CN115463088A - Ophthalmic nanoemulsion composition containing prostaglandin derivative - Google Patents
Ophthalmic nanoemulsion composition containing prostaglandin derivative Download PDFInfo
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- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
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- 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
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Abstract
The invention provides an ophthalmic nano-emulsion composition containing prostaglandin derivatives, which comprises an active ingredient, a cosolvent, an oily ingredient and water, wherein the active ingredient comprises latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof, the cosolvent is polyoxyethylene castor oil and is 0.05w/v% to 5w/v%, and the oily ingredient is 0.02w/v% to 0.2w/v%. The ophthalmic nanoemulsion composition containing the prostaglandin derivative provided by the invention has better stability and storage convenience.
Description
Technical Field
The invention relates to an ophthalmic composition, in particular to an ophthalmic nano-emulsion composition containing prostaglandin derivatives.
Background
Latanoprost (Latanoprost), travoprost (Travoprost), bimatoprost (Bimatoprost) and Tafluprost (Tafluprost) are all common prostaglandin derivatives (prostaglandin analogs) and have similar characteristics and effects, and are mainly used for reducing intraocular pressure and treating related diseases caused by excessive intraocular pressure (intraocular pressure) such as glaucoma (glaucoma).
Taking latanoprost as an example, the latanoprost is an ester prodrug (produgs) which can penetrate into cornea (cornea) and be hydrolyzed into active free acid by esterase when being applied to eyes, and the latanoprost and prostaglandin F after being activated 2α (prostaglandin F 2α ) An agonist (agonst) having a similar structure and also being an F-type prostaglandin receptor (prostagladin F receptor), can improve the permeability of the sclera (sclera) to fluid and increase the outflow of aqueous humor (aqueous humor), thereby achieving the effect of reducing intraocular pressure.
The chemical name of latanoprost is Z-7- [ (1R, 2R,3R, 5S) -3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl]Cyclopentyl group]-5-heptenoic acid isopropyl ester with molecular formula C 26 H 40 O 5 Molecular weight is 432.59 g/mol, and the chemical structural formula is shown as follows:
latanoprost is currently used as a commercially available eye drop
The active ingredients of (a), the main indications of which are lowering intraocular pressure and treating glaucoma, etc. However, since latanoprost has low water solubility, poor chemical stability and sensitivity to light or temperature, it is liable to cause a decrease in the amount of latanoprost to affect the therapeutic effect, and it is liable to generate impurities at high levels to cause unknown toxicity, the aforementioned sulbactam eye drops must be transported and stored under refrigeration at a low temperature of 2 ℃ to 8 ℃ in the absence of light without being unsealed.
In view of the foregoing problems, the invention patent of US 9,089,480 B2 proposes an oil-in-water (oil-in-water) emulsion of an anionic colloid, which contains a prostaglandin derivative such as latanoprost as an active ingredient, and mentions that the stability of the prostaglandin derivative can be further improved as compared with that of a commercially available sulbactam eye drop. However, although the technical solution proposed in the patent of US 9,089,480 B2 can increase the stability of prostaglandin derivatives, it still easily generates high content of impurities, which may cause unknown toxicity, and it is opaque emulsion, which results in the problem of temporary blurred vision and discomfort when applied to the eyes of patients.
Therefore, there is still a great need for developing a new technical means to make an ophthalmic composition containing prostaglandin derivative as an active ingredient have good stability, i.e. can be stored at room temperature without reducing the content of prostaglandin derivative and generating high content of impurities, thereby providing a safe and effective treatment option for patients regardless of convenience in administration or storage.
Disclosure of Invention
In view of the drawbacks of the prior art, the present invention is directed to provide a prostaglandin derivative-containing ophthalmic nanoemulsion composition, which comprises latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof as active ingredients and has good stability, i.e., can be stored at room temperature while still retaining a high content of active ingredients and not easily generating high content of impurities, and further has the effects of stable effect, high safety, and convenient administration and storage.
In order to achieve the above objects, the present invention provides an ophthalmic nanoemulsion composition containing a prostaglandin derivative, which comprises an active ingredient, a cosolvent, an oily ingredient and water, wherein the active ingredient comprises latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof, the cosolvent is polyoxyethylated castor oil (polyoxyethylated castor oil), and the content of the cosolvent is greater than or equal to 0.05 weight/volume percent (w/v%) and less than or equal to 5w/v%, and the content of the oily ingredient is greater than or equal to 0.02w/v% and less than or equal to 0.2w/v%, based on the total volume of the ophthalmic nanoemulsion composition containing the prostaglandin derivative.
