CN116531319A - Antibacterial ophthalmic gel and preparation method and application thereof - Google Patents

Antibacterial ophthalmic gel and preparation method and application thereof Download PDF

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Publication number
CN116531319A
CN116531319A CN202310588366.4A CN202310588366A CN116531319A CN 116531319 A CN116531319 A CN 116531319A CN 202310588366 A CN202310588366 A CN 202310588366A CN 116531319 A CN116531319 A CN 116531319A
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poloxamer
ophthalmic
levofloxacin
cyclodextrin
hydroxypropyl
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张培雯
樊莲莲
苏文成
代晶
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Peoples Hospital of Deyang City
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Peoples Hospital of Deyang City
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Abstract

The invention discloses an ophthalmic antibacterial gel and a preparation method and application thereof. The ophthalmic antibacterial gel mainly comprises the following raw materials in percentage by mass: levofloxacin-0.3-0.5% and hydroxypropyl-β-cyclodextrin-4-10%, poloxamer 407-25-30%, poloxamer 188-2-8% and the balance being purified water; the pH value of the ophthalmic antibacterial gel is 6.0 to the upper part8.0. The ophthalmic antibacterial gel of the invention aims at the particularity of eye infection and the technical deficiency of the prior ophthalmic antibacterial gel, hydroxypropyl-βAfter the cyclodextrin is used for clathrating the levofloxacin, a firmer three-dimensional structure is formed between the clathrate compound and the poloxamer, so that the solubility of the medicine is changed, the antibacterial gel has better medicine release effect, excellent permeation and antibacterial effect and good stability.

Description

Antibacterial ophthalmic gel and preparation method and application thereof
Technical Field
The invention relates to ophthalmic medicine, in particular to an ophthalmic antibacterial gel, and a preparation method and application of the ophthalmic antibacterial gel.
Background
Infectious endophthalmitis is one of the most serious complications of endophthalmitis, and often causes serious consequences of vision loss due to untimely findings and treatment. The cause of the analysis is the pathogenic bacteria causing postoperative infectious endophthalmitis, mainly in the eyelid and conjunctival sac. As a necessary way of the intraocular operation, a large amount of colonization flora is distributed in conjunctival sac and eyelid, the colonization flora can enter the eye through operation stimulation or extrusion, and cornea, vitreous body and the like are all avascular transparent tissues, so that good environment for growth and reproduction of the displaced pathogenic bacteria can be provided.
The treatment of infectious endophthalmitis is focused on the rapid elimination of infection, enabling the intravitreal drug concentration to reach an effective dose rapidly, and topical antibacterial treatment remains the primary approach. However, in general, the blood-ocular barrier makes it difficult for the antibacterial agent to pass through, and the tear protection mechanism makes the eye drops easily diluted and lost, which can lead to difficulty in achieving the desired effect of the local antibacterial treatment.
Clinical experiments prove that the ophthalmic gel taking the levofloxacin as the active ingredient is the first choice medicament for preventing and treating eye infection before or after operation. The levofloxacin is levo-isomer ofloxacin, the molecular structure of the levo-isomer ofloxacin contains hydrophilic carboxyl and oxazine rings and hydrophobic N-methylpiperazine, the levo-ofloxacin is white or pale yellow powder, the levo-ofloxacin is odorless, the levo-ofloxacin is easy to be discolored and decomposed when being irradiated by light, and the medicine has light instability. The levofloxacin serving as a third-generation fluoroquinolone antibacterial drug has an in-vitro antibacterial activity which is 1 times stronger than that of ofloxacin, is commonly used for treating symptoms such as hospital acquired pneumonia, community acquired pneumonia, acute bacterial sinusitis, acute bacterial attacks of chronic bronchitis, complicated skin or skin soft tissue infection and the like, has a wide antibacterial spectrum and a strong antibacterial effect, has stronger antibacterial activity on gram-positive bacteria, gram-negative bacteria, mycoplasma and the like, and has a good antibacterial effect on main bacterial groups (such as coagulase-negative staphylococci and staphylococcus aureus) of eye infection. The medicine is administrated to eyes in the form of hydrogel, the residence time of the medicine in the eyes is between that of eye drops and eye pastes, and the medicine is easy to clean, so that the aim of delaying the release of the medicine can be reliably achieved.
