure to chemical substance is uncomfortable or causes serious adverse reaction, the result of some fine difference production very may be used It can cause serious adverse reaction or blindness etc., ophthalmically acceptable perfluoropropane gas still remains unknown cause in the qualified situation of inspection Serious blinding adverse reaction, causes tens of people to blind.Therefore, it is necessary to can study Etimicin prepare the anti-sense of local administration The valuable application of acquisition in the opthalmological of infectious diseases etc., and suitable or effective administration concentration or dosage etc..
The content of the invention
The present invention relates to pharmaceutical technology field, is related to the pharmaceutical composition of topical ophthalmic, specifically provides effective agent Amount or the Etimicin or Etimicin Sulfate of valuable therapeutic dose or its pharmaceutically acceptable salt or different crystal forms or nothing Shape thing or its solvate or its inclusion compound etc. prepare prevention or treatment conjunctivitis, angular blepharitis, trachoma, keratitis, Severe conjunctival inflammation (vernal keratoconjunctivitis), sclerotitis, episcleritis, retinal vasculitis, the eye disease of sensitive bacterial infection Application on the medical composite for eye of disease, xerophthalmia or scheroma or dry eye syndrome etc..
The Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or unformed of the present invention It is any one or more of in opthalmological or medicine of the manufacture through topical ocular administration in thing or its solvate or its inclusion compound etc. Application in compositions, or the pharmaceutical composition of topical ophthalmic, containing Etimicin or its pharmaceutically acceptable salt or not It is any one or more of in the isomorphism or amorphous article or its solvate or its inclusion compound, and its pharmaceutically acceptable load Body, wherein the Etimicin concentration that the composition contains is 0.05~1.0wt%；Or it can be expressed as：Per 1000ml eye drops Or contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or nothing in 1000g eye-drops preparations Shape any one or more of in thing or its solvate or its inclusion compound etc., with the weight of Etimicin be calculated as 0.5~10g or The unit of 500,000 units~10,000,000 is calculated as with the potency of Etimicin or Etimicin Sulfate, remaining is pharmaceutically acceptable load Body.
In the eye-drops preparations of the present invention, pharmaceutically acceptable carrier may include water, pharmaceutically acceptable thickener, pH Conditioning agent and or pharmaceutically acceptable preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, absorption enhancement Agent, solubilizer, excipient, diluent, moisturizer etc. or they in it is any one or more of.
Its pharmaceutically acceptable salt of Etimicin or different crystal forms or amorphous article or its solvate or its inclusion compound Played in eye drops or gel for eye use or topical ophthalmic with Etimicin Sulfate or Etimicin same treatment with it is pre- Anti- effect.
The pharmaceutical composition of the topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or the ophthalmically acceptable systems of 1000g Contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article in agent or its is molten It is any one or more of in agent compound or its inclusion compound etc., 1.0~10.0g is calculated as or with Etimicin with the weight of Etimicin Active potency is calculated as the unit of 1,000,000 units~10,000,000, remaining is pharmaceutically acceptable carrier；Pharmaceutically acceptable carrier Including water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable preservative or bacteriostatic agent, antioxygen Agent, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, moisturizer or in them any type or It is a variety of.
The pharmaceutical composition of the topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or the ophthalmically acceptable systems of 1000g Contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article in agent or its is molten It is any one or more of in agent compound or its inclusion compound etc., 1.0~8g is calculated as with the weight of Etimicin or is lived with Etimicin Property potency is calculated as the unit of 1,000,000 units~8,000,000, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically may be used The preservative or bacteriostatic agent of receiving, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, dilution Agent, moisturizer or they in it is any one or more of.
The pharmaceutical composition of the topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or the ophthalmically acceptable systems of 1000g Contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article in agent or its is molten It is any one or more of in agent compound or its inclusion compound etc., 1.0~6g is calculated as with the weight of Etimicin or is imitated with Etimicin Valency is calculated as the unit of 1,000,000 units~6,000,000, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of the topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or the ophthalmically acceptable systems of 1000g Contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article in agent or its is molten It is any one or more of in agent compound or its inclusion compound etc., 2.0~6.0g is calculated as or with Etimicin with the weight of Etimicin Potency is calculated as the unit of 2,000,000 units~6,000,000, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically may be used The preservative or bacteriostatic agent of receiving, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, dilution Agent, moisturizer, attenuation agent or they in it is any one or more of.In general, in addition to water, these compounds are used in eye drops Weight range generally can be 0.0001~30.0%.
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 1.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 1000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 1.5g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 1500000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 2.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 2000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 2.5g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 2500000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 3.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 3000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 3.5g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 3500000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 4.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 4000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 4.5g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 4500000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 5.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 5000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 6.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 6000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 7.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 7000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 8.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 8000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 9.0g is calculated as with the weight of Etimicin or is calculated as with Etimicin potency 9000000 units, remaining is pharmaceutically acceptable carrier；
The pharmaceutical composition of topical ophthalmic of the present invention, Ke Yishi：Per 1000ml eye drops or 1000g eye-drops preparations In contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its solvent It is any one or more of in compound or its inclusion compound etc., 10.0g is calculated as or in terms of Etimicin potency by the weight of Etimicin For 10,000,000 units, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier or sorbefacient or moisturizer etc. can include：Water, chirality or racemization or D- Or L- or the amino acid of racemization or its salt, such as D- or L- or DL-lysine, Lysine Acetate, cysteine, methionine, smart ammonia Acid or acetic arginine or L-aminobutanedioic acid or Monosodium L-aspartate, glutamic acid, glycine, taurine, alanine, valine, bright ammonia Acid, isoleucine, serine, threonine, cysteine, cystine, methionine, asparagine, glutamine, 5- hydroxyls rely ammonia Acid, histidine, phenylalanine, tyrosine, tryptophan, 3- hydroxy-prolines, 4- hydroxy-prolines, proline, homocysteine, Homocystine, homoserine, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- Amino-2-methyl propionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, the sweet ammonia of phenyl Acid, canavanine, canaline, 4- hydroxyarginines, 4- hydroxyls ornithine, homoarginine, 4- hydroxyhomoarginines, β-rely Propylhomoserin, 2,4-diamino-butanoic, 2,3- diaminopropionic acids, 2- methyl serines etc. or unit or polybasic carboxylic acid or its pharmaceutical salts, Gallic acid, propylgallate, progallin A, gallate, malic acid, butanedioic acid, ascorbic acid, L- Vitamin Cs Acid, sodium ascorbate, arabo-ascorbic acid, sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, calcium pantothenate, vitamin B1, vitamin B2, vitamin E, beta carotene, Pyridoxamine Hydrochloride, glutathione, allantoin, citric acid or sodium citrate or Lactic acid, sodium lactate, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate or trehalose, urea, thiocarbamide or maltose Alcohol, sorbierite, mannitol, lactitol, xylitol, antierythrite, Hyaluronic Acid or sodium hyaluronate or its hydrate or their medicine Learn the one or more in acceptable salt or their isomers etc., sorbierite include D- D-sorbites, anhydrous sorbierite or One or more in half water thing of sorbierite or 1 water sorbierite or sorbitol instant etc., it is above-mentioned to include its isomers；In general, Concentration range can be 0.000~5.0% used in these compounds.Above-mentioned wetting agent etc. has in the present compositions Help reduce medicine to local adverse reaction.
Pharmaceutically acceptable carrier can include pharmaceutically acceptable antioxidant and stabilizer, they can be sulfurous Acid and its salt, bisulfites, pyrosulfite, dithionite, thioacetic acid and its pharmaceutical salts, thiolactic acid and its medicine With salt, thio-2 acid and salt, monohydroxy or multi-hydroxy carboxy acid and pharmaceutical salts, tartaric acid, sorbic acid or its pharmaceutical salts, nitric acid Salt, acetic acid pharmaceutical salts, citrate, EDTA and edta salt including EDETATE SODIUM, tetra- sodium of EDTA, Ca-EDTA sodium salt (including second 2 hydrate of sodium ethylene diamine tetracetate calcium or sodium ethylene diamine tetracetate calcium, 4 hydrate of sodium ethylene diamine tetracetate calcium), (the 2- hydroxyls of N- bis- Ethyl) glycine, maltitol, xylitol, sorbierite, mannitol, vitamin E, beta carotene, Pyridoxamine Hydrochloride, ox sulphur One or several kinds in acid, amino acid or their pharmaceutically acceptable salt etc..
Pharmaceutically acceptable carrier can include pharmaceutically acceptable chelating agent can be EDTA and edta salt including EDETATE SODIUM, tetra- sodium of EDTA or its hydrate, Ca-EDTA sodium salt (including sodium ethylene diamine tetracetate calcium or sodium ethylene diamine tetracetate 2 hydrate of calcium, 4 hydrate of sodium ethylene diamine tetracetate calcium), the one or several kinds in N- bis- (2- ethoxys) glycine etc..
The eye-drops preparations of the present invention can include one or more pharmaceutically acceptable water soluble adjuvants as thickener or steady Determine agent, may be selected from the composition being made of water-soluble polymer and penetration enhancer and their mixture.The drop of the present invention The water-soluble polymer that can be used in ocular fluid include but is not limited to natural and synthesis polymer, polysaccharide, poly- aminoglycoside, It is cellulose derivative, guar gum, xanthans, glucan, carboxyl vinyl polymer, Sodium Polyacrylate, hyaluronidase, transparent Matter acid, Sodium Hyaluronate, chondroitin sulfate, locust bean gum, poloxamer, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, It is gellan gum, alginic acid, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, poly- Derivative of vinylpyrrolidone, polyvinyl alcohol or dextrin and dextrin etc. and their mixture.Used in these compounds Concentration range can be 0.00~15.0%.Above-mentioned water-soluble thickener in the present composition can coordinate for xerophthalmia Treat or prevent.
