CN111973622B - Ofloxacin eye external composition - Google Patents
Ofloxacin eye external composition Download PDFInfo
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- CN111973622B CN111973622B CN202010714004.1A CN202010714004A CN111973622B CN 111973622 B CN111973622 B CN 111973622B CN 202010714004 A CN202010714004 A CN 202010714004A CN 111973622 B CN111973622 B CN 111973622B
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- ofloxacin
- gamma
- polyglutamic acid
- eye
- acid
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- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0048—Eye, e.g. artificial tears
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- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to the technical field of an eye external composition, in particular to an eye external composition of ofloxacin, which comprises an effective amount of ofloxacin, gamma-polyglutamic acid, sodium salvianic acid A, at least one of pH value regulator, osmotic pressure regulator, viscosity regulator, solubilizer, cosolvent or antioxidant and a carrier. The inventor finds in experiments that the addition of trace gamma-polyglutamic acid in the composition can obviously improve the antibacterial effect of low-dose ofloxacin, and the addition of the gamma-polyglutamic acid and sodium salvianic acid A in a specific ratio can obviously inhibit the cytotoxicity of high-dose ofloxacin.
Description
Technical Field
The invention relates to the technical field of an eye external composition, in particular to an ofloxacin eye external composition.
Background
The eyes are one of the most important organs of the human body, and provide a guarantee for adapting to social life. In the information age of the body, along with the change of life style and working condition of people, the eye time of people is several times longer than that of the past decades, people rely on video display terminals such as computers, televisions and the like to perform various activities, such as working with computers for a long time, watching televisions, playing video games with PSP or mobile phones, wearing contact lenses and pupils, driving for a long time, and mental stress, can easily cause people to suffer from eye fatigue, and further cause eye dryness, eye astringency and eye acid distention, blurred vision and even vision decline, directly affect the work and life of people, eye fatigue is mainly caused by that the eye blink times are reduced when people pay attention to watch a computer screen at ordinary times, eye tear secretion is correspondingly reduced, and simultaneously, the eye is stimulated by flickering a screen strongly, so that pain occurs at corresponding parts such as neck, shoulder and the like of people, and a series of diseases such as acanthocele keratitis, giant keratitis, keratitis and bacterial keratitis are also caused and aggravated. Therefore, external preparations for the eye, such as eye drops, eye washes, eye ointments, eye creams, eye gels, eye films, etc., which are directly used for ocular mucosa or for the treatment of ocular diseases through ocular mucosa internal tissues without oral administration or injection administration, are becoming popular.
However, most of the existing external preparations for eyes are packaged in multiple doses, and once the preparation is unsealed, the preparation is extremely easy to be polluted by microorganisms in skin, tears and air in the repeated use and retention processes, so that potential safety hazards are generated due to bacterial growth. In order to prevent the external preparation for eyes from being polluted by bacteria in use, most of external preparations for eyes including antibiotics are added with bacteriostats. The bacteriostat can exert bacteriostasis by interfering the growth, reproduction and metabolism of microorganism organisms, but most of the bacteriostat used in the external preparation for eyes have different degrees of irritation or side effects on eyes. The prior art has Chinese patent with publication number of CN109381467A, which discloses an eye washing liquid for improving the visual fatigue of a mobile phone and relieving xerophthalmia and a preparation method thereof, and the formula of the washing liquid is as follows: 10-20% of humectant, 0.01-0.1% of osmotic pressure regulator, 0.1-1% of pH regulator, 0.01-1% of bacteriostat, 0.001-0.01% of viscosity regulator, 1-5% of antioxidant anti-inflammatory agent and the balance of purified water, wherein the bacteriostat is more than one of trichloro-tert-butanol, benzene nitrate, ethidium bromide acetate, potassium sorbate and ethylparaben. The eye cleaning liquid is mainly used for cleaning eyes, comprises the surfaces of eyes and eyeballs, can remove foreign matters or secretion such as dust, particles, pollen and the like, relieves dry eyes, eyestrain, blurred vision and the like which are caused by long-term use of a mobile phone and fixation of a fluorescent screen before computer operation, and can also enhance eye resistance, relieve eyestrain, relieve discomfort of eyes and the like. However, liang Guangjiang et al report (rabbit eye irritation experiments with several commonly used bacteriostats in eye drops, volume 21 of Chinese pharmacy 2010, stage 21, 1964) "the eye irritation with several commonly used bacteriostats was sequentially from small to large arrangement of thimerosal, benzalkonium chloride, benzalkonium bromide, chlorhexidine, chlorobutanol, ethylparaben, boric acid. After multiple doses, the average score of eye irritation response is significantly higher than that of the single dose group because of the increased number of doses. "according to an British study it was pointed out that the parabens (ethylparaben) found in tumors by the team of molecular biologists Philippa Darbre showed that they were derived from substances used on the skin, such as underarm deodorant, cream and body spray, and that this result explained why nearly 60% of breast tumors were found in the upper outer near underarm portions of the breast. Shows that the chlorbutanol and the ethylparaben have certain cytotoxicity.