Conventionally, an ophthalmic gel containing levofloxacin is prepared by taking levofloxacin as a single active ingredient and adding hydrogel auxiliary materials, for example, the technology disclosed in Chinese patent literature is named as "a levofloxacin hydrochloride gel type eye drop" (publication No. CN 102949334A, publication No. 2013, month 06), "a levofloxacin hydrochloride gel type eye drop preparation method" (publication No. CN 102949335A, publication No. 2013, month 06), "an ophthalmic gel, its preparation method, application and use method" (publication No. CN 106963726A, publication No. 2017, month 21) and the like. However, since the stability of levofloxacin is easily affected by external light, the hydrogel containing single levofloxacin has poor stability under the influence of light and relatively limited antibacterial effect when it is dropped into eyes of human body. In addition, hydrogels comprising single levofloxacin have relatively limited penetration in the human eye, are difficult to effectively penetrate the skin of the eye, and thus cannot effectively antibacterial clean the inner side of the eye, the maximum sebaceous gland of the whole body, the meibomian gland formation, and have relatively limited antibacterial effects on the meibomian glands.
The Chinese patent literature discloses a technology of 'levofloxacin lactate eye sustained-release gel and a preparation method thereof' (publication No. CN 1562038A, publication No. 01 month 12), wherein levofloxacin lactate is used as an active substance, and thickener, preservative, isotonic regulator, permeation accelerator and water are added to prepare the eye gel. In this technique, it is disclosed that a component including hydroxypropyl-beta-cyclodextrin is used as a permeation enhancer, and the content of the permeation enhancer is 0.005 to 20%. The gel prepared by the technology has certain permeation effect at the skin of eyes of a human body due to the content selection of the permeation enhancer and the compatibility with the levofloxacin, but has poor stability and limited permeation effect.
Disclosure of Invention
The technical purpose of the invention is that: aiming at the particularity of the eye infection and the technical deficiency of the prior ophthalmic antibacterial gel, the ophthalmic antibacterial gel with good stability and excellent permeation and antibacterial effects is provided, and the preparation method and the application of the ophthalmic antibacterial gel.
The technical aim of the invention is achieved by the following technical scheme, namely the ophthalmic antibacterial gel mainly comprises the following raw materials in percentage by mass:
the pH value of the ophthalmic antibacterial gel is 6.0-8.0.
Further, the antibacterial gel mainly comprises the following raw materials in percentage by mass:
the pH value of the ophthalmic antibacterial gel is 6.0-8.0.
As one of the preferred schemes, the pH value of the ophthalmic antibacterial gel is regulated by proper amount of sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate and/or sodium hydroxide.
The eye antibacterial gel is prepared by mutually cooperating and matching levofloxacin serving as an antibacterial drug, hydroxypropyl-beta-cyclodextrin serving as a permeation enhancer and poloxamer 407 and poloxamer 188 serving as gel matrixes.
In the technical measures, according to repeated experiments, the relation between the apparent permeability coefficient of the hydroxypropyl-beta-cyclodextrin and the mass concentration of the hydroxypropyl-beta-cyclodextrin is an inverted U-shaped curve, and the content of 4-10% (especially 4-8%) of the hydroxypropyl-beta-cyclodextrin is used as the optimal selection, so that the apparent permeability coefficient of the medicine can be obviously improved. Repeated experiments show that when the mass concentration of the hydroxypropyl-beta-cyclodextrin is less than 4% or more than 12%, the potential energy of the drug in the water phase can be reduced, the apparent permeability coefficient of the drug is reduced, and the experimental data are shown in the following table 1. Therefore, in the technical measures, the mass concentration of the hydroxypropyl-beta-cyclodextrin serving as the permeation and synergistic agent is selected to be 4-10% (particularly 4-8%), so that the apparent permeation coefficient of the medicine can be remarkably improved, the stability is good, the permeation effect at the skin of eyes of a human body is excellent, the inside of eyes and the maximum sebaceous gland-meibomian gland of the whole body can be effectively antibacterial and cleaned, and the antibacterial effect on the meibomian glands is excellent.
TABLE 1 apparent permeability coefficient of hydroxypropyl-cyclodextrin as a function of its mass concentration
Note that GBR (glutathione-sodium bicarbonate ringer solution) served as a blank control;
HL is cornea hydration value;
papp is apparent permeability coefficient;
the ratio is the ratio of Papp between each group and the GBR solution group.