Using viscosity enahncers the viscosity of the composition of the present invention can also be made to be more than the viscous of simple aqueous as needed Degree, so as to improve the eye absorption of reactive compound by the target tissue or increase the retention time in eye.These are viscous Spending reinforcing agent is included for example, polysaccharide, glucan, hyaluronic acid, poloxamer, polyvinyl alcohol, chondroitin sulfate, polyvinyl pyrrole Pyrrolidone, methylcellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sea Algae is sugared or other reagents well known by persons skilled in the art.These reagents can typically be made with the concentration of 0.01%-5wt% With.
Thickener more preferably poloxamer, chondroitin sulfate, methylcellulose, hydroxypropyl methyl cellulose, exocellular polysaccharide Glue, hydroxyethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, hyaluronic acid or Sodium Hyaluronate, trehalose etc., eye drops In the more excellent concentration with 0.02%-1wt% use.
In gelling agent, the auxiliary gel matrix material for forming gel can be included, may be selected from poloxamer, glucose phosphate Ester, glucose phosphate ester derivant, xanthans, carboxyl vinyl polymer, Sodium Polyacrylate, cellulose derivative, polysaccharide, sulphur Aching and limp ossein, hyaluronic acid or Sodium Hyaluronate, guar gum, polyvinyl alcohol, alginic acid etc..
The excipient of hydrogel can also be chitosan, poly- (hydroxyethyl meth acrylate), poly- (N- ethenyl pyrrolidones Ketone), polyvinyl alcohol, the polymer of acrylic acid, one or more therein, wherein the carbomer series such as carbomer series may include The one or more therein such as carbomer 934, carbomer940, Acritamer 940, Carbopol 941, CARBOPOL 974P, in general, this Concentration range used in a little compounds can be in 0.001-25.0%.
Hyaluronic acid or Sodium Hyaluronate include but not limited to macromolecular hyaluronic acid (molecular weight ranges 1,800,000~ 2200,000), middle molecular weight hyaluronic acid (molecular weight ranges 1,000,000~1,800,000), micromolecule hyaluronic acid (molecule Measure scope 200,000~1,000,000), more preferably in, micromolecule hyaluronic acid.
Pharmaceutically acceptable auxiliary material is also selected from polyoxygenated including solubilizer (including may include surfactant), solubilizer Ethene list oleic acid sorbitan ester, Tween-80, VE succinic acid macrogol ester (vitamin E TPGS), glycerine-poly- second Glycol epoxide stearate, PEG-32 glyceryl palmitostearates, lauryl sodium sulfate, Sorbitan monolaurate, Polyethylene glycol, polyethylene glycol 100-20000 (polyethylene glycol 200, polyethylene glycol 400, Macrogol 600, Macrogol 4000, Macrogol 6000, PEG 8000 etc.), polyethylene glycol-12-hydroxystearate, polyvinylpyrrolidone, polyethylene Alcohol, amino acid or its pharmaceutical salts, pharmaceutically acceptable alcohols, pharmaceutically acceptable polyalcohol, poloxamer, poloxamer188, It is azone, laurocapram, cyclodextrin or cyclodextrin pharmaceutically acceptable derivates, amide-type or urea and derivative, inorganic Acid is inorganic acid salt, pharmaceutically acceptable organic acid or acylate, pharmaceutically acceptable carbohydrate or sugar lime, pharmaceutically acceptable Amine etc. or their chiral isomer etc. or their pharmaceutically acceptable salt in one or more；Cyclodextrin includes Alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin etc..
The preparation of the pharmaceutical composition of the present invention with multiple dose form when being provided for preventing the preservative of contamination of products Or bacteriostatic agent, pharmaceutically acceptable preservative or bacteriostatic agent can be included, such as organic acid bacteriostatic agent, benzoic acid, sorb Acid or its pharmaceutical salts, dehydroactic acid sodium, the esters of oxybenzene esters compound or nipalgin, methyl hydroxybenzoate, P-hydroxybenzoic acid Propyl ester, phenmethylol, benzyl carbinol, phenoxetol, anesin, quaternary ammonium derivative (Domiphen bromide, benzalkonium chloride, benzalkonium bromide, Hexadecyl ammonium methyl, cetylpyridinium chloride, Benzethonium etc.), (polyquaternium -1, PQ-1, moors sharp chlorine to polyquaternium Ammonium), it is organic Mercury derivatives (thiomersalate, thimerosal, phenylmercuric acetate and phenylmercuric nitrate etc.), pharmaceutically acceptable Phenol compound, o-phenyl phenol, chloreresol, chlorohexidene etc. or their pharmaceutically acceptable salt etc. in one kind or It is several.In general, concentration range used in these compounds can be 0.0005-5.0%, this depends on selected preservative Or bacteriostatic agent；Esters, sorbic acid or its pharmaceutical salts of nipalgin, thimerosal, polyquaternium -1 are more preferably used as resisting micro- life Thing preservative；These preservatives are typically used with the concentration of 0.001%-1.0wt%；
The pharmaceutically acceptable isotonic regulator that uses can be included but not in the preparation of the pharmaceutical composition of the present invention It is limited to：Sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium phosphate, sodium sulphate, sodium nitrate, glucose, boric acid, borax, glycerine, It is propane diols, polyethylene glycol, PEG-400, PEG300, PEG-200, glucose, fructose, maltitol, xylitol, sorbierite, sweet Reveal the one or more in alcohol, inverted sugar, dextran, sodium lactate or sodium lactonic, gluconic acid or sodium gluconate etc.； Physiological saline (being usually the solution of sodium chloride)；Or isotonic adjusting is carried out with buffer solution, buffer solution can be Sharpe phosphoric acid Salt buffer (is made of, Acidic Liquid two kinds of storing solutions：8.4g/l containing anhydrous sodium dihydrogen phosphate, alkalies：Phosphoric acid disodium hydrogen 9.4g/l, in use, be obtained by mixing according to different proportion, if necessary plus appropriate sodium chloride is into isotonic), Palitzsch's buffer solution (it is made of two kinds of storing solutions, Acidic Liquid：Boronic acid containing 12.4g/l, alkalies：Borax 19.1g/l, in use, according to not year-on-year Example is obtained by mixing, and if necessary plus appropriate sodium chloride is into isotonic), Ji Fei Shi buffer solutions, [buffer solution etc. is in medicament for borate buffer etc. It is described on：Tu Xide, the Zhang Jun longevity, Zhu Jiabi, pharmacy (third edition), 2002, Beijing, People's Health Publisher].
The component and recipe quantity of the pharmaceutically acceptable pH adjusting agent used in the preparation of the pharmaceutical composition of the present invention It is this area conventional selection, can is pharmaceutically acceptable inorganic acid or organic acid or its pharmaceutical salts, inorganic base or organic The lewis acid or alkali of alkali or its pharmaceutical salts or broad sense, can contain one or several kinds, it includes but not limited to salt Acid, sulfuric acid or its pharmaceutical salts, boric acid or its pharmaceutical salts, borax, phosphoric acid or its pharmaceutical salts, acetic acid or its pharmaceutical salts, such as sodium acetate Deng lactic acid and lactic acid pharmaceutical salts, citric acid or its pharmaceutical salts, tartaric acid or citric acid or its pharmaceutical salts, disodium hydrogen phosphate, phosphoric acid Sodium dihydrogen, potassium dihydrogen phosphate, ascorbic acid, sodium ascorbate, arabo-ascorbic acid, sodium isoascorbate, sodium hydroxide, hydroxide Potassium, sodium carbonate, sodium acid carbonate, trihydroxy aminomethane, diethanol amine, monoethanolamine, diisopropanolamine (DIPA), 2- amino -2- (hydroxyl first Base) 1,3-PD amine, N- methyl glucoses amine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, such as glucuronic acid, grape Saccharic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, amino acid or their pharmaceutically acceptable salt or its hydrate etc. In one or several kinds.
The preparation of the topical ocular administration of the preparation of the present invention includes eye drops, situ-gel eye drops, heat-sensitive gel drop Ocular fluid, gel for eye use, eye ointment etc.；Eye drops can unit dose package or multiple-unit container.Wherein, situ-gel eye drops or temperature-sensitive Gel eyedrop, the pharmaceutically acceptable auxiliary material of gel for eye use may include thickener, surfactant, antioxidant, chelating Agent or metal ion couplant, preservative or bacteriostatic agent, pH adjusting agent, osmotic pressure regulator etc..
Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its is molten Any one or more of thermosensitive type situ-gel eye drops in agent compound or its inclusion compound, its pharmaceutically acceptable auxiliary material can Including thickener, surfactant, antioxidant, chelating agent, preservative, pH adjusting agent, osmotic pressure regulator etc..
The thermosensitive type situ-gel eye drops or temperature-sensitive of a kind of Etimicin Sulfate or its pharmaceutically acceptable salt etc. coagulate The preparation method of glue eye drops, it may include following steps：(1) partial purification water is heated to 50 DEG C~60 DEG C, will pharmaceutically may be used The auxiliary material of receiving is dissolved in purified water, dissolving postcooling to room temperature；(2) Etimicin Sulfate is added to institute in step (1) Solution in, stirring is to being completely dissolved；(3) by thermosensitive type gel rubber material dispersing and dissolving in the partial purification water that water temperature is room temperature In；(4) solution of step (2) and (3) is mixed, solution ph is adjusted to 6.2~7.8, be settled to required volume, crossed and filter out Bacterium, it is aseptic subpackaged in eye drop bottle, to obtain the final product.