The ophthalmic nanoemulsion composition containing the prostaglandin derivative can form an oil-in-water type by a technical means of simultaneously containing a cosolvent with a specific type and a specific content range, an oily component with a specific content range and water in the ophthalmic nanoemulsion composition containing the prostaglandin derivative, so that the solubility and the stability of the prostaglandin derivative are simultaneously increased.
According to the present invention, the prostaglandin derivative refers to a compound having a similar action to that of prostaglandin, i.e., also capable of binding to and acting on a prostaglandin receptor, for example, but not limited to, latanoprost, travoprost, bimatoprost or tafluprost.
According to the present invention, the polyoxyethylene castor oil refers to a series of compounds obtained by reacting various amounts of ethylene oxide (ethylene oxide) with castor oil (castor oil) or hydrogenated castor oil (hydrogenated castor oil).
Preferably, the co-solvent comprises polyoxyethylene 35castor oil (polyoxyl 35castor oil), polyoxyethylene 40hydrogenated castor oil (polyoxyl 40hydrogenated castor oil), polyoxyethylene 60hydrogenated castor oil (polyoxyl 60hydrogenated castor oil), or a combination thereof.
Preferably, the cosolvent is contained in an amount of 0.1w/v% or more and 5w/v% or less, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative. More preferably, the co-solvent is present in an amount of 0.5w/v% or more and 5w/v% or less, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative. Still more preferably, the content of the co-solvent is 0.5w/v% or more and 3w/v% or less based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative. By further controlling the content of the cosolvent in a specific range, the stability of the ophthalmic nanoemulsion composition containing the prostaglandin derivative can be further improved.
In some embodiments of the present invention, the co-solvent is present in an amount greater than 1w/v% and less than or equal to 5w/v%, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative. In other embodiments of the present invention, the co-solvent is present in an amount greater than 1w/v% and less than or equal to 3w/v%, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
Preferably, the oily component comprises castor oil, medium Chain Triglycerides (MCT), mineral oil (mineral oil), sheep oil (lanolin oil), soybean oil (soy bean oil), or combinations thereof. More preferably, the oily component comprises castor oil, sheep oil, soybean oil, or a combination thereof. By further controlling the selection of the oily component to a specific kind, the stability of the ophthalmic nanoemulsion composition containing a prostaglandin derivative can be further improved.
According to the present invention, the medium chain triglyceride means that it has saturated fatty acids having a carbon number of 6 to 12.
In some embodiments of the present invention, the cosolvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof, the oily component is castor oil, medium-chain triglyceride, mineral oil, sheep oil, soybean oil or a combination thereof, and the cosolvent is present in an amount of 0.1w/v% or more and 3w/v% or less and the oily component is present in an amount of 0.02w/v% or more and 0.2w/v% or less, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
In other embodiments of the present invention, the cosolvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof, the oily component is castor oil, medium-chain triglyceride, mineral oil, sheep oil, soybean oil or a combination thereof, and the cosolvent is present in an amount of 1w/v% or more and 3w/v% or less and the oily component is present in an amount of 0.02w/v% or more and 0.2w/v% or less, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
In other embodiments of the present invention, the cosolvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof, the oily component is castor oil, medium chain triglyceride, mineral oil, sheep oil, soybean oil or a combination thereof, and the cosolvent is present in an amount of 0.5w/v% or more and 1.25w/v% or less based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative, and the oily component is present in an amount of 0.02w/v% or more and 0.2w/v% or less.
In other embodiments of the present invention, the cosolvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof, the oily component is castor oil, medium-chain triglyceride, mineral oil, sheep oil, soybean oil or a combination thereof, and the cosolvent is present in an amount of 1w/v% or more and 1.25w/v% or less based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative, and the oily component is present in an amount of 0.02w/v% or more and 0.2w/v% or less.
