CN116672310A - Ophthalmic composition for improving stability of easily-hydrolyzed medicine, preparation method and application - Google Patents

Ophthalmic composition for improving stability of easily-hydrolyzed medicine, preparation method and application Download PDF

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CN116672310A
CN116672310A CN202310663287.5A CN202310663287A CN116672310A CN 116672310 A CN116672310 A CN 116672310A CN 202310663287 A CN202310663287 A CN 202310663287A CN 116672310 A CN116672310 A CN 116672310A
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oil
composition
emulsion
stability
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杨帆
薛水玉
唐梦华
乔玉峰
王稳定
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Shanxi Lipuda Pharmaceutical Technology Co ltd
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Shanxi Lipuda Pharmaceutical Technology Co ltd
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
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    • 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
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Abstract

The invention discloses an ophthalmic composition for improving stability of easily-hydrolyzed medicine, a preparation method and application thereof, belongs to the technical field of pharmaceutical preparations, and relates to an ophthalmic medicine. 0.001 to 1.0% of active ingredient by total mass of the composition, 0.5 to 6.0% of oil phase by total mass of the composition, 0.05 to 3.0% of emulsifier by total mass of the composition, 0.1 to 4.0% of auxiliary emulsion by total mass of the composition, 0.01 to 2.0% of pH regulator by total mass of the composition, 0.01 to 1.0% of pH buffer by total mass of the composition, 0.3 to 3.0% of osmotic pressure regulator by total mass of the composition, and the balance of water. According to the invention, the lipophilic end of the easily-hydrolyzed drug is embedded into the oil phase or oil-water interface of the emulsion to prepare the drug delivery system of the nanoemulsion, so that the stability of the drug is improved, the irritation to eyes is reduced, and the bioavailability of the drug is improved.

Description

Ophthalmic composition for improving stability of easily-hydrolyzed medicine, preparation method and application
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, relates to an ophthalmic drug, and in particular relates to an ophthalmic emulsion composition for improving the stability of an easily-hydrolyzed drug, a preparation method and application.
Background
The eye is one of the most precise organs of the human body, and the pH value of normal tolerance is 5.0-9.0, so that the pharmacopoeia strictly prescribes the pH of the ophthalmic preparation. When the pH value is 6.0-8.0, eyes are not uncomfortable, when the pH value of the eye drops is too high or too low, the eyes are stimulated, the lacrimal secretion is too high, the instantaneous frequency is increased, the drug concentration is reduced, a large amount of drugs are lost, the administration frequency is increased to achieve the curative effect, when the ophthalmic preparation is used, a part of drugs enter the nasal cavity and the alimentary canal through the nasolacrimal duct to be finally absorbed by the whole body, and the administration frequency is increased to achieve the risks of easily inducing adverse reactions and causing poisoning in the curative effect.
The medicines such as esters, amides, glycosides and the like contain easily hydrolyzed structures, are easily hydrolyzed, and generally speaking, the stronger the alkalinity of the solution is, the faster the hydrolysis is. At present, the method for solving the problem of the hydrolysis of the ophthalmic drugs mainly comprises the following steps:
1. making into semisolid preparation (eye ointment, eye cream, eye gel). Such as physostigmine salicylate eye ointment (national standard H44023096) for treating primary angle closure glaucoma; aureomycin hydrochloride eye ointment (national drug standard words H41021881, H20066025, etc.) for treating superficial eye infection caused by sensitive gram-negative bacteria; hydrobromic acid post-ma tuo pin eye ointment (national drug standard words H51021554, H11020935) for mydriasis, and the like. Semi-solid ophthalmic formulations, while stable in stability, tend to cause blurred vision, and limited use generally affects patient compliance.