Ofloxacin (OFX) is a quinolone broad-spectrum antibacterial agent, has strong antibacterial activity on gram-negative bacteria such as escherichia coli, salmonella, shigella and the like, gram-positive bacteria such as staphylococcus aureus, streptococcus pneumoniae and the like, can be used for treating diseases such as genitourinary system infection, respiratory tract infection, gastrointestinal tract infection and the like caused by sensitive bacteria, and can be prepared into eye drops for treating ophthalmic diseases such as blepharitis, dacryocystitis, hordeolum, conjunctivitis and the like. Based on a certain antibacterial effect of ofloxacin, and poor antibacterial effect on anaerobes, fungi and other microorganisms, the eye drops have certain potential safety hazards on patients due to microbial infection in the use process, so that a certain amount of a proper amount of a reduced antibacterial agent can be added in the preparation of the eye drops. However, wang Deping et al report (toxicity of ofloxacin to human corneal epithelial cells and studies of their cell and molecular mechanisms), university of Shandong, vol. 51, 5 th edition, 2016) that OFX at a mass concentration of 0.375g/L or more was found to increase plasma membrane permeability of HCEP (non-transfected human corneal epithelial) cells with time dependence, causing plasma membrane PS eversion, DNA fragmentation, and ultrastructural disorders, mitochondrial swelling, chromatin concentration, and apoptotic body formation. In Chinese patent with publication number of CN109846820A, an ofloxacin eye drop and a preparation method thereof are disclosed, wherein the ofloxacin eye drop comprises the following components in parts by weight: 2.5 to 3.5 parts of ofloxacin, 0.5 to 2 parts of carboxymethyl chitosan oligosaccharide, 7 to 9 parts of osmotic pressure regulator, 0.1 to 0.3 part of solubilizer and 950 to 1100 parts of water for injection. The ofloxacin dosage in the invention is not lower than 2.245g/L, exceeds the reported mass concentration of 499 percent, and certain damage to the corneal cells is necessarily generated.
The foregoing background is only for the purpose of providing an understanding of the inventive concepts and technical aspects of the present invention and is not necessarily prior art to the present application and is not intended to be used to evaluate the novelty and creativity of the present application in the event that no clear evidence indicates that such is already disclosed at the filing date of the present application.
Disclosure of Invention
In view of the above, in order to solve the problems that the antibacterial effect of low-dose ofloxacin is insufficient and the irritation of high-dose ofloxacin is high, the invention aims to provide an eye external composition of ofloxacin, and the antibacterial effect of low-dose ofloxacin can be obviously improved by adding trace gamma-polyglutamic acid into the composition, and the cytotoxicity of high-dose ofloxacin can be obviously inhibited by adding gamma-polyglutamic acid and sodium salvianic acid in a specific ratio.
In order to achieve the above object, the present invention provides the following technical solutions.
[1] The application of gamma-polyglutamic acid in improving the bacteriostatic action of low-dose ofloxacin.
In the foregoing application, the content of the gamma-polyglutamic acid is 4.0 to 150.0% of the content of ofloxacin.
[2] An ofloxacin ophthalmic topical composition comprising:
an effective amount of ofloxacin;
gamma-polyglutamic acid with ofloxacin content of 4.0-150.0%; and is also provided with
Does not contain other pharmaceutically acceptable auxiliary materials of fungus inhibiting or antiseptic substances.
In order to solve the problems that ofloxacin has insufficient antibacterial effect at low dose and stronger irritation to corneal cells at high dose, we have found that after experiments, the antibacterial capability of the ofloxacin eye external composition at low dose can be remarkably improved after a trace amount of gamma-polyglutamic acid is added into the ofloxacin eye external composition, even if no fungus inhibiting or preservative substance is added, the eye external composition can still exert strong inhibition effect on bacteria and fungi, ensure that the ofloxacin eye external composition is prevented from being polluted by microorganisms in skin, tears, air and the like in the application period, eliminate potential safety hazards possibly caused by bacterial breeding, and thoroughly eliminate the irritation or side effect of an exogenous antibacterial agent to eyes, thereby improving the safety and sustainable applicability of the ofloxacin eye external composition.
It should be noted that the ophthalmic external composition of the present invention is a multi-dose ophthalmic external composition, and it is understood that the ophthalmic external composition may be formulated into a liquid preparation, a semisolid preparation, an aerosol, including but not limited to a usual cleaning solution for contact lenses, a care solution, and an external ophthalmic preparation, including but not limited to an eye drop, an eye lotion, an eye ointment, an eye cream, an eye gel, an eye mask, etc., according to the common general knowledge in the art such as the relevant definitions of pharmacy, and thus the specific use time thereof is generally 24h to 7d.
The ofloxacin ophthalmic external composition may be a liquid eye drop or a liquid suspension eye drop.
The ofloxacin eye external composition can be eye gel and eye ointment.