In other embodiments of the present invention, the cosolvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil, or a combination thereof, the oily component is castor oil, medium-chain triglyceride, soybean oil, or a combination thereof, and the cosolvent is present in an amount of greater than or equal to 0.05w/v% and less than or equal to 5w/v%, and the oily component is present in an amount of greater than or equal to 0.02w/v% and less than or equal to 0.2w/v%, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
In other embodiments of the present invention, the co-solvent is polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof, the oily component is castor oil, medium chain triglyceride, soybean oil or a combination thereof, and the content of the co-solvent is greater than or equal to 0.5w/v% and less than or equal to 5w/v% and the content of the oily component is greater than or equal to 0.02w/v% and less than or equal to 0.2w/v% based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
According to the present invention, the active ingredient may be latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof in a therapeutically effective amount, i.e. in an amount effective to treat elevated intraocular pressure, ocular hypertension, glaucoma or any symptom associated therewith. Preferably, the content of the active ingredient is greater than or equal to 0.001w/v% and less than or equal to 0.1w/v% based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative. More preferably, the content of the active ingredient is greater than or equal to 0.001w/v% and less than or equal to 0.01w/v% based on the total volume of the prostaglandin derivative-containing ophthalmic nanoemulsion composition.
Preferably, the active ingredient is latanoprost.
The ophthalmic nanoemulsion composition containing a prostaglandin derivative according to the present invention may further comprise any ingredient suitable for ophthalmic drugs without affecting the therapeutic effect of the active ingredient. For example, the prostaglandin derivative-containing ophthalmic nanoemulsion composition may further include a chelating agent, an isotonic agent, a buffer, an acid-base number modifier, a preservative, or a combination thereof, but is not limited thereto. The chelating agent may be ethylenediaminetetraacetic Acid (EDTA), citric Acid (citric Acid), or a combination thereof, but is not limited thereto; the isotonic agent may be sodium chloride (sodium chloride), potassium chloride (potassium chloride), glycerin (glycerol), propylene glycol (propylene glycol), sorbitol (sorbitol), or a combination thereof, but is not limited thereto; the buffer may be boric acid (boric acid) or a salt thereof such as sodium borate (sodium borate), acetic acid (acetic acid) or a salt thereof such as sodium acetate (sodium acetate), phosphoric acid (phosphoric acid) or a salt thereof such as disodium hydrogen phosphate (sodium hydrogen phosphate), tartaric acid (tartric acid) or a salt thereof such as sodium tartrate (sodium tartrate), or a combination thereof, but is not limited thereto; the ph adjuster may be sodium hydroxide (sodium hydroxide), potassium hydroxide (potassium hydroxide), sodium carbonate (sodium carbonate), hydrochloric acid (hydrochloric acid), or a combination thereof, but is not limited thereto; the preservative may be benzalkonium chloride (benzalkonium chloride), benzethonium chloride (benzethonium chloride), parabens, or a combination thereof, but is not limited thereto.
According to the present invention, the amount of the chelating agent, the isotonic agent, the buffer, the pH regulator or the preservative can be adjusted by those skilled in the art according to the actual implementation. For example, the chelating agent is used in an amount of greater than or equal to 0.05w/v% and less than or equal to 0.15w/v%, based on the total volume of the prostaglandin derivative-containing ophthalmic nanoemulsion composition, but is not limited thereto; the dosage of the isotonic agent is more than or equal to 0.1w/v% and less than or equal to 1w/v%, but not limited thereto.
In some embodiments of the present invention, the prostaglandin derivative-containing ophthalmic nanoemulsion composition further comprises a chelating agent, an isotonic agent, and a buffer, and the chelating agent is ethylenediaminetetraacetic acid, the isotonic agent is sodium chloride, and the buffer is boric acid and sodium borate.
According to the present invention, the acid-base value (pH value) of the ophthalmic nanoemulsion composition containing a prostaglandin derivative is within a range of acid-base values suitable for administration to the eye. For example, the ph of the ophthalmic nanoemulsion composition containing a prostaglandin derivative may be 6.0 to 7.5 or 6.5 to 6.9, but is not limited thereto.
Preferably, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has a light transmittance of greater than or equal to 90%. More preferably, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has a light transmittance of greater than or equal to 93%. The ophthalmic nanoemulsion composition containing the prostaglandin derivative of the invention can further have higher light transmittance, thereby avoiding the problem of discomfort caused by temporary blurred vision when being applied to eyes.
In some embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has a light transmittance of greater than or equal to 90% and less than or equal to 99%. In other embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has a light transmittance of greater than or equal to 93% and less than or equal to 99%.