2. Is prepared into eye suspension. For example, anthocyanin is recognized as one of the strongest antioxidants, can effectively prevent protein oxidation and lens turbidity of the eye lens, can also prevent cataract, has great development potential in the field of ophthalmic medicines, but has poor stability, patent CN113876706A discloses that anthocyanin extract is used as a wall layer, anthocyanin nanospheres are prepared by taking anthocyanin extract as a core material, anthocyanin suspension eye drops (not marketed) are prepared by taking the nanospheres as active ingredients, the stability and the storage period of the anthocyanin suspension eye drops are improved, however, the suspension eye drops have strict regulations on the fineness of medicine particles, obvious foreign body sensation is easy to be generated when oversized patients take medicines, so that the transient times are increased, the tear secretion is excessive, and finally the medicines are discharged along with tears, and the medicine effect is reduced; when the concentration of the active ingredient is too low, a large amount of the drug particles easily pass through the blood brain barrier, causing serious consequences, and in addition, as the drug particles in the suspension are dispersed in a particle state, the filtration sterilization is difficult, and the sterilization can only be performed by a dry heat or radiation sterilization mode, but the package material or part of the active ingredient of some ophthalmic preparations cannot withstand high-temperature sterilization, and the radiation sterilization has the problems of insufficient sterilization or strict requirements on sterilization equipment and the like.
3. In the preparation of eye drops, the pH of the preparation is generally reduced as much as possible within the range specified in Chinese pharmacopoeia so as to slow down the hydrolysis rate of the medicine. Such as low-concentration atropine sulfate eye drops for slowing down myopia progression of children, the product is not currently available on the market in China and can only be sold in the form of an in-hospital preparation. Due to the existence of ester groups in the atropine molecular structure, the stability of the atropine in neutral and alkaline solutions is poor, and the atropine with low concentration is easier to hydrolyze, so that the content of active ingredients is reduced, and the curative effect is affected. At present, the pH of the atropine sulfate eye drops is regulated to 5.0 (pharmacopoeia prescribes that the pH of the eye drops is between 5.0 and 9.0) in various domestic hospitals, and the purposes of delaying the hydrolysis of the atropine sulfate eye drops are achieved by refrigerating and preserving the atropine sulfate eye drops. Even so, most of the low-concentration atropine sulfate eye drops can be stored for 12 months at most, and even more, the effective period of some hospital preparations is only a few months. On the other hand, as a medicine for slowing the myopia development of children, the administration time is required to last for 2 years at least. The existing low-concentration atropine sulfate eye drops not only have the problem of poor comfort level of patients (lower pH and poor tolerance of children), but also increase the frequency of purchasing medicines and the preservation cost of families of patients.
4. Low concentration atropine is the only drug demonstrated to be effective in controlling myopia progression, however, the instability of low concentration atropine solutions has been a technical hurdle to be broken through. In order to solve the obstacles, patent US9421199B2 discloses that deuterated water is used as a solvent to improve the stability of the low-concentration atropine eye drops, but the introduction of isotopes inevitably affects the safety of products, has higher requirements on the production control aspect of the products, and limits the popularization of the method. Patent CN110934816 discloses that the stability of a low-concentration atropine ophthalmic preparation is improved by controlling the total impurity content of the atropine sulfate bulk drug to be less than or equal to 0.25% and/or the single impurity content to be less than or equal to 0.05%, but the bulk drug needs to be crushed to be below a certain granularity in advance and subjected to repeated slurry washing when the commercial atropine is purified, which is time-consuming, and a large amount of organic solvents (at least 11 ml of solvents are needed for purifying 1 g of atropine sulfate) are needed, so that a large amount of hazardous waste is necessarily generated, and further popularization of the method is limited. Patent CN113440486A, CN115813855a discloses that a sealed split device is adopted to store atropine freeze-drying agent and re-dissolved diluent in two cavities respectively, so as to simulate the current drug environment of the preparation in a hospital to the greatest extent, solve the problem of stability of low-concentration atropine in the quality guarantee period of the product, but the method has high requirements on the production control of the product and package, and is not suitable for multi-dose package.
Although the method can solve the stability problem of the easily hydrolyzed medicine to a certain extent, the problems of poor medication compliance of patients, short medicine storage time, reduced effectiveness caused by stimulated dilution of tears and the like still exist. In addition, according to statistics of national basic medical insurance, industrial injury insurance and fertility insurance drug catalogs in 2020, ophthalmic liquid preparations are the most mainstream ophthalmic drug preparation type at present, and account for about 68% of all ophthalmic chemical drug types. In view of the above, there is a need in the art to develop an ophthalmic liquid formulation composition that improves the stability of easily hydrolyzed drugs without affecting the comfort of patients while ensuring therapeutic effects, and the successful development of the composition will have great significance in clinical applications and have great market prospects.