The prescription of gel for eye use can be as follows：
Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its is molten Agent compound or its inclusion compound (0.5~10g), gel-type vehicle (carbomer series, carbomer 934, carbomer940, carbomer 940th, Carbopol 941, CARBOPOL 974P etc., polyvinyl alcohol, chitosan, poloxamer, methylcellulose, hydroxyethyl cellulose Deng), pharmaceutically acceptable thickener, stabilizer (antioxidant or stabilizer), preservative or bacteriostatic agent, osmotic pressure regulator, PH adjusting agent etc., and pure water add to 1000g.
Wherein, gel-type vehicle is usually 0.5~100.0g, more preferably 1~60.0g, more preferably 1~20.0g；
Stabilizer (antioxidant or stabilizer) is usually 0.05~200g, more preferably 1~150g, more preferably 1~120g；
Preservative or bacteriostatic agent are usually 0.005~20g, more preferably 0.01~2g；
Osmotic pressure regulator is usually 0.1~80.0g, more preferably 1~60.0g, more preferably 1~40.0g；
PH adjusting agent is usually 0.1~20.0g, more preferably 1~20.0g, more preferably 1~10.0g；
And supply 1000ml or 1000g with water.
Eye drip liquid and preparation method thereof may include the following steps：
The preparation process of eye drops：Etimicin Sulfate or Etimicin are dissolved in distilled water or pure water or water for injection Or in the pure water or water for injection of acidifying, auxiliary material is dissolved in pure water or the injection of distilled water or pure water or water for injection or acidifying With in water, both are mixed, is stirred and evenly mixed, adjust solution ph for 5.8-7.8 between (more preferably pH value be 6.0-7.5 it Between), osmotic pressure is adjusted, adds water to full dose, filtering, filling, sterilizing, packaging.
Eye drops removes heat source and bacteria remover filter type in preparing can add the activated carbon with liquid measure 0.005~1% Heat source is removed, 0.20~0.8 μm of filtering with microporous membrane, pressure sterilizing, can also use ultrafiltration.In hyperfiltration process, ultrafilter is optional With flat, rolling, tubular type, hollow fiber form or justify boxlike etc., more preferably rolling and hollow fiber form ultrafilter, using retention After relative molecular mass is 30,000 to 300,000 membrane filtration, or again using the ultrafiltration of retention relative molecular mass 4000~60000 The ultrafiltration membrane of membrane filtration, preferably relative molecular mass 6000~30000.
The present invention provides can be selected effective for the pharmaceutical preparation of topical treatment ocular infection disease and xerophthalmia Elementary sum accords with toxicity and the relevant dosage range of curative effect, these are not open before.
The preparation of the present invention prevent or treat the conjunctivitis of people or mammal, angular blepharitis, trachoma, keratitis, Severe conjunctival inflammation (vernal keratoconjunctivitis), sclerotitis, episcleritis, retinal vasculitis, the eye disease of sensitive bacterial infection When sick, xerophthalmia or scheroma or dry eye syndrome etc., the eye drops dosage of 4 method of the embodiment of the present invention may generally be：One day 2-5 Secondary, each 1-3 drops, children can be with weight loss.The dosage of gel for eye use can suitably be adjusted according to the dosage of eye drops It is whole.
The topical treatment whether medicine of the present invention can be used for eyes is studied by following experiment
First, the irritation evaluation experimental of drug combination preparation of the invention to rabbit eyes
1st, test objective
The power reacted after dosing eyes of pharmaceutical composition of the observation present invention, with investigate Etimicin Sulfate or according to for Whether the pharmaceutical composition of rice star and different groups occurs adverse reaction and its degree to rabbit eyes.
2nd, test method：Every group takes weight 2.5-3kg healthy rabbits 4 (half male and half female, random packet), preselects animal flesh Eye observation：Cornea is without muddy, conjunctiva without congested, oedema and secretion, and pupil is circular, and both sides etc. are big, good to light reflection.
Ophthalmic slit lamp inspection：Corneal transparency, no cloudiness, spot screen, iris texture is clear, no congestion and edema.
Fluorescent staining：L0% fluorescence rope sodium injections, face the used time with 5 times of normal saline dilution, fixed rabbit, per lagophthalmos Clean with normal saline flushing after dripping, observation cornea uncolored person is normal for cornea, pre- select anophthalmia disease through above-mentioned and is good for Health rabbit is used for this experiment.
3rd, single-dose Eye irritation is tested
Eye drops and the eye drops of dosage treatment control group 1 that in the present invention prepared by each embodiment method are instilled into every rabbit The eye conjunctiva of right eye is intracapsular, passively closes 10s, and physiological saline is added dropwise as blank control, after administration, lagophthalmos eyelid to left eye with method Passive closure about 10 seconds, after record administration 1,2,4,24,48,72 it is small when, 7 days eye local reaction situations.With reference to《Chemicals Irritation, anaphylaxis and hemolytic investigative technique guideline》Middle Eye irritation reaction standards of grading corneal, iris and conjunctiva point Do not scored (table 1), judges whether eye drops has irritation.
4th, multiple dosing Eye irritation is tested
First dyed before daily 1st dropwise addition eye drops with 2% Fluress and (use the l0% of 5 times of normal saline dilution Fluorescence rope sodium injection), then judge whether cornea is undermined degree of injury with ophthalmic slit lamp inspection, then use physiological saline After gently rinsing, eye drops and the eye drops of dosage treatment control group 1 prepared by each embodiment method instill every rabbit right eye Eye conjunctiva it is intracapsular, passively close 10s, give left eye that physiological saline is added dropwise as control with method, during the daily morning about 9 from every about 3h drops medicine 1 time, drips 3 times, successive administration 7 days altogether, reference《Chemical induced irritation, anaphylaxis and hemolytic investigative technique instruct Principle》Middle Eye irritation reaction standards of grading corneal, iris and conjunctiva score respectively, judge to give drop from its mean scores Whether ocular fluid has irritation.During observation corneal injury is checked with fluorescein sodium, and with slit lamp examination corneal transparence and rainbow Film texture changes.
5th, experimental result (table 2) single-dose Eye irritation is tested：Standards of grading, dosage treatment control are reacted according to Eye irritation Eye drops corneal, the iris stimulate the reaction synthesis mean scores of group 1 are 5, and the eye drops stimulate the reaction of other embodiments is comprehensive It is 0~3 to close mean scores.
Multiple dosing Eye irritation is tested：The Etimicin eye drops successive administration of the present invention 7 days, except dosage treatment control group 1 and the eye drops of embodiment 8 and embodiment 9 outside, it was observed that rabbit cornea it is transparent, without muddiness, iris is without congested, swelling, texture Clearly, without significant difference compared with left eye；Iris after the only single or multiple administrations of the rabbit of embodiment 8 and embodiment 9 or Conjunctiva mild hyperaemia or slight oedema, but comprehensive mean scores are still within 3.Show the Etimicin eye drops of the present invention It is nonirritant to lagophthalmos.After more than 1 eye drip of dosage treatment control group, when checking lagophthalmos, there is scream uneasiness, situation about hiding； In addition, the tissue pathological slice HE dyeing detections of 10 experimental animal eyeballs (including cornea, iris, conjunctiva), except dosage treatment Outside control group 1, notable difference is not found.
Table 1, eye irritation laboratory strength standards of grading
Rank Mean scores Evaluation
1 0~3 It is nonirritant
2 4~8 Slight stimulation
3 9~12 Moderate irritation
4 13~16 Intensity irritation
Table 2, each embodiment single-dose, the irritant experiment result of multiple dosing
Sample Single-dose total score Multiple dosing total score As a result
Embodiment 1 0 0 It is nonirritant
Embodiment 3 0 0 It is nonirritant
Embodiment 4 0 0 It is nonirritant
Embodiment 5 0 0 It is nonirritant
Embodiment 6 0 0 It is nonirritant
Embodiment 7 0 0 It is nonirritant
Embodiment 8 0 0.5 It is nonirritant
Embodiment 9 0.25 1 It is nonirritant
Dosage treatment control group 1 5 12 Light moderate irritation
The preparation of 1 Etimicin eye drops of dosage treatment control group
Prescription：Etimicin Sulfate (in terms of Etimicin) 18g, sodium dihydrogen phosphate 0.6g, disodium hydrogen phosphate 1.2g, hydrogen-oxygen It is appropriate to change sodium solution；Water for injection 400ml, 0.8% physiological saline (sodium chloride) are settled to 1000ml.
Preparation process：Etimicin Sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, the sodium chloride that precision weighs recipe quantity add 400ml waters for injection dissolve, and after stirring evenly, it is 6.8 to adjust pH value with appropriate sodium hydroxide solution, with 0.8% physiology salt Water is settled to 1000ml, obtains liquid；By above-mentioned liquid through 0.45 μm of filtering with microporous membrane, liquid after the assay was approved, by 8ml/ bottles Filling, sealing, 121 DEG C of sterilizings, let cool, examine, packaging.
There is obvious stimulation to make the eyes of rabbit after the eye drops eye drip of experiment discovery dosage treatment control group 1 With, and other each embodiment groups are nonirritant.