Preferably, the prostaglandin derivative-containing ophthalmic nanoemulsion composition has an average hydration diameter of less than or equal to 280 nanometers (nm). More preferably, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydration diameter of less than or equal to 150nm. Still more preferably, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydrated diameter of less than or equal to 40nm. Even more preferably, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydrated diameter of less than or equal to 25nm. The ophthalmic nanoemulsion composition containing prostaglandin derivatives of the present invention may further have a low hydration diameter, i.e., an oil-in-water form capable of forming a nanoemulsion, which facilitates penetration of the cornea of the eye into the interior of the eye, thereby further improving the therapeutic effect.
In some embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydrated diameter of greater than or equal to 5nm and less than or equal to 280nm. In other embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydrated diameter of greater than or equal to 5nm and less than or equal to 150nm. In other embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydration diameter of greater than or equal to 5nm and less than or equal to 40nm. In other embodiments of the present invention, the ophthalmic nanoemulsion composition containing a prostaglandin derivative has an average hydration diameter greater than or equal to 5nm and less than or equal to 25nm.
In addition, the invention also provides the application of the ophthalmic nanoemulsion composition containing the prostaglandin derivative in preparing a medicament for treating diseases caused by high intraocular pressure.
According to the present invention, the disease caused by ocular hypertension refers to related diseases caused by ocular hypertension (ocular hypertension higher than 20 mmhg), for example, the disease caused by ocular hypertension can be glaucoma or ocular hypertension, etc., but is not limited thereto.
In this specification, "weight/volume percent" refers to the weight (grams) of a component as a percentage of the total solution volume (milliliters). For example, "the cosolvent is present in an amount of 0.05w/v% or more based on the total volume of the prostaglandin derivative-containing ophthalmic nanoemulsion composition" means that the cosolvent is present in an amount of 0.05 g or more relative to 100 ml of the prostaglandin derivative-containing ophthalmic nanoemulsion composition.
In the present specification, a range represented by "a small value to a large value" means a range greater than or equal to the small value and less than or equal to the large value, if not specifically indicated. For example: the ph can be 6.0 to 7.5, meaning a ph range of "greater than or equal to 6.0 and less than or equal to 7.5".
Detailed Description
The following examples are provided to illustrate embodiments of the present invention, and those skilled in the art can easily understand the advantages and effects of the present invention without departing from the spirit of the present invention, and make various modifications and changes to implement or use the present invention.
Examples 1 to 21
The preparation procedure of examples 1 to 21 is similar, in particular, latanoprost is selected as the active ingredient and is first mixed with oily ingredients and co-solvents to form an oil phase; further, water, ethylenediaminetetraacetic acid and sodium chloride were uniformly mixed, followed by adding boric acid and sodium borate to maintain the pH of the solution in the range of 6.5 to 6.9, followed by adding the oil phase thereto and uniformly mixing, and finally adding water to make the total volume of the solution 100 ml, to obtain ophthalmic nanoemulsion compositions containing prostaglandin derivatives (hereinafter referred to as ophthalmic nanoemulsion compositions) of examples 1 to 21. Examples 1 to 21 were made with latanoprost, ethylenediaminetetraacetic acid and sodium chloride in amounts of 0.005w/v%, 0.1w/v% and 0.61w/v%, respectively, and examples 1 to 21 were each different mainly in that different kinds or amounts of co-solvents and different kinds or amounts of oily components were selected and listed in table 1 below.
Comparative example 1
Comparative example 1 was prepared according to the example disclosed in the invention patent of US 9,089,480 B2. The main preparation process comprises mixing latanoprost and medium-chain triglyceride at 50 ℃ to form an oil phase, mixing glycerol, polysorbate 80 (polysorbate 80) and water at 50 ℃ to form a water phase, mixing the oil phase and the water phase, heating to 75 ℃ and mixing for 5 minutes by a high-speed shearing machine, cooling to 20 ℃, homogenizing for 20 minutes by a homogenizer, adjusting the pH value of the solution to 7.0 by sodium hydroxide, and adding water to make the total weight of the solution be 100 g, thus obtaining the ophthalmic composition of comparative example 1. The selected contents of latanoprost, medium-chain triglyceride, glycerol and polysorbate 80 were 0.005 weight percent (wt%), 1wt%, 2.4wt% and 0.1wt%, respectively, based on the total weight of the ophthalmic composition of comparative example 1. The major differences between comparative example 1 and examples 1 to 21 are that the ophthalmic composition of comparative example 1 does not use a specific kind and content range of the co-solvent as in the present invention, and the content of the oily component is also significantly higher, and for comparison, the composition of comparative example 1 is also shown in table 1 below.