The invention aims to solve the defects of the easily-hydrolyzed medicine ophthalmic preparation, develop an ophthalmic composition capable of improving the stability of the easily-hydrolyzed medicine, and achieve the purposes of high stability, good compliance and the like under the condition of not influencing the effectiveness of the medicine.
Disclosure of Invention
In view of the above, the present invention provides an ophthalmic emulsion composition for improving the stability of easily hydrolyzable drugs.
It is another object of the present invention to provide a method for preparing the above ophthalmic emulsion composition.
It is a further object of the present invention to provide the use of the above ophthalmic pharmaceutical composition.
The aim of the invention can be achieved by the following technical scheme:
an ophthalmic composition for improving the stability of easily hydrolyzed medicine comprises the following components in parts by mass:
active ingredients accounting for 0.001 to 1.0 percent of the total mass of the composition,
an oil phase accounting for 0.5 to 6.0 percent of the total mass of the composition,
0.05 to 3.0 percent of emulsifying agent of the total mass of the composition,
0.1 to 4.0 percent of auxiliary emulsion of the total mass of the composition,
a pH regulator accounting for 0.01 to 2.0 percent of the total mass of the composition,
a pH buffer in an amount of 0.01 to 1.0% by weight based on the total mass of the composition,
an osmotic pressure regulator accounting for 0.3 to 3.0 percent of the total mass of the composition,
the balance being water.
Further, the easily-hydrolyzed active ingredient is any combination of one or more of physostigmine salicylate, atropine sulfate, aureomycin hydrochloride, pilocarpine, after-hydrobromic-acid martrope, latanoprost and anthocyanin.
The oil phase is one or any combination of several of olive oil, castor oil and derivatives thereof, medium chain triglyceride, long chain triglyceride, soybean oil, corn oil, walnut oil, cotton seed oil, peanut oil, sunflower seed oil, coconut oil, palm oil, sesame oil, almond oil, mineral oil, modified propylene glycol, propylene glycol diester, tricaprylin decanoate glyceride and saffron oil.
The emulsifier is one or more of tween, soybean lecithin, egg yolk lecithin, polyoxyethylene, polyoxypropylene, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, monoglyceride fatty acid ester, triglycerin fatty acid ester, polyglycerol stearate, sucrose monolaurate, fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether or polyoxyethylene polyoxypropylene copolymer, sodium dodecyl sulfate, tyloxapol, poloxamer and octoxynol.
The auxiliary emulsion is one or any combination of more of ethanol, glycol, polyethylene glycol, n-butanol, propylene glycol, glycerol, polyglycerol ester, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, glycerol monostearate, stearic acid or stearyl alcohol.
The ophthalmic composition has a pH of from 5 to 8.
The pH regulator is one or any combination of several of sodium hydroxide, hydrochloric acid, glacial acetic acid, citric acid, sodium citrate, lactic acid, phosphoric acid, boric acid, tromethamine, potassium hydroxide, sodium carbonate and sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, triethanolamine, diethanolamine and ethanolamine.
The pH buffer is one or more of phosphate buffer, carbonate buffer, borate buffer, acetate buffer, citrate buffer, tris buffer, 6-aminocaproic acid and amino acid salt.
The osmolality adjusting agent is an agent useful as an agent for adjusting the osmolality of an ophthalmic formulation.
The ophthalmic composition is an oil-in-water nanoemulsion having an oil droplet size of no greater than 2000 nm, preferably no greater than 950 nm, more preferably no greater than 500 nm.