2nd, the treatment evaluation experimental of drug combination preparation of the invention to Bacteritic Keratitis in Rabbits
1st, in vivo studies rabbit eye injury type bacterial keratitis animal model
Escherichia coli, staphylococcus aureus, Pseudomonas aeruginosa and the blood that will be inoculated on plain agar culture medium flat plate The micrococcus scarlatinae of agar plate is scraped with oese, and 2 × 10 are made into respectively with physiological saline9(photoelectricity is than turbid by CFU/ml Instrument measured concentration), reference literature method (Xiao Yi, Li Chen, Mei Qi Ping, etc.；Rabbit eye injury type bacterial keratitis animal model Foundation, Shaanxi medical journal, 2003；32(2):187-188), with 1.0g/kg urethane auricular vein injecting anesthetic rabbit (healthy rabbits, weight about 2.5-3kg, half male and half female), causes rabbit cornea damage (eyes) with corneal trephine, pulls open eye under lagophthalmos Eyelid, makes rabbit per four kinds of bacterium 0.1ml of ocular infections, continuous to instill 2 days, takes eye discharge with Sterile Saline cotton swab after 2d, puts Enter in 4ml sterile saline bottles, Bacteria Culture is done to its liquid with agar plate method.
After modeling, there is obvious inflammatory reaction in lagophthalmos, and conjunctival hyperemia is serious, and corneal edema, superficial ulcer is formed, ulcer There is more secretion in face, and rabbit activity is reduced, and appetite reduces, and when checking lagophthalmos, scream is uneasy.
2nd, packet is set, random packet：Treatment group A (eye drops prepared by 2 method of bacterial infection+implementation), treatment group B (senses Contaminate the eye drops of 3 method of bacterium+implementation), treatment group C (eye drops of 4 method of bacterial infection+implementation), treatment group D (bacterial infections+reality Apply the eye drops of 6 methods), treatment group E (eye drops of bacterial infection+dosage treatment control group 2), positive controls (bacterial infection+ Drip physiological saline), every group of 5 rabbit.Normal group (normal rabbits, are uninfected by bacterium, only drip physiological saline) 3.Treatment Different eye drops 0.2ml/d (eyes) in the group drop present invention, positive controls and Normal group drop physiological saline 0.1ml/d (eyes), every 0.2ml, 4 times/d, continuity point medicine 7 days (d).Once scored every 24h eyes, continuous observation 7d, appraisal result, which takes statistics, learns t inspections processing.And the 1d before administration, after administration 7d with Sterile Saline cotton swab take discharge of eye into Row Bacteria Culture, is placed in 37 DEG C of incubators and judges yin and yang attribute result after culture 48h.
Wherein, the preparation of the Etimicin eye drops of dosage treatment control group 2：
By the Etimicin Sulfate of recipe quantity [6000 unit of potency of Etimicin Sulfate equivalent to Etimicin 6mg (with Etimicin meter)], sodium chloride, sodium pyrosulfite in 920ml distilled water, stirring and dissolving, with sodium hydroxide solution adjust solution PH value adds water for injection and adds to 1000ml to 7.0 or so, is filtered with 0.22 μm of microporous barrier cartridge filter, after measure is qualified, Filling by 5ml/ bottles, sealing, 100 DEG C sterilize 30 minutes, let cool, and examine, packaging.
3rd, the results show (table 3)：Normal group Bacteria Culture is negative to continuity point medicine after 7 days, positive controls bacterium It is positive, treatment group substantially to cultivate as the positive, treatment group E (eye drops of bacterial infection+dosage treatment control group 2) Bacteria Culture A Bacteria Cultures are largely feminine gender, and the Bacteria Culture for the treatment of group B, treatment group C, treatment group D are negative substantially.
Rabbit discharge of eye bacteria cultivation results：Compared with positive controls, treatment group C, the eye drops for the treatment of group D are to big Positive eye number after the uncommon bacterium of intestines angstrom, staphylococcus aureus, Pseudomonas aeruginosa, the administration of S. pyogenes infection group is after 7d is treated There is notable difference (P<0.01).The eye drops for implementing 4 methods, the eye drops for implementing 6 methods have the therapeutic effect of highly significant；According to It is 0 grade that standards of grading, which carry out rabbit eyes inflammatory score,：Eyelid is clear without hyperemia, corneal transparency, iris texture without redness, conjunctiva Clear, eye becomes clear no secretion, belongs to healing or basic cures.The treatment group B for implementing the eye drops of 3 methods also has highly significant Therapeutic effect, it is 0 grade that rabbit eyes, which are carried out inflammatory score to be 3,：Eyelid is without redness, and conjunctiva is without hyperemia, corneal transparency, iris Clean mark, eye become clear no secretion, belong to healing or basic cure；Another rabbit eyes still have secretion, but conjunctiva without Hyperemia, eyelid also without redness, show that the rabbit state of an illness has improved.
Compared with positive controls, treatment group A also has significant difference (P<0.05), while to rabbit eyes inflammation is carried out Scoring, 0.5 grade to 1 grade：Conjunctiva mild hyperaemia, eye is slightly red and swollen, and secretion covering is less than 6mm；The eye drip of 2 method of obvious embodiment Liquid be also it is effective, though the optimal dosage of non local administration.And the positive for bacteria after the eye drops in treatment of dosage treatment control group 2 Rate does not have difference almost up to 100% with positive controls, and it is 2 grades to 3 grades to carry out inflammatory score to rabbit eyes, illustrates treatment Substantially it is invalid.
The result of lagophthalmos secretion Bacteria Culture after table 3, eye drops in treatment
Embodiment
Except in embodiment and it is indicated otherwise when, all numerical value used should be by specification and claims It is interpreted as being modified with term " about " in all examples, therefore, unless the contrary indication, this specification and appended The numerical parameter gone out given in claims is approximation, the required property that it can be according to sought by by present disclosure Matter and change, at least, and not be intended to limit the application of doctrine of equivalents right, each numerical parameter takes an examination The number and routine for considering effective digital round up method to explain.
Although the number range and parameter that set the wide scope of disclosure are approximations.But institute in a particular embodiment The numerical value provided is reported as precisely as possible, and any number is substantially comprising some by finding in their own test The error that standard deviation is necessarily led to.
It is pointed out that unless in text clearly in addition explanation, used in this specification and the appended claims Singulative "one", " one kind " and "the" include the plural form of referring to thing, so, such as.If refer to containing " one Mixture including two or more compounds during the composition of kind compound ", it is further noted that unless herein clearly In addition ground illustrates that term "or" generally includes "and/or".
This " solvate " referred to herein as further include the molecule of the solvent molecule penetrated into crystal structure, atom and/ Or the crystal form of ion, the solvent molecule of solvate can be at regularly arranged and/or disorderly arranged, including hydrate.
Different crystal forms or polymorphic referred to herein as with identical chemical composition but formed the molecule of crystal, atom and/ Or the different crystal of space arrangement of ion.
Pharmaceutical composition
" pharmaceutical composition " used herein refers to the composition of medicine, and the pharmaceutical composition can contain at least one Pharmaceutically acceptable carrier.
" pharmaceutically acceptable excipient " used herein refers to the medicine that the compound for being suitable for occasionally providing herein is administered With carrier or solvent, it includes, and well known to a person skilled in the art any examples of such carriers suitable for specific administration mode.
In the preparation process of various embodiments of the present invention, the situation of the title of each component has been limited in the prescription of embodiment Under, for simplicity for each component in prescription, can carry out simplifying appellation or the property omitted address.
The concentration unit used in description of the invention has molar concentration (M) or equivalent concentration (N), or percent concentration Second (s), minute (min), hour (h) etc. can be used Deng, chronomere, and volume unit, which can be used, rises (l or a L), milliliter (ml), micro- Rise (μ l), mass unit can use gram (g), milligram (mg) etc..
In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, still It should be appreciated that these descriptions are simply further explanation the features and advantages of the present invention, rather than to the claims in the present invention Limitation.
Illustrate the effect of the present invention with specific embodiment below, but protection scope of the present invention is from the limit of following embodiments System.
Specific embodiment
The preparation of 1 Etimicin Sulfate eye drops of embodiment
Preparation process：Take the Sodium Hyaluronate of recipe quantity to be added to heating for dissolving in suitable water for injection to let cool, separately take Etimicin Sulfate is dissolved in water for injection, sequentially adds boric acid, borax, taurine, the benzalkonium chloride of recipe quantity, and stirring makes Dissolving, then adds sodium hyaluronate solution into solution, stirs, and pH value is adjusted with citric acid solution and sodium hydroxide solution To 6.2, full dose is added water to, it is filling by 5ml/ bottle after measure is qualified through 0.45 μm of miillpore filter pressure filtration, seal, 121 DEG C Sterilizing, lets cool, and examines, packaging.
Take 10 bottles of above-mentioned sample lucifuges to be placed in 25 DEG C or so of room temperature, 6 are placed in the environment of relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is 6.2.
The preparation of 2 Etimicin Sulfate eye drops of embodiment
Preparation process：Take the Sodium Hyaluronate of recipe quantity to be added to heating for dissolving in suitable water for injection to let cool, separately take Etimicin Sulfate is dissolved in water for injection, sequentially adds the sodium dihydrogen phosphate, disodium hydrogen phosphate, nipalgin second of recipe quantity Ester, sodium chloride, niacinamide, are stirred to dissolve, and sodium hyaluronate solution is then added into solution, and stirring, uses lactic acid solution PH value is adjusted to about 6.3 with sodium citrate solution, adds water to full dose, through 0.45 μm of miillpore filter pressure filtration, after measure is qualified, Filling by 8ml/ bottles, sealing, 121 DEG C of sterilizings, let cool, examine, packaging.