Table 1: the co-solvents and oily components selected for the ophthalmic nanoemulsion compositions of examples 1-21 and the contents of these components and the components of the ophthalmic composition of comparative example 1.
Test example 1: stability test
Examples 1 to 21 and comparative example 1 were selected for this test example. Specifically, each group of initial latanoprost content and impurity content was detected by a High performance liquid chromatography (HPLC-UV; using an L1 standard, a silica gel particle size of 5 micrometers (μm), a column diameter of 4.6 cm, a length of 15 cm, a mobile phase of a combination of a phosphate solution having a concentration of 50% and an acetonitrile solution having a concentration of 50%, and a flow rate of the mobile phase of 0.7 ml/min to 1.2 ml/min) before the test was performed, and then the ophthalmic nanoemulsion compositions of examples 1 to 21 and the ophthalmic composition of comparative example 1 were placed in an environment at 40 ℃ for an acceleration test for a total of 2 months in accordance with the acceleration test specifications described in the drug test standards, and then each group of latanoprost content and impurity content after the test was also detected by a High performance liquid chromatography; in addition, the ophthalmic nanoemulsion compositions of examples 1 to 21 and the ophthalmic composition of comparative example 1 were also subjected to a harsh test (stress test) in an environment of 65 ℃ for a total of 14 days, and the latanoprost content and the impurity content of each group were also measured by high performance liquid chromatography after completion of the test. The stability results of the ophthalmic nanoemulsion compositions of examples 1 to 21 and the ophthalmic composition of comparative example 1 under the accelerated test and the harsh test are shown in the following table 2.
Table 2: stability test results of the ophthalmic nanoemulsion compositions of examples 1 to 21 and the ophthalmic composition of comparative example 1.
As can be seen from the results of table 2 above, for the results of latanoprost content, the initial content of comparative example 1 before the test was 63.1%, but only 21.2% remained after the accelerated test, and only 8.2% remained after the harsh test, while examples 1 to 21 all had a latanoprost content (between 56.6% and 98.8%) equal to or higher than that of comparative example 1 before the test, and after the accelerated test, the latanoprost content of examples 1 to 21 was maintained higher than 40% (between 41.3% and 99.4%), wherein the latanoprost content of examples 1 to 8 and 10 to 21 was higher than 70%, and the latanoprost content of examples 1 to 7 and 10 to 21 was higher than 85%; after harsh tests, the latanoprost content in examples 1 to 21 remained higher than 18% (between 18.6% and 99.1%), wherein the latanoprost content in examples 1 to 7 and 10 to 21 was higher than 68%. It can be seen that the ophthalmic nanoemulsion compositions of examples 1 to 21 can indeed retain a higher amount of latanoprost after the accelerated test or the harsh test, compared to comparative example 1.
As can be seen from the results of the impurity contents, the increase in impurity contents of examples 1 to 21, whether subjected to accelerated test or harsh test, was less than that of comparative example 1, specifically, although the impurity content of comparative example 1 was only 1% at the beginning, the increase in impurity contents was increased to 43.1% after accelerated test (increase in amplitude of 42.1%), and further increased to 80.0% after harsh test (increase in amplitude of 79%); in the groups of examples 1 to 21, the increase in impurity content after the accelerated test was less than 22% (between-2.6% and 21.3%), and the increase in impurity content after the harsh test was less than 67% (between-0.2% and 66.5%). Wherein, the case that the increase of the impurity content is less than 0 can be regarded as the experimental error acceptable in detection, which represents that the impurity content is not increased obviously.
From the above results of latanoprost content and impurity content measured after accelerated test and harsh test, it can be seen that the ophthalmic nanoemulsion compositions of examples 1 to 21 indeed have the advantage of generating lower content of impurities in addition to higher content of latanoprost, i.e. the ophthalmic nanoemulsion compositions containing prostaglandin derivatives provided by the present invention indeed have better stability.
Test example 2: light transmittance test
In this test example, examples 1 to 21 and comparative example 1 were similarly selected and tested, and after the completion of the above-mentioned harsh test, the light transmittance test was performed. Specifically, the ophthalmic nanoemulsion compositions of examples 1 to 21, which have been subjected to a severe test, and the ophthalmic composition of comparative example 1, each of which has been subjected to a light transmittance (transmittance) measured by a UV spectrophotometer (manufacturer: hitachi; model: U-2900) in accordance with the specifications for light transmittance (transmittance) described in United States Pharmacopoeia (USP), are listed in Table 3 below.