The invention also provides a preparation method of the ophthalmic composition for improving the stability of the easily-hydrolyzed medicine, which comprises the following steps:
1) Weighing oil phase components such as oil phase, emulsifier and the like according to a proportion, heating to a temperature capable of dissolving solid matters to dissolve the solid matters, and taking the oil phase components as emulsion oil phase;
2) Weighing a certain amount of water, sequentially adding an osmotic pressure regulator, an emulsion assistant, a pH regulator and easily-hydrolyzed medicine components in proportion, stirring to dissolve, and then adding the weighed water in proportion to prepare a water phase;
in the case of multi-dose products, one or more preservatives known to practitioners in the art may be added in an amount of 0.001 to 6.7% of the total mass of the product when preparing the emulsion oil or water phase;
3) Heating the water phase and the emulsion oil phase to a certain temperature respectively, slowly adding the emulsion oil phase into the water phase under rapid stirring, emulsifying under high shear after adding so as to reduce oil drops as much as possible, homogenizing by high-pressure microjet until the particle size of the emulsion oil drops meets the preparation requirement, obtaining coarse emulsion, finally adding the water with the residual prescription amount, and regulating the pH of the emulsion to 5-8 by using a pH regulator;
4) Sterilizing and packaging to obtain the product.
The invention also provides application of the ophthalmic pharmaceutical composition emulsion in preparing medicines for preventing and/or treating ophthalmic diseases.
The composition is an oil-in-water type nano emulsion, can improve the stability of easily hydrolyzed medicines such as esters, amides, glycosides and the like in neutral or alkaline environments, reduces discomfort of patients during the administration while ensuring curative effect, and improves compliance of the patients. When the eye drops are unsuitable in pH, the eye drops can be stimulated to the eye mucosa to cause increased tear secretion, cause drug loss and even damage the cornea to cause inflammation, in order to avoid over-strong irritation and stabilize the drugs, in order to prepare the eye drops, a regulator and/or a buffer is/are added appropriately to regulate the pH of the eye drops according to the properties of the eye drops, and some drugs are unstable in neutral or slightly alkaline environments and are easy to hydrolyze. Aiming at the problem, the nano emulsion is prepared by adopting a proper emulsifying agent and an auxiliary emulsion, and water molecules are prevented from approaching the easily-hydrolyzed part of the medicine, so that the stability of the medicine is improved. The invention is based on the principle that the lipophilic end of the drug (including atropine sulfate, physostigmine salicylate, chlortetracycline hydrochloride, pilocarpine, or any combination of one or more of hydrobromic acid, and latanoprost) is embedded into the oil phase or oil-water interface in the emulsion, so as to prevent water molecules from approaching the easily hydrolyzed ester group, amide group, etc. of the drug, thus achieving the purpose of improving the stability of the drug.
According to the invention, the lipophilic end of the easily-hydrolyzed drug is embedded into the oil phase or oil-water interface of the emulsion to prepare the drug delivery system of the nanoemulsion, so that the stability of the drug is improved, the irritation to eyes is reduced, and the bioavailability of the drug is improved.
Description of the embodiments
The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The following examples and comparative examples were conducted under conventional conditions or conditions recommended by the manufacturer, where specific conditions were not noted. The reagents or apparatus used are not manufacturer specific and are commercially available conventional products useful in pharmaceutical manufacturing.
In a first aspect, the present invention provides an ophthalmic emulsion composition for improving the stability of a readily hydrolyzable drug.
The second aspect of the present invention provides a method of preparing the above ophthalmic emulsion composition.
In a third aspect the present invention provides the use of an ophthalmic pharmaceutical composition as described above.
The following examples illustrate in detail an ophthalmic emulsion composition for improving the stability of a readily hydrolyzable drug and a method for preparing the same, but are not intended to be limiting.
Examples
1) Preparation of an oil phase: weighing light mineral oil (1.0%), heavy mineral oil (1.0%) and tyloxapol (0.6%), heating and stirring to obtain transparent solution to obtain oil phase;
2) Preparation of an aqueous phase: weighing 50 mL of water for injection, sequentially adding the prescribed amount of benzalkonium chloride (0.01%), glycerol (2.5%), poloxamer-188 (0.2%), tromethamine (0.25%), and atropine sulfate (0.01%), and stirring to obtain a transparent solution to obtain a water phase;
3) Preparation of emulsion: slowly adding the oil phase into the water phase under stirring, shearing and homogenizing the obtained liquid to obtain coarse emulsion, fixing the volume of the coarse emulsion to 100 mL by using the residual prescription amount of water, and then regulating the pH value to 6.0 by using hydrochloric acid to obtain the atropine sulfate emulsion.