Take 10 bottles of above-mentioned sample lucifuges to be placed in 25 DEG C or so of room temperature, 6 are placed in the environment of relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is about 6.3.
The preparation of 3 Etimicin Sulfate eye drops of embodiment
Preparation process：Take the Sodium Hyaluronate of recipe quantity to be added in 900ml waters for injection to let cool after heating for dissolving, successively Etimicin Sulfate, boric acid, sodium acetate, sorbic acid, the taurine of recipe quantity are added, is stirred to dissolve, stirs, uses L MALIC ACID Solution and sodium hydroxide solution adjust pH value to 6.5, and the osmotic pressure that solution is adjusted with suitable sodium chloride is about 290mOsmol/ K, adds water to full dose, filling by 5ml/ bottles after measure is qualified through 0.45 μm of miillpore filter pressure filtration, sealing, 121 DEG C of sterilizings, Let cool, examine, packaging.The preparation of 4 Etimicin Sulfate eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3g, trehalose 3g, Boratex 2g, half Guang ammonia of boric acid 0.2g, L- Sour 1g, acetic acid DL-lysine 4g, sodium pantothenate 3g, Domiphen bromide 0.006g, appropriate sodium chloride, 1M L-ASPARTIC ACID solution is appropriate, 1M sodium hydroxide solutions are appropriate, and water for injection adds to 1000ml
Preparation process：Take the trehalose of recipe quantity to be added in 900ml waters for injection to dissolve, sequentially add the sulphur of recipe quantity Sour Etimicin, Boratex, boric acid, cysteine, acetic acid DL-lysine, sodium pantothenate, Domiphen bromide, are stirred to dissolve, stirring, PH value is adjusted to 6.7 with L-ASPARTIC ACID solution and sodium hydroxide solution, and the osmotic pressure of solution is adjusted about with suitable sodium chloride For 295mOsmol/k, full dose is added water to, it is filling by 8ml/ bottles after measure is qualified through 0.45 μm of miillpore filter pressure filtration, it is close Envelope, 121 DEG C of sterilizings, lets cool, and examines, packaging.
Take 10 bottles of above-mentioned sample lucifuges to be placed in 25 DEG C or so of room temperature, 6 are placed in the environment of relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is 6.7.
The preparation of 5 Etimicin Sulfate unit dose package eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, trehalose 3.78g, sodium dihydrogen phosphate 2.4g, phosphoric acid hydrogen Disodium 6.6g, taurine 10g, sodium chloride 4.2g, water for injection are settled to 1000ml.
Preparation process：Etimicin Sulfate, trehalose, sodium dihydrogen phosphate, disodium hydrogen phosphate, the chlorine of recipe quantity are weighed respectively Changing sodium adds 200mL waters for injection to dissolve, and after stirring evenly, is settled to 1000mL with water for injection, obtains liquid；Above-mentioned liquid is passed through 0.45 μm of filtering with microporous membrane 1 time, then through 0.22 μm of filtering with microporous membrane；Liquid after the assay was approved, the filling above-mentioned medicines of 0.25ml Into 1ml unit dose package plastic containers, sealing, gets product liquid.
The preparation of 6 Etimicin Sulfate eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 5g, trehalose 5g, Boratex 2g, niacinamide 0.8g, DL- rely Propylhomoserin 3g, taurine 5g, the 0.01g of polyquaternium -1, appropriate sodium chloride, 1M citric acid solutions are appropriate, and 1M sodium hydroxide solutions are fitted Amount, water for injection add to 1000ml
Preparation process：Take the trehalose of recipe quantity to be added in 850nl waters for injection, be stirred to dissolve, sequentially add place The Etimicin Sulfate just measured, Boratex, niacinamide, DL-lysine, taurine, polyquaternium -1, are stirred to dissolve, use lemon Lemon acid solution and sodium hydroxide solution adjust pH value to 6.8, and the osmotic pressure that solution is adjusted with suitable sodium chloride is about 308mOsmol/k, adds water to full dose, adds the activated carbon with liquid measure 0.05%, stirs 20 minutes or so, through 0.45um miillpore filters Filtering decarbonization, then through 0.22 μm of miillpore filter pressure filtration, filling by 8ml/ bottles after measure is qualified, sealing, 121 DEG C of sterilizings, put It is cold, examine, packaging.The preparation of 7 Etimicin Sulfate eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 6g, trehalose 6g, L-cysteine 1g, taurine 6g, L- Winter propylhomoserin 2g, thimerosal 0.05g, appropriate sodium chloride, 1M L-ASPARTIC ACID solution is appropriate, and 1M sodium hydroxide solutions are appropriate, injection 1000ml is added to water
Preparation process：Take the trehalose of recipe quantity to be added in 880nl waters for injection to dissolve, separately take Etimicin Sulfate molten Solution sequentially adds cysteine, taurine, L-ASPARTIC ACID, the thimerosal of recipe quantity, is stirred to dissolve in water for injection, Then aqueous trehalose is added into solution, is stirred, with L-ASPARTIC ACID solution and sodium hydroxide solution adjust pH value to 6.8, the osmotic pressure that solution is adjusted with suitable sodium chloride is about 310mOsmol/k, full dose is added water to, through 0.22 μm of miillpore filter Pressure filtration, filling by 10ml/ bottles after measure is qualified, sealing, 121 DEG C of sterilizings, let cool, examine, packaging.
The preparation of 8 Etimicin eye drops of embodiment
Prescription：Etimicin 8g, trehalose 8g, DL-malic acid 1g, taurine 10g, sodium pantothenate 1g, Polidronium Chloride 0.01g, appropriate sodium chloride, 1M malic acid solutions are appropriate, and 1M sodium hydroxide solutions are appropriate, and water for injection adds to 1000ml
Preparation process：Take the trehalose of recipe quantity to be added in 920nl waters for injection to dissolve, take Etimicin to be dissolved in L- In the water for injection of L-aminobutanedioic acid acidifying, DL-malic acid, taurine, sodium pantothenate, the Polidronium Chloride of recipe quantity are sequentially added, is stirred Mixing makes dissolving, and the osmotic pressure that solution is adjusted with suitable sodium chloride is about 300mOsmol/k, with malic acid solution and sodium hydroxide Solution adjusts pH value to 6.8, adds water to full dose, adds the activated carbon with liquid measure 0.3%, stirring 20 minutes or so is micro- through 0.22 μm Hole filter membrane pressure filtration, filling by 8ml/ bottles after measure is qualified, sealing, 121 DEG C of sterilizings, let cool, examine, packaging.
Take 10 bottles of above-mentioned sample lucifuges to be placed in 25 DEG C or so of room temperature, 6 are placed in the environment of relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is about 6.8.
The preparation of 9 Etimicin eye drops of embodiment
Prescription：Etimicin 10g, Sodium Hyaluronate 1g, taurine 5g, glycine 15g, trehalose 4g, EDTA-2Na The L- threoses acid solution and appropriate sodium hydroxide solution, water for injection of 0.5g, Polidronium Chloride 0.01g, 1M add to 1000ml.
Preparation method：Take the Sodium Hyaluronate of recipe quantity to be added in 800ml waters for injection to let cool after heating for dissolving, will locate The Etimicin just measured adds suitable 2M threoses acid solution in 100ml waters for injection, and stirring, makes dissolving, then respectively by prescription The glycine of amount, taurine, trehalose, EDTA-2Na, Polidronium Chloride are stirred to dissolve, Ran Houyu in Etimicin solution Sodium hyaluronate solution is uniformly mixed, and is about 6.8 with threose acid solution or with sodium hydroxide solution adjusting pH value, is added water to complete Amount；Using 0.45 μm of membrane filtration, filtrate pH value is measured, it is filling by 5ml/ bottles after passed examination, pack.
The preparation of 10 Etimicin Sulfate eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 4g, trehalose 3.78g, Boratex 1g, boric acid 0.2g, L- half Cystine 0.5g, L-arginine 2g, taurine 5g, sodium sorbate 1g, sodium chloride：Potassium chloride (weight ratio 9:1) appropriate 1M L- L-aminobutanedioic acid solution is appropriate, and 1M sodium hydroxide solutions are appropriate, and water for injection adds to 1000ml
Preparation process：Take the trehalose of recipe quantity to be added in 900ml waters for injection to dissolve, sequentially add the sulphur of recipe quantity Sour Etimicin, Boratex, boric acid, cysteine, arginine, sodium sorbate, are stirred to dissolve, with L-ASPARTIC ACID solution and Sodium hydroxide solution adjusts pH value to about 6.7, with suitable sodium chloride：Potassium chloride (weight ratio 9:1) infiltration of solution is adjusted Pressure is about 300mOsmol/k, adds water to full dose, adds the activated carbon with liquid measure 0.01%, is stirred 20 minutes or so, micro- through 0.22um Hole membrane filtration takes off charcoal, then through the ultrafiltration membrance filter using retention relative molecular mass 8000-20000, after measure is qualified, presses 8ml/ bottles filling, sealing, and 121 DEG C of sterilizings, let cool, examine, packaging.
Take 10 bottles of above-mentioned sample lucifuges to be placed in 25 DEG C or so of room temperature, 6 are placed in the environment of relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is about 6.7.
The preparation of 11 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin Hydrochloride (in terms of Etimicin) 5g, sodium dihydrogen phosphate 0.6g, disodium hydrogen phosphate 1.2g, poly- second 6000 5g of glycol, appropriate sodium chloride, appropriate sodium hydroxide solution；Water for injection is settled to 1000ml.