Table 3: the light transmittance test results of the ophthalmic nanoemulsion compositions of examples 1 to 21 and the ophthalmic composition of comparative example 1.
| Group of | Light transmittance (%) |
| Example 1 | 93.7 |
| Example 2 | 94.9 |
| Example 3 | 95.1 |
| Example 4 | 95.5 |
| Example 5 | 95.2 |
| Example 6 | 95.1 |
| Example 7 | 27.3 |
| Example 8 | 2.0 |
| Example 9 | 5.1 |
| Example 10 | 94.7 |
| Example 11 | 94.4 |
| Example 12 | 97.2 |
| Example 13 | 97.5 |
| Example 14 | 96.9 |
| Example 15 | 96.7 |
| Example 16 | 93.4 |
| Example 17 | 95.2 |
| Example 18 | 95.8 |
| Example 19 | 96.1 |
| Example 20 | 96.4 |
| Example 21 | 96.6 |
| Comparative example 1 | 0.3 |
As can be seen from the results of the light transmittance test in table 3 above, the light transmittance of comparative example 1 is only 0.3%, which shows that the ophthalmic composition of comparative example 1 is really in the form of opaque emulsion, and examples 1 to 21 all have better light transmittance (between 2.0% and 97.5%) than comparative example 1, that is, the ophthalmic nanoemulsion compositions of examples 1 to 21 also have better light transmittance than the ophthalmic composition of comparative example 1. Further looking at the results of examples 1 to 6 and 10 to 21, it can be seen that if the content of the co-solvent is further controlled to be in a specific range of 1w/v% to 5w/v%, the light transmittance can be further significantly improved, which means that the degree of mutual solubility of the components in the ophthalmic nanoemulsion composition is significantly improved, and thus the effect on the visibility of the eye can be avoided after the ophthalmic nanoemulsion composition is applied to the eye, and the comfort during the application can be improved.
Test example 3: mean hydrated diameter measurement
This test example selected examples 1 to 12 and 15 to 21 and comparative example 1 for testing. Specifically, the ophthalmic nanoemulsion compositions of examples 1 to 12 and 15 to 21 and the ophthalmic composition of comparative example 1 were examined for their average hydration diameters by a laser Nano particle size potential analyzer (Nano ZS-90 Zetasizer), and the results thereof are listed in table 4 below.
Table 4: average hydration diameters of the ophthalmic nanoemulsion compositions of examples 1 to 12 and 15 to 21 and the ophthalmic composition of comparative example 1.
| Group of | Average hydrated diameter (nanometer) |
| Example 1 | 13.02 |
| Example 2 | 13.74 |
| Example 3 | 14.86 |
| Example 4 | 15.12 |
| Example 5 | 16.45 |
| Example 6 | 17.29 |
| Example 7 | 22.41 |
| Example 8 | 141.1 |
| Example 9 | 277.7 |
| Example 10 | 19.97 |
| Example 11 | 19.26 |
| Example 12 | 16.16 |
| Example 15 | 39.61 |
| Example 16 | 18.47 |
| Example 17 | 16.17 |
| Example 18 | 17.84 |
| Example 19 | 14.78 |
| Example 20 | 14.41 |
| Example 21 | 13.27 |
| Comparative example 1 | 397.5 |
As can be seen from the results of table 4 above, the ophthalmic nanoemulsion compositions of examples 1 to 12 and 15 to 21 have significantly smaller average hydrated diameter (between 13.02nm and 277.7 nm) compared to comparative example 1, which has average hydrated diameter of 397.5nm, and belong to nanoemulsion to facilitate the penetration through the cornea of the eye to the inside of the eye, so that the therapeutic effect can be exerted more effectively, wherein examples 1 to 7 and 10 to 21 are more characterized by average hydrated diameter of less than 40nm. It can be seen that the ophthalmic nanoemulsion compositions of examples 1 to 12 and 15 to 21 have the characteristics of a nanoemulsion, thereby advantageously providing better therapeutic effects.
In summary, the ophthalmic nanoemulsion composition containing prostaglandin derivatives provided by the present invention can be stored at room temperature while still retaining higher content of active ingredients and generating lower content of impurities by controlling the types and content ranges of the components contained therein, under the condition that latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof is used as the active ingredient, i.e. the ophthalmic nanoemulsion composition has better stability, and is more convenient to store and apply, thereby providing another convenient, safe and effective treatment option for patients.