As is clear from the data in Table 1, as the concentration of HP-beta-CD (i.e., hydroxypropyl-beta-cyclodextrin) increases (2%, 4%, 6%, 8%, 10% and 12%), the apparent permeability coefficient (Papp) of levofloxacin increases and decreases, and as the concentration of HP-beta-CD is 4%, 6% and 8%, the apparent permeability coefficient of levofloxacin increases significantly in the HP-beta-CD group compared to the control group, with 6% of HP-beta-CD maximizing the apparent permeability coefficient of levofloxacin as compared to the control group. The apparent permeability coefficients of the HP-beta-CD group levofloxacin at a concentration of 2% and 12% are less statistically different than those of the control group.
Thus, the apparent permeability coefficient of the hydroxypropyl-beta-cyclodextrin and the mass concentration thereof are in an inverse U-shaped curve relationship, and the hydroxypropyl-beta-cyclodextrin with the content concentration of 4-10 percent (especially 4-8 percent) is the best choice in the compatibility with the levofloxacin.
Hydrogels have temperature sensitive properties that undergo a reversible phase transition with changes in ambient temperature to control the release rate of drug molecules embedded within their system. Poloxamers as gel matrixes are amphiphilic copolymers composed of polyoxyethylene-polyoxypropylene-polyoxyethylene, wherein polyoxyethylene is hydrophilic, polyoxypropylene is hydrophobic, and different types of poloxamers can be obtained by the ratio of the polyoxyethylene to the polyoxypropylene. In the technical measures, the polyoxyethylene proportion of the poloxamer 407 is 70%, and the polyoxyethylene proportion of the poloxamer 188 is 80%.
Poloxamer 407 forms spherical micelles which take hydrophilic polyoxyethylene as a shell and wrap a hydrophobic polyoxypropylene block core in an aqueous solution, and as the mass concentration of the poloxamer 407 solution increases, the number of the micelles increases and mutually piles and tangles to finally form gelation. However, the corresponding gelation temperature will decrease when the viscosity of poloxamer 407 increases sharply, which will directly affect the temperature sensitivity of the hydrogel. In the technical measures, a small amount of poloxamer 188 is added, so that the proportion of hydrophilic polyoxyethylene in the solution is increased, the gelation temperature is increased, and the gelation temperature of poloxamer 407 is reliably supplemented, so that the temperature sensitivity of the formed hydrogel is ensured.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and hydroxypropyl-beta-cyclodextrin with the formula amount to obtain clathrate compound powder;
fully stirring and wetting poloxamer 407 and poloxamer 188 in a formula amount in a proper amount of purified water, and standing to fully swell poloxamer particles to obtain a clear and uniformly dispersed hydrogel matrix solution;
step 2, fully dissolving the clathrate compound powder in a proper amount of purified water;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution, stirring and fully mixing, and diluting with a proper amount of purified water;
and 4, regulating the pH value of the solution in the step 3 to 6.0-8.0 to obtain the ophthalmic antibacterial gel.
As one of the preferable schemes, the specific preparation process of the clathrate compound powder in the step 1 is as follows:
dry grinding the formula amount of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for at least 30 minutes to enable the levofloxacin and the hydroxypropyl-beta-cyclodextrin to be fully ground;
washing the mortar with a proper amount of purified water, and drying the slurry formed by washing in an oven at 40-45 ℃ to obtain clathrate compound powder;
the clathrate compound powder is placed in a dry, airtight and low-temperature environment for standby.
As one of the preferred embodiments, the stirring-wetted poloxamer particles in step 1 are left for at least 12 hours at a temperature of 2-5 ℃.
The preparation method of the antibacterial gel comprises the step of preparing the levofloxacin and the hydroxypropyl-beta-cyclodextrin into an inclusion compound by a dry grinding method.
The hydroxypropyl-beta-cyclodextrin is a cyclic oligosaccharide compound connected by low glucose molecules through 1, 4-glycosidic bonds, and is of a hollow cylindrical three-dimensional structure, the opening of a cavity of the three-dimensional structure is hydrophilic, and the inside of the cavity is hydrophobic. The levofloxacin drug molecules of the guest molecules are reliably (at least mostly) included in the hydroxypropyl-beta-cyclodextrin by fine grinding by a dry grinding method to form special inclusion compound powder. That is, the inclusion technique is utilized to wrap the hydrophobic structural group (N-methylpiperazine) of the levofloxacin, so as to improve the water solubility of the levofloxacin and the light deterioration property of the levofloxacin, ensure the stability of the medicament and reliably delay the release of the medicament.