The pH of the ofloxacin eye external composition is generally between 4.0 and 9.0, preferably between 6.0 and 7.0, which are acceptable by eyes, and the osmotic pressure is generally within the range which is acceptable by eyes and does not cause uncomfortable symptoms.
The content of the ofloxacin in the ofloxacin eye external composition is 0.018-0.375 g/L, and the content of the ofloxacin eye external composition is occupied by the effective amount of ofloxacin.
In the ofloxacin eye external composition, the content of gamma-polyglutamic acid occupies 4.0-150.0% of the content of ofloxacin, and the content of gamma-polyglutamic acid occupies not more than 0.3g/L of the ofloxacin eye external composition.
In the ofloxacin eye external composition, the relative molecular mass of the gamma-polyglutamic acid is 500000 ～ 1000000.
The ofloxacin eye external composition does not contain other pharmaceutically acceptable auxiliary materials of fungus inhibition or corrosion prevention substances, and comprises at least one of pH value regulator, osmotic pressure regulator, viscosity regulator, solubilizer, cosolvent or antioxidant and a carrier.
The ofloxacin eye external composition, the pH value regulator is at least one of phosphoric acid and salts thereof, boric acid and salts thereof, citric acid and salts thereof, acetic acid and salts thereof, tartaric acid and salts thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or tromethamine, preferably 0.2-1.0 mol/L sodium hydroxide solution or 0.1-0.5 mol/L potassium dihydrogen phosphate solution.
The ofloxacin eye external composition, the osmotic pressure regulator is at least one of glycerin, sodium chloride, potassium chloride, sorbitol or mannitol, and the content of the ofloxacin eye external composition is 0.2-10.0 g/L.
The viscosity regulator is at least one of sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxyvinyl polymer or polyvinylpyrrolidone, preferably sodium carboxymethyl cellulose, and the content of the composition occupying the eye of the ofloxacin is 0-2.0 g/L.
The solubilizing agent is at least one of tween-40, tween-60, tween-80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol hydrogenated castor oil, polyethylene glycol 4000, lecithin, sucrose ester, polyoxyethylene alkyl ether or polyoxystearate, and the content of the solubilizing agent occupying the ofloxacin eye external composition is 0-0.2 g/L.
The cosolvent is 30-40 vol% acetic acid solution or 9.5-10.5 vol% diluted hydrochloric acid solution, and the content of the cosolvent occupying the ofloxacin eye external composition is 0-10.0 g/L.
The antioxidant is at least one of vitamin E, sodium thiosulfate or sodium bisulphite, and the content of the antioxidant occupying the ofloxacin eye external composition is 0-0.1 g/L.
The ofloxacin ophthalmic external composition, typical pharmaceutically acceptable carriers are, for example: water for injection, mixtures of water for injection and water miscible solvents for injection (e.g., lower alkanols or aromatic alkanols), vegetable oils, polyalkylene glycols, petroleum-based gels, ethylcellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate, eye ointment bases, eye gel bases and other commonly used acceptable carriers. The carrier is preferably water for injection.
In a specific application scenario, the ofloxacin eye external composition may further include sodium hyaluronate, selenoglycose, chromium yeast, vitamin B12, physiological saline, senecio scandens and the like, and such changes do not affect the protection scope of the present application.
Based on the above considerations and by way of example, the topical compositions for ophthalmic use described herein include, but are not limited to, those listed in the following 1) to 6):
1) Ofloxacin 0.018-0.375 g/L, gamma-polyglutamic acid 0.00072-0.3 g/L, balancing water for injection, pH value regulator regulating system pH to 6.0-7.0;
2) Ofloxacin 0.018-0.375 g/L, gamma-polyglutamic acid 0.00072-0.3 g/L, osmotic pressure regulator 2.0-10.0 g/L, balancing water for injection, pH value regulator regulating system pH to 6.0-7.0;
3) Ofloxacin 0.018-0.375 g/L, gamma-polyglutamic acid 0.00072-0.3 g/L, osmotic pressure regulator 2.0-10.0 g/L, viscosity regulator 0.01-2.0 g/L, balancing injection water, pH value regulator regulating system pH value to 6.0-7.0;
4) 0.018-0.375 g/L ofloxacin, 0.00072-0.3 g/L gamma-polyglutamic acid, 2.0-10.0 g/L osmotic pressure regulator, 0.01-2.0 g/L viscosity regulator, 0.01-0.2 g/L solubilizer, the balance of water for injection and pH regulator regulating the pH value of the system to 6.0-7.0;
5) 0.018-0.375 g/L ofloxacin, 0.00072-0.3 g/L gamma-polyglutamic acid, 2.0-10.0 g/L osmotic pressure regulator, 0.01-2.0 g/L viscosity regulator, 0.01-0.2 g/L solubilizer, 0.01-10.0 g/L cosolvent, the balance of water for injection and pH regulator regulating system pH to 6.0-7.0;
6) Ofloxacin 0.018-0.375 g/L, gamma-polyglutamic acid 0.00072-0.3 g/L, osmotic pressure regulator 2.0-10.0 g/L, viscosity regulator 0.01-2.0 g/L, solubilizer 0.01-0.2 g/L, cosolvent 0.01-10.0 g/L, antioxidant 0.01-0.1 g/L, balance of water for injection, pH regulator regulating system pH to 6.0-7.0.