Preparation process：Precision weighs the Etimicin Hydrochloride of recipe quantity, Macrogol 6000, sodium dihydrogen phosphate, phosphoric acid hydrogen Disodium, sodium chloride add 900ml waters for injection to dissolve, and after stirring evenly, it is about 6.5 to adjust pH value with appropriate sodium hydroxide solution, The osmotic pressure that suitable sodium chloride adjusts solution is about 300mOsmol/k, is settled to 1000ml with water for injection, obtains liquid；Will Above-mentioned liquid is through 0.45 μm of filtering with microporous membrane, and after the assay was approved, under hundred grades of environment, the filling above-mentioned liquids of 0.4ml are extremely for liquid In 1ml unit dose package plastic containers, sealing, gets product.
30 bottles of above-mentioned sample lucifuges are taken to place 6 in the environment of being placed in 25 DEG C or so of room temperature, relative humidity 75% ± 5% Month, solution keeps clear and bright, and the pH value for measuring solution is about 6.5.
The preparation of 12 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 1.0g, trehalose 3g, boric acid 0.8g, borax 6.2g, taurine 5g, vitamin C 2g, natrium adetate 0.2g, 2M citric acid solution and appropriate sodium citrate solution, appropriate water for injection, 0.85% sodium chloride solution is settled to 1000ml in right amount.
Preparation process：Weigh the Etimicin Sulfate of recipe quantity, taurine, vitamin C, trehalose, boric acid, borax, according to Ground acid disodium adds 150ml waters for injection to dissolve, solution is adjusted in right amount with 2M citric acid solutions and sodium citrate solution in beaker PH value be about 7.0, be settled to 1000ml in right amount with 0.85% sodium chloride solution, obtain liquid；Above-mentioned liquid is micro- through 0.45 μm Hole membrane filtration, then through 0.22 μm of filtering with microporous membrane；Liquid after the assay was approved, the filling above-mentioned liquids of 0.25ml to 1ml single doses Measure in packing plastics container, sealing, gets product.
The preparation of 13 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin (in terms of Etimicin) 10g, trehalose 5g, boric acid 0.8g, borax 1.2g, taurine 10g, Vitamin B2Sodium phosphate 2g, 2M citric acid solution and appropriate sodium citrate solution, water for injection are settled to 1000ml.
Preparation process：The Etimicin that precision weighs recipe quantity is placed in the beaker of 200ml waters for injection, adds suitable lemon Lemon acid solution makes dissolving, takes taurine, the vitamin B of recipe quantity2Sodium phosphate, trehalose, boric acid, borax add 700ml injections Water dissolves, and two solution is mixed, the pH value for adjusting solution in right amount with 2M citric acid solutions and sodium citrate solution is about 6.8, is added Water for injection is settled to 1000ml, obtains liquid；By above-mentioned liquid through 0.45 μm of filtering with microporous membrane 1 time, then through 0.22 μm of micropore Membrane filtration；Liquid after the assay was approved, under hundred grades of environment, the filling above-mentioned liquids of 0.3ml to 1ml unit dose package plastic containers In, sealing, gets product.
The preparation of 14 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, trehalose 8g, gallic acid 0.5g, boric acid 0.5g, boron Sand 1.2g, taurine 10g, appropriate water for injection, 3M sodium citrate solutions are appropriate, and 0.8% sodium chloride solution is settled in right amount 1000ml。
Preparation process：Etimicin Sulfate, taurine, trehalose, gallic acid, boric acid, the borax for weighing recipe quantity add 200ml waters for injection dissolve, and two solution are mixed, the pH value for adjusting solution in right amount with 3M sodium citrate solutions is about 6.7, is added 0.8% sodium chloride solution is settled to 1000ml in right amount, obtains liquid；By above-mentioned liquid through 0.45 μm of filtering with microporous membrane 1 time, then pass through 0.22 μm of filtering with microporous membrane；Liquid after the assay was approved, the filling above-mentioned liquids of 0.5ml into 1ml unit dose package plastic containers, Sealing, gets product.
The preparation of 15 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, Sodium Hyaluronate 1g, boric acid 0.8g, borax 2.0g, ox Sulfonic acid 10g, trehalose 3g, appropriate sodium chloride, 2M citric acid solutions and appropriate sodium citrate solution, water for injection are settled to 1000ml。
Preparation process：The Etimicin for weighing recipe quantity is placed in the beaker of 100ml waters for injection, adds suitable citric acid Solution makes dissolving, adds taurine, trehalose, boric acid, the borax of recipe quantity successively wherein, is stirred to dissolve, takes recipe quantity Sodium Hyaluronate is added to dissolve by heating in 800ml waters for injection and lets cool, and then mixes two kinds of solution, then molten with 2M citric acids The pH value that liquid and sodium citrate solution adjust solution in right amount is about 6.8, and the osmotic pressure that suitable sodium chloride adjusts solution is about 305mOsmol/k, adds water for injection to be settled to 1000ml, obtains liquid；By above-mentioned liquid through 0.45 μm of filtering with microporous membrane 1 time, Again through 0.22 μm of filtering with microporous membrane；After the assay was approved, the filling above-mentioned liquids of 0.25ml to 1ml unit dose packages plastics hold liquid In device, sealing, gets product.
The preparation of 16 Etimicin unit dose package eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, chitosan 2g, boric acid 0.8g, borax 1.2g, taurine 10g, trehalose 1g, appropriate water for injection, 1M citric acid solutions are appropriate, 1M hydrochloric acid solutions are appropriate, appropriate sodium chloride, Sharpe phosphoric acid Salt buffer is settled to 1000ml, obtains liquid.
Preparation process：The Etimicin Sulfate that precision weighs recipe quantity is placed in the beaker of 100ml waters for injection, is made molten Solution, adds taurine, boric acid, the borax of recipe quantity, is stirred to dissolve respectively, and the chitosan for weighing recipe quantity is placed in 600ml injections With suitable 1M hydrochloric acid solutions in water, are added, it is stirred to dissolve, two kinds of solution is mixed, with suitable Sharpe phosphate buffer The osmotic pressure that solution is adjusted with suitable sodium chloride is about 300mOsmol/k, and the pH value for adjusting solution is about 6.8, is settled to 1000ml, obtains liquid；By above-mentioned liquid through 0.45 μm of filtering with microporous membrane；Liquid after the assay was approved, the filling above-mentioned liquids of 0.4ml Into 1ml unit dose package plastic containers, sealing, gets product.
The preparation of 17 Etimicin gel eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, poloxamer188 25g, PLURONICS F87 2g, sea Algae sugar 3g, sodium dihydrogen phosphate 3.0g, disodium hydrogen phosphate 4.2g, taurine 10g, natrium adetate 0.3g, Phenoxyethanol 2.0g, 2M Citric acid solution and appropriate sodium hydroxide solution, water for injection are settled to 1000ml.
Preparation process：Weigh the poloxamer188 of recipe quantity, PLURONICS F87 is placed in the beakers of 900ml waters for injection In, it is stirred to dissolve, then take Etimicin Sulfate, taurine, trehalose, sodium dihydrogen phosphate, the phosphoric acid hydrogen two of recipe quantity respectively Sodium, natrium adetate, Phenoxyethanol be added in above-mentioned solution stirring make it is molten, with 2M citric acid solutions and appropriate sodium hydroxide solution The pH value for adjusting solution is about 6.6, adds water for injection to be settled to 1000ml, by above-mentioned liquid through 0.45 μm of filtering with microporous membrane, Filling by 5ml/ bottles after measure is qualified, sealing, 121 DEG C of sterilizings, let cool, examine, packaging.
The preparation of 18 Etimicin gel eye drops of embodiment
Prescription：Etimicin Sulfate (in terms of Etimicin) 3.0g, Acritamer 940 5g, polyvinyl alcohol 1g, trehalose 3g, Taurine 10g, vitamin B11g, benzalkonium bromide 0.02g, natrium adetate 0.3g, polyoxyethylene sorbitan monoleate 1g, appropriate triethanolamine Or 2M citric acid solutions adjust pH value 6.9, water for injection is settled to 1000g.
Preparation process：Take the Acritamer 940 of recipe quantity and polyvinyl alcohol to add water about 860ml, stand, make its swelling, with three Monoethanolamine and/or 2M citric acid solution tune pH value obtain matrix, take the Etimicin Sulfate, trehalose, ox of recipe quantity to about 6.9 Sulfonic acid, vitamin B1, benzalkonium bromide, Tween-80 are added to stirring in 100ml water makes molten, be slowly added into above-mentioned matrix, Stir evenly, then 1000g, vacuum outgas, packing are added water to about 6.9 with triethanolamine and/or 2M citric acid solution tune pH value In in 10g hoses, 100 DEG C of 30min sterilize, to obtain the final product.
Embodiment 19 treats case
Male patient, at 50 years old age, weight 72kg, eyes are dry and astringent, secretion increases, have foreign body sensation and itch and feel and regard Feel that feeling of fatigue, bulbar conjunctiva and papebral conjunctiva hyperemia are scarlet, the past once repeatedly suffers from conjunctivitis in two years, is now diagnosed as slowly by hospital outpatient Property dacryocystitis, blear-eye, the concurrent xerophthalmia of chronic conjunctivitis, with the eye drops in treatment of 14 method of embodiment, 2 drops every time, daily three Secondary, after continuous treatment 9 days, conjunctiva color recovers normal, eyes foreign body sensation and anesthesia of itching, there is no dry and astringent sensation, depending on Feel that feeling of fatigue disappears, eyes secretion recovers normal, and subjective symptoms recovery from illness, never recurs for continuous five days after treatment.