The hydroxypropyl-beta-cyclodextrin is used as a carrier of the inclusion compound, and after being connected with the molecular structure of the levofloxacin, the hydroxypropyl-beta-cyclodextrin can increase the hydrophilicity of the medicine after entering the eyes, increase the medicine concentration gradient of the medicine on the two sides of the skin of the eyes, promote the diffusion and absorption of the medicine, and further enhance the antibacterial effect. Meanwhile, the hydroxypropyl-beta-cyclodextrin can permeate into the cell membrane, and the permeation quantity of the medicine is increased by extracting fat-soluble substances (such as cholesterol and phospholipid) from the cell membrane, so that the antibacterial effect of the levofloxacin is enhanced.
The formation of inclusion compound is a physical process, and the inclusion compound and free levofloxacin are in dynamic equilibrium state in aqueous solution. After two polymers of poloxamer 188 and poloxamer 407 are added, as the poloxamer is an amphiphilic copolymer, hydrophobic fragments on molecules of the poloxamer can enter a hole structure of hydroxypropyl-beta-cyclodextrin, so that the solubility of the hydrophobic fragments is increased. The poloxamer molecules polymerized at a certain temperature do not form micelles due to the increase of solubility, but form a more compact three-dimensional network structure through the cross-linking with the hydroxypropyl-beta-cyclodextrin, so that the original gelation temperature and drug release characteristics of the levofloxacin and poloxamer hydrogel are changed, and the stability is better.
Experiments show that before and after the hydroxypropyl-beta-cyclodextrin is added to form an inclusion compound in an artificial tear simulation environment, the mass concentration ratio of poloxamer 407 to poloxamer 188 is obviously changed, and the specific steps are as follows:
through star point-effect surface experimental design, model fitting is carried out on the mass concentration ratio of each component of the levofloxacin/hydroxypropyl-beta-cyclodextrin inclusion compound and poloxamer 407/poloxamer 188, so that the verified strong antibacterial hydrogel product with the gelation temperature of 32.8-34.0 (the relative error is less than 5%) is obtained, and the requirement of ocular administration in clinical treatment can be reliably met.
Meanwhile, the control of drug release is driven by the double phase transition and inclusion-dissociation of the solution-semisolid in the gel system, so that not only is the hydroxypropyl-beta-cyclodextrin inclusion capacity maintained, but also the drug release performance of the gel is obviously improved. The experimental results show that: the cumulative percent erosion of the levofloxacin/poloxamer hydrogel at 2 hours prior to the addition of hydroxypropyl-beta-cyclodextrin was 19.75% and the cumulative percent release was 15.82%. After the hydroxypropyl-beta-cyclodextrin is added to form a clathrate compound, the cumulative erosion percentage of the levofloxacin Sha Xingjiang effect antibacterial hydrogel at 2 hours is 6.80 percent, and the cumulative release percentage is 32.08 percent; the cumulative erosion percentage for 12h was 23.01% and the cumulative release percentage was 88.48%. At the same time point (2 h), the cumulative erosion percentage of the coated potent antimicrobial hydrogel product is significantly lower than that of the non-coated ordinary hydrogel, but the cumulative release percentage is significantly higher than that of the non-coated ordinary hydrogel. The fact proves that the solubility of the levofloxacin after being included by the hydroxypropyl-beta-cyclodextrin is increased, so that the release amount of the medicine is increased and the release is accelerated; however, a firmer three-dimensional structure is formed between the inclusion compound and poloxamer, so that the product has better drug release effect, and experimental results show that the erosion amount of the saturated hydrogel is reduced, the retention time of the drug at the action part is prolonged, and the effects of improving the absorption availability of the drug and strong-effect antibacterial effect are achieved through quick release.
Use of an ophthalmic antibacterial gel as described above for the treatment of infectious endophthalmitis. The ophthalmic antibacterial gel adopting the technical measures obviously improves the light deterioration characteristic of the levofloxacin, has good permeability and stable performance, has reliable inhibition effect on colonisation flora existing in a capsule and an eyelid, and meets the technical requirements of pathological treatment of infectious endophthalmitis.
The beneficial technical effects of the invention are as follows: the ophthalmic antibacterial gel prepared by the technical measures aims at the particularity of eye infection and the technical defects of the existing ophthalmic antibacterial gel, after the hydroxypropyl-beta-cyclodextrin is used for clathrating the levofloxacin, a firmer three-dimensional structure is formed between the clathrate compound and the poloxamer, the dissolubility of the medicine is changed, so that the antibacterial gel has better drug release effect and excellent permeation and antibacterial effects.