4) Sterilizing and sub-packaging: sterilizing the emulsion prepared in the step 3, sampling and checking appearance, pH value, osmotic pressure, sterility, viscosity, content and impurities, and filling the qualified emulsion with a filling amount of 3 mL to obtain the multi-dose atropine sulfate eye drops.
Example 2：
Substantially the same as in example 1 was conducted except that 0.05% disodium edentate was added in example 2, except that the other differences were as shown in tables 1 to 9.
Example 3：
The preparation method was substantially identical to that of example 1, except that in example 3, the pH adjustor was disodium hydrogen phosphate (0.025%) and sodium dihydrogen phosphate (0.003%) in the preparation of an aqueous phase, and the other differences are shown in tables 1 to 9.
Example 4：
The preparation method was substantially identical to that of example 1, except that in example 4, the pH adjustor was boric acid (0.045%) and borax (0.002%) in the preparation of an aqueous phase, and the other differences are shown in tables 1 to 9.
Example 5：
Substantially the same as in example 1 was conducted, except that in example 5, tween-80 (1.2%) and EL-20 (0.4%) were used as the emulsifying agents, and the other differences were shown in tables 1 to 9.
Example 6：
Substantially the same as in example 1 was conducted, except that in example 6, the emulsifier was OP-9 (0.4%) and Tween-80 (0.42%), and the other differences were found in tables 1 to 9.
Example 7：
Substantially the same as in example 1 was conducted except that in example 7, the oil phase was medium chain triglyceride (1.5%), and the other differences were as shown in tables 1 to 9.
Example 8：
Substantially the same as in example 1 was conducted except that in example 8, castor oil (1.2%) was used as the oil phase, and the other differences were as shown in tables 1 to 9.
Example 9：
Substantially the same as in example 1 was conducted except that in example 9, isopropyl myristate (2.0%) was used as the oil phase, and the other differences were as shown in tables 1 to 9.
Example 10：
Substantially the same as in example 1 was conducted, except that in example 10, atropine sulfate eye drops were found to have ph=5.0, and the other differences are found in tables 1 to 9.
Example 11：
Substantially the same as in example 1 was conducted, except that in example 11, atropine sulfate eye drops were found to have ph=6.5, and the other differences are found in tables 1 to 9.
Example 12：
The preparation process was substantially identical to that of example 1, except that in example 12, the amount of light mineral oil was 0.5%, the amount of heavy mineral oil was 0.5%, and the other differences were as shown in tables 1 to 9.
Example 13：
The preparation process was substantially identical to that of example 1, except that in example 13, the amount of light mineral oil was 1.5% and the amount of heavy mineral oil was 1.5%, with the other differences shown in tables 1 to 9.
Example 14：
Substantially the same as in example 1 was conducted, except that in example 14, the auxiliary emulsion was ethylene glycol (2.5%), and the other differences were as shown in tables 1 to 9.
Example 15：
Substantially the same as in example 1 was conducted, except that in example 15, mannitol (2.2%) was used as the co-emulsion, and the other differences were as shown in tables 1 to 9.
Example 16：
Substantially the same as in example 1 was conducted except that in example 16, ethyl hydroxybenzoate (0.03%) as a preservative was used, and the other differences were as shown in tables 1 to 9.
Example 17：
The preparation process was substantially identical to that of example 1, except that in example 17, atropine sulfate 0.001% and tromethamine 0.08% were used, with the other differences shown in tables 1 to 9.
Example 18：
The preparation process was substantially identical to that of example 1, except that in example 18, atropine sulfate 0.5% and tromethamine 0.69% were used, with the other differences shown in tables 1 to 9.
Example 19：
The preparation process was substantially identical to that of example 1, except that in example 19, atropine sulfate 0.05% and tromethamine 0.43% were used, with the other differences shown in tables 1 to 9.
Examples20：
The preparation process was substantially identical to that of example 1, except that in example 20, atropine sulfate 0.1% and tromethamine 0.57% were used, with the other differences shown in tables 1 to 9.
Example 21：
The preparation method was substantially identical to that of example 1, except that in example 21, the eye drops were formulated with pilocarpine nitrate 0.5%, benzalkonium chloride 0.03%, tromethamine 0.67%, medium chain triglycerides 1.5%, glycerin 2.3%, poloxamer-188 (0.2%), tyloxapol 0.6%.