In some preferred embodiments, the ofloxacin ophthalmic external composition further comprises sodium danshensu, the content of which is 18.5 to 22.0%, preferably 18.5 to 21.0%, more preferably 19.0 to 20.0%, most preferably 20.0% of the content of gamma-polyglutamic acid.
The ingestion of higher doses of ofloxacin can be irritating to ocular keratocytes, and there are also reports in the prior art that ofloxacin can produce significant cytotoxicity to HCEP cells by inducing cell cycle arrest and apoptosis at mass concentrations above 1/8 (0.375 g/L) of its clinically therapeutic mass concentration (typically 3.0 g/L), which further limits the use of ofloxacin. After further experiments, the two components can exert high-efficiency synergistic effect to obviously inhibit cytotoxicity of high-dose ofloxacin after adding a specific amount of sodium salvianic acid A relative to gamma-polyglutamic acid into the ofloxacin eye external composition containing gamma-polyglutamic acid, so that the high-dose ofloxacin exerts antibacterial effect and simultaneously reduces the irritation to eyes, and the phenomena of eye redness, pain and itch and the like of partial administrated people caused by multi-dose administration and continuous frequent administration in the process of administering the ofloxacin eye external composition are greatly avoided.
In some preferred embodiments, the ofloxacin content occupies an eye of the ofloxacin topical composition in an amount that can be extended to 0.018 to 1.500g/L.
In some preferred embodiments, the relative molecular mass of the gamma-polyglutamic acid is 500000 ～ 1000000.
In some preferred embodiments, the content of gamma-polyglutamic acid is 20.0 to 150.0% of the content of ofloxacin, and the content of gamma-polyglutamic acid occupies not more than 1.0g/L of the composition for external use on the eye of ofloxacin.
In some preferred embodiments, the ofloxacin ophthalmic topical composition is preferably ofloxacin eye drops.
Based on the above considerations and by way of example, the topical compositions for ophthalmic use described herein include, but are not limited to, those listed in the following 1) to 6):
1) 0.018-0.75 g/L ofloxacin, 0.0036-1.0 g/L gamma-polyglutamic acid, 18.5-22.0% sodium danshensu, the balance of water for injection, pH value regulator regulating system pH to 6.0-7.0;
2) 0.018-0.75 g/L of ofloxacin, 0.0036-1.0 g/L of gamma-polyglutamic acid, 18.5-22.0% of sodium salvianic acid A, 2.0-10.0 g/L of osmotic pressure regulator, and the balance of water for injection, wherein the pH value regulator regulates the pH value of the system to 6.0-7.0;
3) 0.018-0.75 g/L of ofloxacin, 0.0036-1.0 g/L of gamma-polyglutamic acid, sodium salvianic acid with the content of 18.5-22.0% of gamma-polyglutamic acid, 2.0-10.0 g/L of osmotic pressure regulator, 0.01-2.0 g/L of viscosity regulator, the balance of water for injection, and pH value regulator regulating system pH value to 6.0-7.0;
4) 0.018-0.75 g/L ofloxacin, 0.0036-1.0 g/L gamma-polyglutamic acid, sodium danshensu with 18.5-22.0% gamma-polyglutamic acid content, 2.0-10.0 g/L osmotic pressure regulator, 0.01-2.0 g/L viscosity regulator, 0.01-0.2 g/L solubilizer, the balance of water for injection, pH regulator regulating system pH to 6.0-7.0;
5) 0.018-1.00 g/L ofloxacin, 0.0036-1.0 g/L gamma-polyglutamic acid, sodium danshensu with 18.5-22.0% gamma-polyglutamic acid content, 2.0-10.0 g/L osmotic pressure regulator, 0.01-2.0 g/L viscosity regulator, 0.01-0.2 g/L solubilizer, 0.01-10.0 g/L cosolvent, the balance of water for injection and pH value regulator regulating system pH value to 6.0-7.0;
6) 0.018-1.50 g/L ofloxacin, 0.0036-1.0 g/L gamma-polyglutamic acid, sodium salvianic acid with 18.5-22.0% gamma-polyglutamic acid content, 2.0-10.0 g/L osmotic pressure regulator, 0.01-2.0 g/L viscosity regulator, 0.01-0.2 g/L solubilizer, 0.01-10.0 g/L cosolvent, 0.01-0.1 g/L antioxidant, and the balance of injection water, pH regulator regulating system pH to 6.0-7.0.
[3] The application of gamma-polyglutamic acid and sodium danshensu in reducing the cytotoxicity of ofloxacin.
In the application, the content of the sodium salvianic acid A is 18.5-22.0% of the content of the gamma-polyglutamic acid.