The prepared antibacterial gel is subjected to experiments of stability, safety and antibacterial effect respectively.
With respect to stability experiments, it was long-term storable at low temperature and still a yellow clear liquid after 4 weeks of standing. In a high-speed centrifugal state (2000 g, 10min of centrifugation), the gel solution is uniform, layering and precipitation phenomena are avoided, and the state is stable. It is stable to light and heat.
Regarding the safety experiment, the hydroxypropyl-beta-cyclodextrin and the poloxamer are both safe, non-irritating and high in biocompatibility. In-vitro animal experiments show that after the antibacterial gel is coated for multiple times for stimulation, the skin of the control group experimental rabbit with intact skin does not have irritation reactions such as erythema, edema and the like, the control group experimental rabbit with damaged skin also does not have irritation reactions, and the average score of the skin reactions after 48 hours of coating is 0. After 72 hours, the wound of the control group experimental rabbits with damaged skin is healed and crusted, and the normal state is basically recovered.
Regarding the antibacterial effect experiment, after the levofloxacin Sha Xingxing is formed into the inclusion compound, the permeability of the membrane and the combination of protein are changed, so that the antibacterial effect of the medicine is enhanced. In vitro animal experiments show that compared with common levofloxacin hydrogel, the gel provided by the invention can obviously inhibit bacterial growth and obviously enhance the antibacterial effect.
Detailed Description
The invention relates to ophthalmic medicines, in particular to an ophthalmic antibacterial gel, a preparation method and application thereof, and the technical scheme of the main body of the invention is specifically described below by combining a plurality of embodiments.
Example 1
The ophthalmic antibacterial gel of the invention is used for treating infectious endophthalmitis, and mainly comprises the following raw materials in percentage by mass: 0.3%, hydroxypropyl- β -cyclodextrin: 6%, poloxamer 407:26%, poloxamer 188:5% and the balance of purified water.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and the hydroxypropyl-beta-cyclodextrin according to the formula amount to obtain clathrate compound powder according to the following process:
-dry grinding formulated amounts of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for about 35 minutes, such that the levofloxacin and hydroxypropyl-beta-cyclodextrin are finely ground;
-rinsing the mortar with about 10% purified water, and drying the slurry formed by rinsing in an oven at about 40 ℃ to obtain clathrate powder;
-the clathrate powder obtained is kept ready for use in a dry, closed, low temperature environment;
the poloxamer 407 and the poloxamer 188 with the formula amounts are fully stirred and wetted in about 50 percent of purified water with the temperature of about 40 ℃, then the mixture is stood for about 12 hours at the temperature of about 4 ℃ to fully swell poloxamer particles, so as to obtain clear, uniformly dispersed and non-agglomerated hydrogel matrix solution;
step 2, stirring the clathrate compound powder obtained in the step 1 in about 30% of purified water to fully dissolve the clathrate compound powder;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution obtained in the step 1, stirring and mixing thoroughly, and diluting with about 10% purified water;
and 4, adjusting the pH value of the solution in the step 3 to be about 7.0 by adopting proper amounts of sodium dihydrogen phosphate and potassium dihydrogen phosphate, thus obtaining the ophthalmic antibacterial gel.
Example 2
The ophthalmic antibacterial gel of the invention is used for treating infectious endophthalmitis, and mainly comprises the following raw materials in percentage by mass: 0.3%, hydroxypropyl- β -cyclodextrin: 8%, poloxamer 407:29%, poloxamer 188:3% and the balance of purified water.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and the hydroxypropyl-beta-cyclodextrin according to the formula amount to obtain clathrate compound powder according to the following process:
-dry grinding formulated amounts of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for about 40 minutes, such that the levofloxacin and hydroxypropyl-beta-cyclodextrin are finely ground;
-rinsing the mortar with about 8% purified water, and drying the slurry formed by rinsing in an oven at about 42 ℃ to obtain clathrate powder;
-the clathrate powder obtained is kept ready for use in a dry, closed, low temperature environment;
the poloxamer 407 and the poloxamer 188 with the formula amounts are fully stirred and wetted in the purified water with the temperature of about 52 percent at the temperature of about 36 ℃, then the mixture is kept stand for about 15 hours at the temperature of about 3 ℃ to fully swell the poloxamer particles, so as to obtain the clear, uniformly dispersed and non-agglomerated hydrogel matrix solution;
step 2, stirring the clathrate compound powder obtained in the step 1 in about 25% of purified water to fully dissolve the clathrate compound powder;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution obtained in the step 1, stirring and mixing thoroughly, and diluting with about 15% purified water;
and 4, adjusting the pH value of the solution in the step 3 to be about 6.0 by adopting proper amounts of acetic acid and sodium acetate, thus obtaining the ophthalmic antibacterial gel.