Embodiment 20 treats case
Male patient, 46 years old age, weight 68kg, eyes have photophobia, foreign body sensation, dry sensation more days obvious, are examined by hospital Breaking as trachomatous xerophthalmia, the eye drops in treatment prepared with 15 method of embodiment, 1 drips every time, 5 times a day, after continuously treating six days, Patient's eyes no longer photophobia, eyes foreign body sensation and dry sensation disappear, and the recovery from illness of patient's subjective symptoms, continuous three days never after treatment Recurrence.
Industrial applicibility etc. and its explanation etc.：
The present invention is described in detail above by embodiment and embodiment, it will nevertheless be understood that these are said Bright that any restrictions are not formed to the scope of the present invention, related technical personnel substantially can be in the spirit without departing from the present invention and guarantor In the case of protecting scope, technical solutions and their implementation methods of the present invention can be carried out with a variety of modifications, improvement and replacement and group Close, to realize the technology of the present invention, these are because falling within the scope of protection of the present invention.In particular, it will be understood that The change of many details is possible, and all similar replacements and change are apparent for a person skilled in the art , they are considered as being included in the spirit, scope and content of the present invention, and the present invention is not limited to above-described embodiment.

Claims (12)

1. the pharmaceutical composition of topical ophthalmic, contains Etimicin or its pharmaceutically acceptable salt or different crystal forms or unformed It is any one or more of in thing or its solvate or its inclusion compound, and its pharmaceutically acceptable carrier, wherein the combination The Etimicin concentration that thing contains is 0.05-1.0wt%；It is characterized in that：Per 1000ml eye drops or in 1000g eye-drops preparations Containing Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvate or its pharmaceutically Acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, be calculated as with the weight of Etimicin 0.5~10.0g is calculated as the unit of 500,000 units~10,000,000 with Etimicin activity, remaining is pharmaceutically acceptable carrier.
2. the pharmaceutical composition of topical ophthalmic according to claim 1, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or Etimicin Sulfate or its pharmaceutically acceptable salt or pharmaceutically acceptable in 1000g eye-drops preparations It is any one or more of in different crystallizations or its solvate or its inclusion compound, 1.0 are calculated as with the weight of Etimicin~ 10.0g is calculated as the unit of 1,000,000 units~10,000,000 with Etimicin activity, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
3. local medical composite for eye according to claims 1 to 2, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 1.0~8.0g or is calculated as the unit of 1,000,000 units~8,000,000 with Etimicin activity, remaining is pharmaceutically Acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
4. local medical composite for eye according to claims 1 to 3, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 1.0~6.0g or is calculated as the unit of 1,000,000 units~6,000,000 with Etimicin activity, remaining is pharmaceutically Acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
5. local medical composite for eye according to claims 1 to 4, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 2.0~6.0g or is calculated as the unit of 2,000,000 units~6,000,000 with Etimicin activity, remaining is pharmaceutically Acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
6. local medical composite for eye according to claims 1 to 5, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 2.0g or is calculated as 2,000,000 units with Etimicin activity, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
7. local medical composite for eye according to claims 1 to 5, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 3.0g or is calculated as 3,000,000 units with Etimicin activity, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
8. local medical composite for eye according to claims 1 to 5, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 4.0g or is calculated as 4,000,000 units with Etimicin activity, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
9. local medical composite for eye according to claims 1 to 5, it is characterised in that：Per 1000ml eye drops or Contain Etimicin or its pharmaceutically acceptable different crystallization or its pharmaceutically acceptable solvent in 1000g eye-drops preparations Compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable inclusion compound or they in it is any one or more of, with according to for The weight of meter Xing is calculated as 5.0g or is calculated as 5,000,000 units with Etimicin activity, remaining is pharmaceutically acceptable carrier；
Pharmaceutically acceptable carrier includes water, pharmaceutically acceptable thickener, pH adjusting agent and or pharmaceutically acceptable Preservative or bacteriostatic agent, antioxidant, stabilizer, isotonic regulator, sorbefacient, solubilizer, excipient, diluent, guarantor Humectant or they in it is any one or more of.
10. the pharmaceutical composition of topical ophthalmic according to claims 1 to 9, it is characterised in that：
In its pharmaceutically acceptable carrier, it can include：Water, D- or L- or the amino acid of racemization or its salt, such as D- or L- or DL-lysine, Lysine Acetate, cysteine, methionine, arginine or acetic arginine or L-aminobutanedioic acid or L-aminobutanedioic acid Sodium, glutamic acid, glycine, taurine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, Cystine, methionine, asparagine, glutamine, 5- oxylysines, histidine, phenylalanine, tyrosine, tryptophan, 3- Hydroxy-proline, 4- hydroxy-prolines, proline, homocysteine, homocystine, homoserine, ornithine, citrulling, flesh Acid, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino-2-methyls propionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, phenylglycine, canavanine, canaline, 4- hydroxyl essence ammonia Acid, 4- hydroxyls ornithine, homoarginine, 4- hydroxyhomoarginines, beta-lysine, 2,4-diamino-butanoic, 2,3- diaminourea third Acid, 2- methyl serines etc. or unit or polybasic carboxylic acid or its pharmaceutical salts, gallic acid, propylgallate, gallic acid second It is ester, gallate, malic acid, butanedioic acid, ascorbic acid, L-AA, sodium ascorbate, arabo-ascorbic acid, different anti-bad Hematic acid sodium, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, calcium pantothenate, vitamin B1, vitamin B2, vitamin E, beta carotene, salt Sour Pyridoxamine, glutathione, allantoin, citric acid or sodium citrate or lactic acid, sodium lactate, lactobionic acid, sodium lactonic, grape It is saccharic acid, sodium gluconate or trehalose, urea, thiocarbamide or maltitol, sorbierite, mannitol, lactitol, xylitol, red One in moss sugar alcohol, Hyaluronic Acid or sodium hyaluronate or its hydrate or their pharmaceutically acceptable salt or their isomers etc. Kind is a variety of, and sorbierite includes D- D-sorbites, anhydrous sorbierite or half water thing of sorbierite or 1 water sorbierite or sorbitol instant One or more in, it is above-mentioned to include its isomers；Concentration range used in these compounds can 0.000~ 5.0%；
Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable inorganic acid or organic acid or its pharmaceutical salts, inorganic base Or organic base or the lewis acid or alkali of its pharmaceutical salts or broad sense, can be hydrochloric acid, sulfuric acid or its pharmaceutical salts, boric acid Or its pharmaceutical salts, borax, phosphoric acid or its pharmaceutical salts, acetic acid or its pharmaceutical salts, such as sodium acetate, lactic acid and lactic acid pharmaceutical salts, Chinese holly It is rafter acid or its pharmaceutical salts, tartaric acid or citric acid or its pharmaceutical salts, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, anti-bad Hematic acid, sodium ascorbate, arabo-ascorbic acid, sodium isoascorbate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium acid carbonate, three Hydroxyl amino methane, diethanol amine, monoethanolamine, diisopropanolamine (DIPA), 2- amino -2- (methylol) 1,3-PDs amine, N- methyl Grape amine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, Soviet Union Saccharic acid, glucoheptonic acid, amino acid or their pharmaceutically acceptable salt or its hydrate or one kind in its isomers or It is several；
Pharmaceutically acceptable antioxidant and stabilizer can be sulfurous acid and its salt, bisulfites, pyrosulfite, company two Sulphite, thioacetic acid and its pharmaceutical salts, thiolactic acid and its pharmaceutical salts, thio-2 acid and salt, monohydroxy or polyhydroxy Carboxylic acid and pharmaceutical salts, tartaric acid, sorbic acid or its pharmaceutical salts, nitrate, acetic acid pharmaceutical salts, citrate, EDTA and edta salt, Including EDETATE SODIUM, tetra- sodium of EDTA, Ca-EDTA sodium salt (including 2 water of sodium ethylene diamine tetracetate calcium or sodium ethylene diamine tetracetate calcium Compound, 4 hydrate of sodium ethylene diamine tetracetate calcium), N- bis- (2- ethoxys) glycine, maltitol, xylitol, sorbierite, Mannitol, vitamin E, beta carotene, Pyridoxamine Hydrochloride, taurine, amino acid or their pharmaceutically acceptable salt its water One or several kinds in compound or its isomers etc.；