[4] A method for preparing the ofloxacin ophthalmic external composition as described in the above item [2], which comprises:
1) Weighing part of the carrier according to the formula, adding ofloxacin, gamma-polyglutamic acid and other components except for a pH regulator, and uniformly stirring at 75-90 ℃;
2) After a small amount of carriers are reserved, adding the rest carriers into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH value regulator, uniformly stirring, and cooling to room temperature;
3) Adding the rest carrier to the mixture in the step 2), fine-filtering for 3-5 times by a secondary filter in the class A environment, and filling into a sterile tank, and canning after the test is qualified.
In some preferred embodiments, the stirring rate of step 1) is not less than 150r/min.
In some preferred embodiments, the stirring rate of step 2) is not less than 150r/min.
In some preferred embodiments, the filter cartridge specifications of the secondary filter of step 3) are 0.45 μm, 0.22 μm, and the pressure is less than or equal to 0.12MPa, respectively.
The application provides an ofloxacin eye external composition, which can be prepared by applying the existing preparation process of liquid eye drops, and compared with ofloxacin eye drops without gamma-polyglutamic acid, the gamma-polyglutamic acid is added in the technical scheme of the application, so that the kinematic viscosity of the ofloxacin eye drops can be improved to 15mm 2 The retention time of ofloxacin eye drops in eyes can be obviously improved above/s, so that the effective components in the eye drops are better absorbed and utilized by organisms. In addition, aiming at the defect of insufficient antibacterial effect of low-dose ofloxacin, the addition of trace gamma-polyglutamic acid can obviously improve the antibacterial capability of the ofloxacin eye drops, so that the eye drops containing lower-dose ofloxacin do not need to be additionally added with antibacterial or antiseptic additives, and the irritation or side effect of an exogenous antibacterial agent on eyes can be thoroughly eliminated while the eye drops cannot be polluted by microorganisms. The inventors have also found that in the presence of gamma-polyglutamic acidAfter the danshensu sodium with specific quantity relative to the gamma-polyglutamic acid is added into the ofloxacin eye external composition of the amino acid, the gamma-polyglutamic acid and the danshensu sodium can play a relatively high-efficiency synergistic effect to obviously inhibit the cytotoxicity of high-dose ofloxacin, so that the high-dose ofloxacin plays a bacteriostatic role and simultaneously reduces the irritation to eyes, thereby avoiding the side effects of eye redness, pain and itching and the like possibly caused by the application of the high-dose ofloxacin, and expanding the dose limitation of the ofloxacin in a safety range.
The above-mentioned preferable conditions can be combined with each other to obtain a specific embodiment on the basis of common knowledge in the art.
The raw materials or the reagents involved in the invention are all common commercial products, and the related operations are all routine operations in the field unless specified.
The beneficial effects of the invention are as follows:
1) The gamma-polyglutamic acid can improve the kinematic viscosity of ofloxacin eye drops to 15mm 2 The retention time of ofloxacin eye drops in eyes can be obviously improved, so that the effective components in the eye drops are better absorbed and utilized by organisms;
2) The addition of the trace gamma-polyglutamic acid can obviously improve the antibacterial capacity of the ofloxacin eye drops, so that the eye drops containing the low-dose ofloxacin do not need to be additionally added with fungus inhibiting or antiseptic additives, and the irritation or side effect possibly caused by an exogenous bacteriostatic agent to eyes can be thoroughly eliminated while the eye drops are ensured not to be polluted by microorganisms;
3) The gamma-polyglutamic acid and sodium salvianic acid can exert high-efficiency synergistic effect to obviously inhibit cytotoxicity of high-dose ofloxacin, so that the irritation to eyes is reduced while the high-dose ofloxacin exerts antibacterial effect, and side effects such as red swelling, pain and itching of eyes and the like possibly caused by the application of the high-dose ofloxacin are avoided.
The invention adopts the technical proposal to realize the aim, makes up the defects of the prior art, has reasonable design and convenient operation.
Drawings
The foregoing and/or other objects, features, advantages and embodiments of the invention will be apparent from the following description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graph showing kinematic viscosity data of an ofloxacin ophthalmic topical composition of the present invention;
fig. 2 and 3 are schematic diagrams showing cytotoxicity statistics of the components of the ofloxacin ophthalmic external composition of the present invention on human corneal epithelial cells.
Detailed Description
Suitable substitutions and/or modifications of the process parameters will be apparent to those skilled in the art from the disclosure herein, however, it is to be expressly pointed out that all such substitutions and/or modifications are intended to be encompassed by the present invention. While the products and methods of preparation of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the products and methods of preparation described herein without departing from the spirit and scope of the invention.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The present invention uses the methods and materials described herein; other suitable methods and materials known in the art may be used. The materials, methods, and examples described herein are illustrative only and not intended to be limiting. All publications, patent applications, patents, provisional applications, database entries, and other references mentioned herein, and the like, are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
All percentages, parts, ratios, etc., are by weight unless otherwise specified; the other specification includes, but is not limited to, "wt%" means weight percent, "mol%" means mole percent, "vol%" means volume percent.