Example 3
The ophthalmic antibacterial gel of the invention is used for treating infectious endophthalmitis, and mainly comprises the following raw materials in percentage by mass: 0.4%, hydroxypropyl- β -cyclodextrin: 4%, poloxamer 407:25%, poloxamer 188:2% and the balance of purified water.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and the hydroxypropyl-beta-cyclodextrin according to the formula amount to obtain clathrate compound powder according to the following process:
-dry grinding formulated amounts of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for about 43 minutes, such that the levofloxacin and hydroxypropyl-beta-cyclodextrin are finely ground;
-rinsing the mortar with about 12% purified water, and drying the slurry formed by rinsing in an oven at about 45 ℃ to obtain clathrate powder;
-the clathrate powder obtained is kept ready for use in a dry, closed, low temperature environment;
the poloxamer 407 and the poloxamer 188 with the formula amounts are fully stirred and wetted in purified water with the temperature of about 45 percent at about 35 ℃, then the mixture is stood for about 12 hours at the temperature of about 5 ℃ to fully swell poloxamer particles, so as to obtain clear, uniformly dispersed and non-agglomerated hydrogel matrix solution;
step 2, stirring the clathrate compound powder obtained in the step 1 in about 35% of purified water to fully dissolve the clathrate compound powder;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution obtained in the step 1, stirring and mixing thoroughly, and diluting with about 8% purified water;
and 4, adjusting the pH value of the solution in the step 3 to be about 8.0 by adopting proper amounts of sodium dihydrogen phosphate, potassium dihydrogen phosphate and sodium hydroxide, thus obtaining the ophthalmic antibacterial gel.
Example 4
The ophthalmic antibacterial gel of the invention is used for treating infectious endophthalmitis, and mainly comprises the following raw materials in percentage by mass: 0.5%, hydroxypropyl- β -cyclodextrin: 10%, poloxamer 407:27%, poloxamer 188:4% and the balance of purified water.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and the hydroxypropyl-beta-cyclodextrin according to the formula amount to obtain clathrate compound powder according to the following process:
-dry grinding formulated amounts of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for about 31 minutes, such that the levofloxacin and hydroxypropyl-beta-cyclodextrin are finely ground;
-rinsing the mortar with about 15% purified water, and drying the slurry formed by rinsing in an oven at about 41 ℃ to obtain clathrate powder;
-the clathrate powder obtained is kept ready for use in a dry, closed, low temperature environment;
the poloxamer 407 and the poloxamer 188 with the formula amounts are fully stirred and wetted in about 40 percent of purified water with the temperature of about 38 ℃, then the mixture is stood for about 16 hours at the temperature of about 2 ℃ to fully swell poloxamer particles, so as to obtain clear, uniformly dispersed and non-agglomerated hydrogel matrix solution;
step 2, stirring the clathrate compound powder obtained in the step 1 in about 30% of purified water to fully dissolve the clathrate compound powder;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution obtained in the step 1, stirring and mixing thoroughly, and diluting with about 15% purified water;
and 4, adjusting the pH value of the solution in the step 3 to be about 6.0 by adopting a proper amount of sodium dihydrogen phosphate to obtain the ophthalmic antibacterial gel.
Example 5
The ophthalmic antibacterial gel of the invention is used for treating infectious endophthalmitis, and mainly comprises the following raw materials by mass percent, namely Sha Xing 0.3.3% of levofloxacin and 0.3% of hydroxypropyl-beta-cyclodextrin: 7%, poloxamer 407:30%, poloxamer 188:8% of purified water and the balance of purified water.