Claims (11)
1. An ophthalmic nanoemulsion composition containing a prostaglandin derivative, which comprises an active ingredient, a cosolvent, an oily ingredient and water, wherein the active ingredient comprises latanoprost, travoprost, bimatoprost, tafluprost or a combination thereof, the cosolvent is polyoxyethylene castor oil, the content of the cosolvent is greater than or equal to 0.05 weight/volume percent and less than or equal to 5 weight/volume percent, and the content of the oily ingredient is greater than or equal to 0.02 weight/volume percent and less than or equal to 0.2 weight/volume percent based on the total volume of the ophthalmic nanoemulsion composition containing the prostaglandin derivative.
2. The ophthalmic nanoemulsion composition containing a prostaglandin derivative according to claim 1, wherein the co-solvent comprises polyoxyethylene 35castor oil, polyoxyethylene 40hydrogenated castor oil, polyoxyethylene 60hydrogenated castor oil or a combination thereof.
3. The prostaglandin derivative-containing ophthalmic nanoemulsion composition of claim 1, wherein the cosolvent is present in an amount greater than or equal to 0.1 wt/vol% and less than or equal to 5 wt/vol%, based on the total volume of the prostaglandin derivative-containing ophthalmic nanoemulsion composition.
4. The ophthalmic nanoemulsion composition containing a prostaglandin derivative of claim 3, wherein the content of the cosolvent is greater than or equal to 0.5 wt/vol% and less than or equal to 5 wt/vol% based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
5. The ophthalmic nanoemulsion composition containing a prostaglandin derivative according to claim 1, wherein the oily component comprises castor oil, medium chain triglycerides, mineral oil, sheep oil, soybean oil or a combination thereof.
6. The ophthalmic nanoemulsion composition containing a prostaglandin derivative according to claim 5, wherein the oily ingredient comprises castor oil, sheep oil, soybean oil or a combination thereof.
7. The ophthalmic nanoemulsion composition containing a prostaglandin derivative according to any one of claims 1 to 6, wherein the content of the active ingredient is greater than or equal to 0.001 weight/volume percent and less than or equal to 0.1 weight/volume percent, based on the total volume of the ophthalmic nanoemulsion composition containing a prostaglandin derivative.
8. The prostaglandin derivative-containing ophthalmic nanoemulsion composition of any one of claims 1 to 6, wherein the prostaglandin derivative-containing ophthalmic nanoemulsion composition further comprises a chelating agent, an isotonizing agent, a buffer, an acid-base number modifier, a preservative, or a combination thereof.
9. The prostaglandin derivative-containing ophthalmic nanoemulsion composition of any one of claims 1 to 6, wherein the prostaglandin derivative-containing ophthalmic nanoemulsion composition has a light transmittance of greater than or equal to 90%.
10. The prostaglandin derivative-containing ophthalmic nanoemulsion composition of any one of claims 1 to 6, wherein the prostaglandin derivative-containing ophthalmic nanoemulsion composition has an average hydration diameter of less than or equal to 280 nanometers.
11. Use of the prostaglandin derivative-containing ophthalmic nanoemulsion composition according to any one of claims 1 to 10 for the preparation of a medicament for the treatment of ocular hypertension-induced diseases.
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| CN1871014A (en) * | 2003-11-07 | 2006-11-29 | 千寿制药株式会社 | Pharmaceutical composition containing prostaglandin |
| US20090298956A1 (en) * | 2008-05-28 | 2009-12-03 | Chowhan Masood A | Self-preserved emulsions |
| CN101897949A (en) * | 2010-02-24 | 2010-12-01 | 温士顿医药股份有限公司 | Ophthalmic medicament composition for forming low-irritation transparent emulsion formulation for surface immune adjustment and inflammation reduction of relevant tissue of eyes or eye periphery |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871014A (en) * | 2003-11-07 | 2006-11-29 | 千寿制药株式会社 | Pharmaceutical composition containing prostaglandin |
| US20090298956A1 (en) * | 2008-05-28 | 2009-12-03 | Chowhan Masood A | Self-preserved emulsions |
| CN101897949A (en) * | 2010-02-24 | 2010-12-01 | 温士顿医药股份有限公司 | Ophthalmic medicament composition for forming low-irritation transparent emulsion formulation for surface immune adjustment and inflammation reduction of relevant tissue of eyes or eye periphery |
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