When an amount, concentration, or other value or parameter is given as either a range, preferred range, or a series of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when a range of "1 to 5 (1 to 5)" is described, the described range should be understood to include ranges of "1 to 4 (1 to 4)", "1 to 3 (1 to 3)", "1 to 2 (1 to 2) and 4 to 5 (4 to 5)", "1 to 3 (1 to 3) and 5", and the like. Where a range of values is described herein, unless otherwise stated, the range is intended to include the range endpoints and all integers and fractions within the range.
When the term "about" is used to describe a numerical value or an endpoint of a range, the disclosure should be interpreted to include the particular value or endpoint referred to.
Furthermore, unless expressly indicated to the contrary, "or" means "or" inclusive, rather than exclusive "or" unless expressly indicated to the contrary. For example, the following conditions apply to either condition a "or" B: a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), and a and B are both true (or present).
Furthermore, the indefinite articles "a" and "an" preceding an element or component of the present invention are intended to mean that the element or component is present (i.e. takes place) in a non-limiting number. Thus, "a" or "an" is to be understood to include one or at least one of the elements or components in the singular, unless the amount is explicitly stated as being the singular, the plural as well.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation. The term "comprising" an element defined by the term "comprising" does not exclude the presence of other identical elements in a process, method, article or apparatus that comprises the element.
Unless specifically stated otherwise, the materials, methods, and examples described herein are illustrative only and not intended to be limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.
The present invention is described in detail below.
Example 1: ofloxacin eye drops:
prescription:
the preparation method comprises the following steps:
1) Adding cosolvent, ofloxacin, gamma-polyglutamic acid and osmotic pressure regulator into 500mL of water for injection, and stirring uniformly at 90 ℃ and 300 r/min;
2) Adding 450mL of water for injection into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH regulator, uniformly stirring at 300r/min, and cooling to room temperature;
3) And 2) carrying out fine filtration on the mixture obtained in the step 2) for 5 times by using a secondary filter (0.45 mu m and 0.22 mu m and 0.1 MPa) under the A-level environment until the volume of the mixture is 1000mL, and filling the mixture into a sterile tank after the mixture is inspected to be qualified.
Example 2: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 1.
Example 3: ofloxacin eye drops:
prescription:
the preparation method is the same as in example 1.
Example 4: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 1.
Example 5: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 1.
Comparative examples 1 to 5: ofloxacin eye drops:
comparative examples 1 to 5 each provided several other ofloxacin eye drops, the formulations were as follows:
note that: and/- - -indicates no addition.
The preparation method comprises the following steps:
1) Adding cosolvent, ofloxacin and osmotic pressure regulator into 500mL of water for injection, and stirring uniformly at 90 ℃ and 300 r/min;
2) Adding 450mL of water for injection into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH regulator, uniformly stirring at 300r/min, and cooling to room temperature;
3) And 2) carrying out fine filtration on the mixture obtained in the step 2) for 5 times by using a secondary filter (0.45 mu m and 0.22 mu m and 0.1 MPa) under the A-level environment until the volume of the mixture is 1000mL, and filling the mixture into a sterile tank after the mixture is inspected to be qualified.
Experimental example 1: determination of eye drop kinematic viscosity:
the kinematic viscosities of the eye drops in examples 1 to 5 and comparative examples 1 to 5 were measured by referring to the "Chinese pharmacopoeia" (2015 edition) fourth general rule 0633 viscosity measurement method, and the statistical results are shown in FIG. 1. As can be seen from FIG. 1, the ofloxacin eye drops in the technical schemes of examples 1 to 5 of the application all have the kinematic viscosity of up to 15mm 2 The retention time of ofloxacin eye drops in eyes can be obviously improved above/s, so that the effective components in the eye drops are better absorbed and utilized by organisms; the kinematic viscosity of ofloxacin eye drops in comparative examples 1 to 5 is lower than 10mm 2 And/s, the fact that the kinematic viscosity is reduced to different degrees without adding gamma-polyglutamic acid is shown, so that the residence time of the active ingredients in eyes is influenced, and the absorption and the utilization of the active ingredients are not facilitated.
Experimental example 2: antibacterial efficacy measurement:
the antibacterial efficacy of the eye drops in examples 1 to 5 and comparative examples 1 to 5 was measured by referring to the antibacterial efficacy measurement method of the fourth general rule 1121 of the Chinese pharmacopoeia (2015 edition), and the statistical results are shown in the following table.
Note that: NR- -the test bacteria did not resume growth; n- -not increased, means that the number of test bacteria increased by no more than 0.5lg for the previous measurement time.