Example 22：
The preparation method was substantially identical to that of example 1, except that in example 22, the eye drops were formulated with physostigmine salicylate 0.25%, benzalkonium chloride 0.02%, tromethamine 0.28%, olive oil 2.0%, glycerin 2.0%, span-20 (0.3%), tween-80 (0.6%).
Example 23：
The preparation method was substantially identical to that of example 1, except that in example 23, the eye drops were formulated with 1.0% of post-hydrobromic acid, 0.03% of benzalkonium chloride, 0.71% of tromethamine, 1.5% of light mineral oil (1.5%), 2.0% of heavy mineral oil (1.5%), 2.0% of glycerin, 0.2% of poloxamer-188 (0.2%), and 0.6% of tyloxapol.
Example 24：
The preparation method was substantially identical to that of example 1, except that in example 24, the eye drops were formulated with latanoprost 0.005%, benzalkonium chloride 0.01%, tromethamine 0.15%, light mineral oil (0.5%), heavy mineral oil (0.5%), glycerin 2.0%, poloxamer-188 (0.05%), and tyloxapol 0.15%.
Example 25：
Substantially the same as the preparation method of example 1, except that in example 24, the eye drops were formulated with chlortetracycline hydrochloride 0.5%, benzalkonium chloride 0.02%, tromethamine 0.54%, light mineral oil (1.0%), heavy mineral oil (1.0%), glycerin 2.0%, poloxamer-188 (0.1%), tyloxapol 0.3%;
comparative example 1: substantially the same as in example 1, except that in comparative example 1, atropine sulfate eye drops have a ph=7.0, and the other differences are shown in tables 1 to 9;
comparative example 2: substantially the same as in example 1, except that in comparative example 2, a single emulsifier OP-10 was used, and the other differences are shown in tables 1 to 9;
comparative example 3: substantially the same as in example 1, except that no bacteriostatic agent was added in comparative example 3, and the other differences are shown in tables 1 to 9;
comparative example 4: substantially the same as in example 1, except that in comparative example 4, the filling amount of atropine sulfate eye drops was 8 mL, and the other differences are shown in tables 1 to 9;
comparative example 5: substantially the same as in example 1, except that in comparative example 5, the filling amount of atropine sulfate eye drops was 30 mL, and the other differences are shown in tables 1 to 9;
the formulations prepared in comparative examples 1 to 25 and comparative examples 1 to 5 in example 26 were allowed to stand at 30.+ -. 2 ℃ per 35% RH.+ -. 5% RH to examine the long-term stability, and the results are shown in tables 1 to 7 below.
Table 1: stability test results of different formulations for 0 day
Table 2: stability test results of different formulations placed 3M
Table 3: stability test results of different formulations placed 6M
Table 4: stability test results of different formulations placed 9M
Table 5: stability test results of different formulations placed 12M
Table 6: stability test results of different formulations placed 18M
Table 7: stability test results of different formulations placed 24M
Test example 2:
the formulations prepared in examples 1 to 25 and comparative examples 1 to 5 were allowed to stand at 40.+ -. 2 ℃ per 25% RH.+ -. 5% RH to examine the acceleration stability, and the results are shown in tables 8 to 9 below.
Table 8: results of stability experiments of different formulations to accelerate 3M
Table 9: results of stability experiments of different formulations to accelerate 6M
It is to be understood that the above examples of the present invention are provided for clarity of illustration only and are not limiting of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. Not all embodiments are exhaustive. All obvious changes or modifications which are extended by the technical proposal of the invention are within the protection scope covered by the invention.

Claims (10)

1. An ophthalmic composition for improving the stability of a readily hydrolyzable drug, comprising the following components in parts by mass:
the composition comprises an easily-hydrolyzable active ingredient accounting for 0.001 to 1.0 percent of the total mass of the composition,
an oil phase accounting for 0.5 to 6.0 percent of the total mass of the composition,
0.05 to 3.0 percent of emulsifying agent of the total mass of the composition,
0.1 to 4.0 percent of auxiliary emulsion of the total mass of the composition,
a pH regulator accounting for 0.01 to 2.0 percent of the total mass of the composition,
a pH buffer in an amount of 0.01 to 1.0% by weight based on the total mass of the composition,
an osmotic pressure regulator accounting for 0.3 to 3.0 percent of the total mass of the composition,
the balance being water.
2. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the easily-hydrolyzed active ingredient is one or any combination of more of physostigmine salicylate, atropine sulfate, aureomycin hydrochloride, pilocarpine, after hydrobromic acid, captopril, latanoprost and anthocyanin.
3. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the oil phase is one or any combination of several of olive oil, castor oil and derivatives thereof, medium chain triglyceride, long chain triglyceride, soybean oil, corn oil, walnut oil, cotton seed oil, peanut oil, sunflower seed oil, coconut oil, palm oil, sesame oil, almond oil, mineral oil, modified propylene glycol, propylene glycol diester, tricaprylin decanoate glyceride and saffron oil.
4. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the emulsifier is one or more of tween, span, soybean lecithin, egg yolk lecithin, polyoxyethylene, polyoxypropylene, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, monoglyceride fatty acid ester, triglycerin fatty acid ester, polyglycerol stearate, sucrose monolaurate, fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether or polyoxyethylene polyoxypropylene copolymer, sodium dodecyl sulfate, tyloxapol, poloxamer and octoxynol.
5. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the auxiliary emulsion is one or any combination of more of ethanol, glycol, polyethylene glycol, n-butanol, propylene glycol, glycerol, polyglycerol ester, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, glycerol monostearate, stearic acid or stearyl alcohol.
6. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the ophthalmic composition has a pH of from 5.0 to 8.0.
7. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claim 1, characterized in that: the pH regulator is one or any combination of several of sodium hydroxide, hydrochloric acid, glacial acetic acid, citric acid, sodium citrate, lactic acid, phosphoric acid, boric acid, tromethamine, potassium hydroxide, sodium carbonate and sodium bicarbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, triethanolamine, diethanolamine and ethanolamine;
the pH buffer is one or more of phosphate buffer, carbonate buffer, borate buffer, acetate buffer, citrate buffer, tris buffer, 6-aminocaproic acid and amino acid salt;
the osmolality adjusting agent is an agent useful as an agent for adjusting the osmolality of an ophthalmic formulation.
8. The ophthalmic composition for improving the stability of a readily hydrolyzable drug according to claims 1 to 7, characterized in that said ophthalmic composition is an oil-in-water nanoemulsion having an oil droplet size of not more than 2000 nm.
9. A process for the preparation of an ophthalmic composition for improving the stability of a readily hydrolysable drug as claimed in any one of claims 1 to 8, comprising the steps of:
1) Weighing oil phase and emulsifier in proportion, heating to a temperature capable of dissolving solid matters to dissolve the solid matters, and taking the oil phase and the emulsifier as emulsion oil phases;
2) Weighing a certain amount of water, sequentially adding an osmotic pressure regulator, an emulsion assistant, a pH regulator and an easily-hydrolyzed active ingredient which are weighed according to a proportion, and stirring and dissolving to prepare a water phase;
3) Heating the water phase and the emulsion oil phase respectively, slowly adding the emulsion oil phase into the water phase under rapid stirring, emulsifying under high shear, homogenizing by high pressure micro-jet to obtain coarse emulsion, adding the rest water with the formula amount, and regulating the pH of the emulsion to 5.0-8.0 by using a pH regulator;
4) Sterilizing and packaging to obtain emulsion preparation.
10. Use of an emulsion of an ophthalmic pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament for the prevention and/or treatment of ophthalmic diseases.
CN202310663287.5A 2023-06-06 2023-06-06 Ophthalmic composition for improving stability of easily-hydrolyzed medicine, preparation method and application Pending CN116672310A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117860671A (en) * 2024-01-17 2024-04-12 华南农业大学 Aureomycin hydrochloride suspension, preparation method, preservation method, diluent and dilution method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117860671A (en) * 2024-01-17 2024-04-12 华南农业大学 Aureomycin hydrochloride suspension, preparation method, preservation method, diluent and dilution method thereof

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