The preparation method of the ophthalmic antibacterial gel comprises the following technological measures:
step 1, grinding the levofloxacin and the hydroxypropyl-beta-cyclodextrin according to the formula amount to obtain clathrate compound powder according to the following process:
-dry grinding formulated amounts of levofloxacin and hydroxypropyl-beta-cyclodextrin in a mortar for about 33 minutes, such that the levofloxacin and hydroxypropyl-beta-cyclodextrin are finely ground;
-rinsing the mortar with about 10% purified water, and drying the slurry formed by rinsing in an oven at about 43 ℃ to obtain clathrate powder;
-the clathrate powder obtained is kept ready for use in a dry, closed, low temperature environment;
the poloxamer 407 and the poloxamer 188 with the formula amounts are fully stirred and wetted in purified water with the temperature of about 45 percent at about 36 ℃, then the mixture is stood for about 12 hours at the temperature of about 4 ℃ to fully swell poloxamer particles, so as to obtain clear, uniformly dispersed and non-agglomerated hydrogel matrix solution;
step 2, stirring the clathrate compound powder obtained in the step 1 in about 35% of purified water to fully dissolve the clathrate compound powder;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution obtained in the step 1, stirring and mixing thoroughly, and diluting with about 10% purified water;
and 4, adjusting the pH value of the solution in the step 3 to be about 7.0 by adopting a proper amount of sodium hydroxide, thus obtaining the ophthalmic antibacterial gel.
The above examples are only intended to illustrate the present invention, not to limit it.
Although the invention has been described in detail with reference to the above embodiments, it will be understood by those of ordinary skill in the art that: it can still be modified or some of the technical features thereof can be replaced equally, for example, it can be used for the preoperative or postoperative treatment of other bacterial infections of the eye; such modifications and substitutions do not depart from the spirit and scope of the invention.

Claims (7)

1. The ophthalmic antibacterial gel is characterized by mainly comprising the following raw materials in percentage by mass:
0.3 to 0.5 percent of levofloxacin,
Hydroxypropyl radicalβ4-10% of cyclodextrin,
Poloxamer 407-30%,
Poloxamer 188 2-8%,
The balance being purified water;
the pH value of the ophthalmic antibacterial gel is 6.0-8.0.
2. The ophthalmic antibacterial gel according to claim 1, characterized in that it is mainly composed of the following raw materials in mass percent:
0.3% of levofloxacin,
Hydroxypropyl radicalβ4-8% of cyclodextrin,
Poloxamer 407-30%,
Poloxamer 188 2-8%,
The balance being purified water;
the pH value of the ophthalmic antibacterial gel is 6.0-8.0.
3. The ophthalmic antimicrobial gel according to claim 1 or 2, wherein the pH of the ophthalmic antimicrobial gel is adjusted with an amount of sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate and/or sodium hydroxide.
4. A method for preparing an ophthalmic antimicrobial gel according to claim 1 or 2, characterized in that it comprises the following technical measures:
step 1. Mixing the formulation of levofloxacin and hydroxypropyl-β-cyclodextrin, grinding to obtain clathrate powder;
fully stirring and wetting poloxamer 407 and poloxamer 188 in a formula amount in a proper amount of purified water, and standing to fully swell poloxamer particles to obtain a clear and uniformly dispersed hydrogel matrix solution;
step 2, fully dissolving the clathrate compound powder in a proper amount of purified water;
step 3, slowly adding the solution obtained in the step 2 into the hydrogel matrix solution, stirring and fully mixing, and diluting with a proper amount of purified water;
and 4, regulating the pH value of the solution in the step 3 to 6.0-8.0 to obtain the ophthalmic antibacterial gel.
5. The method for preparing an ophthalmic antibacterial gel according to claim 4, wherein the specific preparation process of the clathrate powder in step 1 is:
mixing the levofloxacin and the hydroxypropylβCyclodextrin, dry milling in a mortar for at least 30 minutes to give levofloxacin and hydroxypropyl-βThe cyclodextrin is finely ground to completion;
washing the mortar with a proper amount of purified water, and drying the slurry formed by washing in an oven at 40-45 ℃ to obtain clathrate compound powder;
the clathrate compound powder is placed in a dry, airtight and low-temperature environment for standby.
6. The method of preparing an ophthalmic antibacterial gel according to claim 4, wherein the stirring-wetted poloxamer particles in step 1 are left at a temperature of 2-5 ℃ for at least 12 hours.
7. Use of an ophthalmic antibacterial gel according to claim 1 or 2, characterized in that it is used for the treatment of infectious endophthalmitis.
CN202310588366.4A 2023-05-24 2023-05-24 Antibacterial ophthalmic gel and preparation method and application thereof Pending CN116531319A (en)

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