As can be seen from the table, the ofloxacin eye drops provided in examples 1 to 5 of the present application have remarkable antibacterial effect, whether the molecular weight of the gamma-polyglutamic acid is changed (examples 1 to 3), the high-dose ofloxacin is administered with low content of gamma-polyglutamic acid (example 4) or the low-dose ofloxacin is administered with high content of gamma-polyglutamic acid (example 5), the growth of bacteria and fungi can be remarkably inhibited, the experimental bacteria can not resume to grow, and the ofloxacin eye drops all reach the antibacterial effect standard of "a"; in contrast, comparative examples 1 to 5, which lack ofloxacin (comparative example 2) and to which no γ -polyglutamic acid (comparative examples 1, 3 to 5) was added, had significantly decreased bacteriostatic efficacy, and none of them could meet the bacteriostatic efficacy standard of "B".
Example 6: another ofloxacin eye drops:
prescription:
the preparation method comprises the following steps:
1) Adding cosolvent, ofloxacin, gamma-polyglutamic acid, sodium salvianic acid A and osmotic pressure regulator into 500mL of water for injection, and stirring uniformly at 90 ℃ at 300 r/min;
2) Adding 450mL of water for injection into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH regulator, uniformly stirring at 300r/min, and cooling to room temperature;
3) And 2) carrying out fine filtration on the mixture obtained in the step 2) for 5 times by using a secondary filter (0.45 mu m and 0.22 mu m and 0.1 MPa) under the A-level environment until the volume of the mixture is 1000mL, and filling the mixture into a sterile tank after the mixture is inspected to be qualified.
Example 7: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 6.
Example 8: another ofloxacinEye drops:
prescription:
the preparation method is the same as in example 6.
Example 9: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 6.
Example 10: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 6.
Example 11: another ofloxacin eye drops:
prescription:
the preparation method is the same as in example 6.
Comparative examples 6 to 10: ofloxacin eye drops:
prescription:
note that: and/- - -indicates no addition.
The preparation method comprises the following steps:
1) Adding cosolvent, ofloxacin, gamma-polyglutamic acid (if contained), sodium tanshinol (if contained) and osmotic pressure regulator into 500mL of water for injection, and stirring uniformly at 90 ℃ at 300 r/min;
2) Adding 450mL of water for injection into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH regulator, uniformly stirring at 300r/min, and cooling to room temperature;
3) And 2) carrying out fine filtration on the mixture obtained in the step 2) for 5 times by using a secondary filter (0.45 mu m and 0.22 mu m and 0.1 MPa) under the A-level environment until the volume of the mixture is 1000mL, and filling the mixture into a sterile tank after the mixture is inspected to be qualified.
Experimental example 3: cytotoxicity assay:
HCEC (human corneal epithelial cells) in good culture condition was inoculated into 96-well plates at a density of 5000 cells per well, 200 μl per well was cultured with 10% fbs-DMEM medium to the logarithmic phase, and after the medium was removed, ofloxacin, γ -polyglutamic acid (if included) and sodium danshensu (if included) components of ofloxacin eye drops in examples 6 to 11 (S6 to S11) and comparative examples 6 to 13 (D6 to D13) were added to 10% fbs-DMEM medium while keeping their original contents, and cells of 10% fbs-DMEM medium without drug were used as control (C) and incubated in an incubator for 48 hours; in the incubation process, the old culture solution is removed, each well is replaced by 200 mu L of serum-free DMEM culture solution containing 1.1mmol/LMTT, incubation is continued for 4 hours at 37 ℃ in the dark, 150 mu L of DMSO is added, a 490nm light absorption value (OD value) of cells in each well is detected by an enzyme-labeled instrument, and the cell viability is judged according to the OD value. The statistical results are shown in fig. 2 and 3.
As can be seen from FIGS. 2 and 3, the preferable examples 6 to 8 and comparative example 6 of the present application each have ofloxacin content of less than 0.375g/L, and thus exhibit extremely weak cytotoxicity to human corneal epithelial cells, which is hardly different from that of the blank group. When the ofloxacin content is increased to more than 0.375g/L, the data in comparative examples 9 to 11 and comparative examples 7 to 11 show that compared with comparative examples 7 to 11 without gamma-polyglutamic acid and/or sodium danshensu, the ofloxacin eye drop component in examples 9 to 11 with trace amounts of gamma-polyglutamic acid and sodium danshensu added is basically nontoxic to human corneal epithelial cells, and the difference between the growth condition of human corneal epithelial cells and a blank control group is not obvious; however, when the gamma-polyglutamic acid and/or sodium danshensu are/is absent from the components, the eye drop component has strong toxicity to human corneal epithelial cells, the difference of cell growth between the blank control groups is obvious, and the cytotoxicity is positively correlated with the ofloxacin content and the application time as shown in the combination of the comparative examples 6 to 11, regardless of the lower dosage of ofloxacin (comparative examples 7 and 8) or the higher dosage of ofloxacin (comparative examples 9 to 12). In addition, as can be seen from comparative analysis examples 11 and 12 and 13, when the ratio of sodium danshensu to gamma-polyglutamic acid exceeds the range described in the present application, if the ratio is 10% (comparative example 12) and 30% (comparative example 13), the synergistic effect of the gamma-polyglutamic acid and sodium danshensu cannot be effectively exerted, which means that the synergistic effect of gamma-polyglutamic acid and sodium danshensu can be exerted only after a specific amount of sodium danshensu is added to gamma-polyglutamic acid, so that the cytotoxicity of high-dose ofloxacin can be obviously inhibited, and the irritation of ofloxacin to eyes can be reduced while the high-dose ofloxacin exerts the antibacterial effect, and the phenomena of red swelling, pain and the like of eyes of partial users caused by multi-dose administration and continuous frequent administration in the process of the composition for external application to eyes of ofloxacin can be greatly avoided.