Pharmaceutically acceptable chelating agent can be EDTA and edta salt including EDETATE SODIUM, tetra- sodium of EDTA, Ca-EDTA sodium salt (including 2 hydrate of sodium ethylene diamine tetracetate calcium or sodium ethylene diamine tetracetate calcium, 4 hydrate of sodium ethylene diamine tetracetate calcium), N- bis- It is a kind of or several in (2- ethoxys) glycine or its hydrate of their pharmaceutically acceptable salt or its isomers etc. Kind；
Pharmaceutically acceptable preservative or bacteriostatic agent, selected from organic acid bacteriostatic agent, oxybenzene esters compound or nipalgin Esters, methyl hydroxybenzoate, propylparaben, phenmethylol, benzyl carbinol, phenoxetol, anesin, quaternary ammonium derive Thing, Domiphen bromide, benzalkonium chloride, benzalkonium bromide, hexadecyl ammonium methyl, cetylpyridinium chloride, Benzethonium, polyquaternary amine Salt, polyquaternium -1, organic Mercury derivatives, thiomersalate, thimerosal, phenylmercuric acetate and phenylmercuric nitrate, pharmacy In upper acceptable phenol compound, o-phenyl phenol, chloreresol, chlorohexidene etc. or their pharmaceutically acceptable salt etc. One or more.In general, concentration range used in these compounds is 0.0005-5.0%, this prevents depending on selected Rotten agent or bacteriostatic agent；Polyquaternium -1 is more preferably used to be used as anti-microbial preservative；Typically with 0.001%-1.0wt%'s Concentration uses these preservatives；
Pharmaceutically acceptable isotonic regulator, pharmaceutically acceptable isotonic regulator can be sodium chloride, potassium chloride, chlorination Calcium, sodium bromide, sodium phosphate, sodium sulphate, sodium nitrate, glucose, boric acid, borax, glycerine, propane diols, polyethylene glycol, PEG- 400th, PEG300, PEG-200, glucose, fructose, maltitol, xylitol, sorbierite, mannitol, inverted sugar, dextran, One or more in its hydrate of sodium lactate or sodium lactonic, gluconic acid or sodium gluconate or its isomers；
Pharmaceutically acceptable carrier also includes solubilizer, solubilizer be selected from polyethylene glycol oxide list oleic acid sorbitan ester, tween- 80th, VE succinic acid macrogol ester (vitamin E TPGS), glycerine-polyethylene glycol epoxide stearate, PEG-32 are stearic It is sour tripalmitin, lauryl sodium sulfate, Sorbitan monolaurate, polyethylene glycol, polyethylene glycol 400-6000, poly- It is ethylene glycol -12- hydroxy stearic acid esters, polyvinylpyrrolidone, polyvinyl alcohol, amino acid or its pharmaceutical salts, pharmaceutically acceptable Alcohols, pharmaceutically acceptable polyalcohol, poloxamer, poloxamer188, azone, laurocapram, cyclodextrin or cyclodextrin medicine Acceptable derivates, amide-type or urea and derivative on, inorganic acid or inorganic acid salt, pharmaceutically acceptable organic acid or Acylate, pharmaceutically acceptable carbohydrate or sugar lime, pharmaceutically acceptable amine etc. or their chiral isomer etc. or it Pharmaceutically acceptable salt in one or more；
Pharmaceutically acceptable carrier --- thickener or stabilizer, may be selected from by water-soluble polymer and penetration enhancer and The composition of their mixture composition.The water-soluble polymer that can be used in the eye drops of the present invention includes but is not limited to Natural and synthesis polymer, polysaccharide, poly- aminoglycoside, cellulose derivative, guar gum, xanthans, glucan, carboxy vinyl Based polyalcohol, Sodium Polyacrylate, hyaluronidase, hyaluronic acid, Sodium Hyaluronate, chondroitin sulfate, locust bean gum, Bo Luosha Nurse, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, gellan gum, alginic acid, methylcellulose, hydroxy ethyl fiber The derivative of element, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or dextrin and dextrin Thing etc. and their mixture；Thickener more preferably poloxamer, chondroitin sulfate, methylcellulose, hydroxypropyl methyl fiber Element, gellan gum, hydroxyethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, hyaluronic acid or Sodium Hyaluronate, seaweed Sugar etc., the more excellent concentration with 0.02%-1wt% uses in eye drops；
The excipient of pharmaceutically acceptable carrier --- gel can also be chitosan, poly- (hydroxyethyl meth acrylate), The one or more therein such as poly- (n-vinyl pyrrolidone), polyvinyl alcohol, the polymer of acrylic acid, carbomer series, its Middle carbomer series may include that carbomer 934, carbomer940, Acritamer 940, Carbopol 941, CARBOPOL 974P etc. are therein It is one or more.
11. the pharmaceutical composition of topical ophthalmic according to claims 1 to 10, it is characterised in that：It is pharmaceutically acceptable Carrier is more preferably：Water, poloxamer, hyaluronic acid, Sodium Hyaluronate, chondroitin sulfate, polyvinyl alcohol, polyvinylpyrrolidine Ketone, polyethylene glycol, gellan gum, alginic acid, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, amino acid Or their pharmaceutically acceptable salt, unit or polybasic carboxylic acid or its pharmaceutical salts, gallic acid, no propylgallate, food Sub- acetoacetic ester, gallate, malic acid, butanedioic acid, ascorbic acid, L-AA, sodium ascorbate, arabo-ascorbic acid, Sodium isoascorbate, nicotinic acid, niacinamide, pantothenic acid, sodium pantothenate, calcium pantothenate, vitamin B1, vitamin B2, vitamin E, β-carrot Element, Pyridoxamine Hydrochloride, glutathione, allantoin, citric acid or sodium citrate or lactic acid, sodium lactate, lactobionic acid, lactobionic acid Sodium, gluconic acid, sodium gluconate or trehalose, urea, thiocarbamide or maltitol, sorbierite, mannitol, lactitol, wood Sugar alcohol, antierythrite, Hyaluronic Acid or sodium hyaluronate or its hydrate or its hydrate of their pharmaceutically acceptable salt or its is different One or more in structure body.
12. the pharmaceutical composition of topical ophthalmic according to claims 1 to 9, it is characterised in that：Pharmaceutical composition prepares pre- Anti- or treatment conjunctivitis, angular blepharitis, keratitis, sclerotitis, trachoma, the eye disease of sensitive bacterial infection, scheroma or Application on the local eye medicinal of xerophthalmia or dry eye syndrome.
CN201610883803.5A 2016-10-09 2016-10-09 The medical composite for eye of local administration Pending CN107913246A (en)

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CN108853012A (en) * 2018-06-15 2018-11-23 中山万远新药研发有限公司 The eye drip aqueous solution increased for treating intraocular pressure
CN110639010A (en) * 2019-11-15 2020-01-03 云山化妆品研究开发(广州)有限公司 Traditional Chinese medicine composition containing recombinant hirudin suitable for eyes and preparation method thereof
CN111202746A (en) * 2020-02-27 2020-05-29 潍坊医学院附属医院 Compound preparation for eyes and preparation method thereof
CN111789827A (en) * 2019-04-01 2020-10-20 北京盈科瑞创新药物研究有限公司 Etomicin sulfate aerosol inhalation preparation and preparation method thereof
CN111920940A (en) * 2020-09-16 2020-11-13 童妍(上海)医疗器械有限公司 Eye preparation and preparation method and application thereof
CN111973554A (en) * 2020-09-03 2020-11-24 浙江目中明生物科技有限公司 Eye-protecting liquid
CN112826829A (en) * 2019-11-25 2021-05-25 多姆皮制药公司 Ophthalmic preparation
EP4039248A1 (en) * 2021-02-04 2022-08-10 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Ophthalmic composition
CN115025115A (en) * 2022-06-29 2022-09-09 江苏汉晨药业有限公司 Compound urinary vitamin ammonia eye drops
WO2024100628A1 (en) * 2022-11-11 2024-05-16 Bausch + Lomb Ireland Limited Hydration formulation
EP4454639A1 (en) * 2023-04-14 2024-10-30 Omnivision GmbH Ophthalmic composition comprising carbomer and taurine

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CN108671270A (en) * 2018-05-25 2018-10-19 爱博诺德（北京）医疗科技有限公司 Viscoelastic agent material with redox characteristic
CN108853012A (en) * 2018-06-15 2018-11-23 中山万远新药研发有限公司 The eye drip aqueous solution increased for treating intraocular pressure
CN108853012B (en) * 2018-06-15 2019-03-15 中山万远新药研发有限公司 The eye drip aqueous solution increased for treating intraocular pressure
CN111789827A (en) * 2019-04-01 2020-10-20 北京盈科瑞创新药物研究有限公司 Etomicin sulfate aerosol inhalation preparation and preparation method thereof
CN110639010A (en) * 2019-11-15 2020-01-03 云山化妆品研究开发(广州)有限公司 Traditional Chinese medicine composition containing recombinant hirudin suitable for eyes and preparation method thereof
CN112826829A (en) * 2019-11-25 2021-05-25 多姆皮制药公司 Ophthalmic preparation
CN111202746B (en) * 2020-02-27 2021-03-16 潍坊医学院附属医院 Compound preparation for eyes and preparation method thereof
CN111202746A (en) * 2020-02-27 2020-05-29 潍坊医学院附属医院 Compound preparation for eyes and preparation method thereof
CN111973554A (en) * 2020-09-03 2020-11-24 浙江目中明生物科技有限公司 Eye-protecting liquid
CN111920940A (en) * 2020-09-16 2020-11-13 童妍(上海)医疗器械有限公司 Eye preparation and preparation method and application thereof
EP4039248A1 (en) * 2021-02-04 2022-08-10 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Ophthalmic composition
WO2022167569A1 (en) * 2021-02-04 2022-08-11 Warszawskie Zaklady Farmaceutyczne Polfa S.A. Ophthalmic composition
CN115025115A (en) * 2022-06-29 2022-09-09 江苏汉晨药业有限公司 Compound urinary vitamin ammonia eye drops
CN115025115B (en) * 2022-06-29 2023-11-24 江苏汉晨药业有限公司 Compound urinary-vitamin ammonia eye drops
WO2024100628A1 (en) * 2022-11-11 2024-05-16 Bausch + Lomb Ireland Limited Hydration formulation
EP4454639A1 (en) * 2023-04-14 2024-10-30 Omnivision GmbH Ophthalmic composition comprising carbomer and taurine

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Application publication date: 20180417