The conventional technology in the above embodiments is known to those skilled in the art, and thus is not described in detail herein.
In view of the numerous embodiments of the present invention, the experimental data of each embodiment is huge and is not suitable for the one-by-one listing and explanation here, but the content of the verification needed by each embodiment and the obtained final conclusion are close. Therefore, the verification contents of the respective examples are not described one by one, and the present invention is described as being excellent only by examples 1 to 11, comparative examples 1 to 13, and experimental examples 1 to 3.
The specific embodiments described herein are offered by way of example only to illustrate the spirit of the invention. Various modifications or additions to the described embodiments may be made by those skilled in the art to which the invention pertains or may be substituted in a similar manner without departing from the spirit of the invention or beyond the scope of the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
While the above detailed description has shown, described, and pointed out novel features as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the device or method illustrated may be made without departing from the spirit of the disclosure. In addition, the various features and methods described above may be used independently of one another, or may be combined in various ways. All possible combinations and subcombinations are intended to fall within the scope of this disclosure. Many of the embodiments described above include similar components, and thus, these similar components are interchangeable in different embodiments. While the invention has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents thereof. Therefore, the present invention is not intended to be limited by the specific disclosure of the preferred embodiments herein.
Claims (4)
1. An ofloxacin eye drop comprising:
ofloxacin 0.018-0.375 g/L;
0.015-0.3 g/L of gamma-polyglutamic acid, wherein the relative molecular mass of the gamma-polyglutamic acid is 500000 ～ 1000000;
pharmaceutically acceptable auxiliary materials including pH value regulator, osmotic pressure regulator, viscosity regulator, solubilizer,
At least one of a cosolvent or an antioxidant, and a carrier;
does not contain fungi inhibiting or antiseptic substances.
2. The ofloxacin eye drop as claimed in claim 1, wherein the preparation method of the eye drop comprises the following steps:
1) Weighing part of the carrier according to the formula, adding ofloxacin, gamma-polyglutamic acid and other components except for a pH regulator, and uniformly stirring at 75-90 ℃;
2) After a small amount of carriers are reserved, adding the rest carriers into the mixture in the step 1), regulating the pH value to 6.0-7.0 by using a pH value regulator, uniformly stirring, and cooling to room temperature;
3) Adding the rest carrier to the mixture in the step 2), fine-filtering for 3-5 times by a secondary filter in the class A environment, and filling into a sterile tank, and canning after the test is qualified.
3. The ofloxacin eye drops are characterized by comprising the following components:
1.5g of ofloxacin;
1.5g of gamma-polyglutamic acid, the molecular weight of the gamma-polyglutamic acid being 1000000;
0.22g of sodium salvianic acid A;
0.5mol/L sodium hydroxide solution, and adjusting the pH value to 6.0-7.0;
mannitol 6.0g;
6.0g of 35vol% acetic acid;
the volume of the water for injection is fixed to 1000mL.
4. The ofloxacin eye drops are characterized by comprising the following components:
1.5g of ofloxacin;
1.5g of gamma-polyglutamic acid, the molecular weight of the gamma-polyglutamic acid being 1000000;
0.3g of sodium salvianic acid A;
0.5mol/L sodium hydroxide solution, and adjusting the pH value to 6.0-7.0;
mannitol 6.0g;
6.0g of 35vol% acetic acid;
the volume of the water for injection is fixed to 1000mL.
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| CN109846820A (en) * | 2019-04-09 | 2019-06-07 | 广东三蓝药业股份有限公司 | A kind of ofloxacin eye drops and preparation method thereof |
| CN111281980A (en) * | 2020-02-05 | 2020-06-16 | 石家庄学院 | Water-soluble gamma-polyglutamic acid-tilmicosin compound and preparation method thereof |
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| CN109846820A (en) * | 2019-04-09 | 2019-06-07 | 广东三蓝药业股份有限公司 | A kind of ofloxacin eye drops and preparation method thereof |
| CN111281980A (en) * | 2020-02-05 | 2020-06-16 | 石家庄学院 | Water-soluble gamma-polyglutamic acid-tilmicosin compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 张丽琼等.丹参治疗眼病的机制.第九届全国中西医结合眼科学术交流会暨第八次东北亚国际眼科学术会.2010,5-6. * |
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