CN115998675A - Voriconazole eye drops, preparation method and application thereof - Google Patents
Voriconazole eye drops, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a voriconazole eye drop, which comprises the following components in terms of mass concentration (w/v): 0.5 to 1.5 percent of voriconazole, 15 to 25 percent of hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate (the amount of which is 0.20 to 0.40 percent when counted by sodium dihydrogen phosphate monohydrate), and water. The invention relates to a preparation method of the voriconazole eye drops and application thereof in preparing an eye medicine for treating fungal infection. The voriconazole eye drops can realize perfect balance of the solubility, the pH and the osmotic pressure of voriconazole in the preparation under the condition of normal temperature preparation, and does not need to add osmotic pressure regulator, preservative, additional pH regulator or other auxiliary materials, thus not only having simple formula, simple preparation process and low cost, but also having good stability, low irritation and good curative effect, and can be directly prepared into eye drops without freeze-drying preservation, and convenient use.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations. In particular, the invention relates to voriconazole eye drops, a method for the preparation thereof, and the use thereof in the preparation of an ophthalmic medicament for the treatment of fungal infections.
Background
Voriconazole (Voriconazole) is a broad spectrum of triazole antifungal agents. Voriconazole is low in solubility in water and unstable. Cyclodextrin is generally used as a solubility enhancer of voriconazole at present to increase the solubility of voriconazole, but the problem that an aqueous solution of voriconazole cannot be stably stored for a long time still exists.
For the stability problem of the voriconazole solution, researchers adopt hydroxypropyl-beta-cyclodextrin to clathrate the voriconazole, then add a proper amount of cross-linking agent (such as dextran and the like) to associate with hydrogen bonds on the hydroxypropyl-beta-cyclodextrin, and firmly fix the voriconazole which is not completely clathrated in a compound formed by the clathrate compound and the cross-linking agent, thereby improving the physical stability of the voriconazole. However, the preparation steps of this method are complicated and the stability of the voriconazole solution cannot be significantly improved.
In addition, to address the stability problems of voriconazole solutions described above, voriconazole is currently typically prepared as a lyophilized powder. For example, in patent document CN103690968A, a sulfenyl ether- β -cyclodextrin is used as a solubilizer, and a phosphate buffer solution of a proper pH is used as an auxiliary agent to prepare a voriconazole pharmaceutical composition. However, the pharmaceutical composition is an injection and requires freeze-drying for preservation, and can only be used as a freeze-dried injection. In addition, the inventor finds that the voriconazole preparation disclosed in the patent application has low osmotic pressure and high irritation, and is not suitable for being used as eye drops. In patent document CN1125653C, sulfobutyl ether- β -cyclodextrin is also used as a solubilizer, and voriconazole is prepared in the form of a lyophilized preparation for intravenous or intramuscular injection. Although it is disclosed IN patent document IN344786B that it is applicable to ophthalmology, it requires a complex pH adjuster and buffer, and it is required to be dissolved again when used, which causes inconvenience to the patient.
In addition, in order to prepare voriconazole formulations, in addition to solubilizers and stabilizers, other adjuvants such as complex pH adjusting agents, osmotic pressure adjusting agents, preservatives and the like are generally required to be added in the prior art, and the raw materials are various and the preparation process is complex.
Patent document CN110812323B discloses an ophthalmic composition, a preparation method and use thereof, wherein an ophthalmic solution can be prepared. However, it adopts polyvinyl alcohol and glycine as stabilizers, and requires addition of pH adjuster, osmotic pressure adjuster, and its formulation and preparation process are complicated.
Patent document CN101849905a discloses a voriconazole eye drop and a preparation method thereof, wherein sodium hyaluronate and a bacteriostat are also added in the formula, naCl or glycerol is used for regulating osmotic pressure, ethanol is also added in the preparation method for volatilizing the voriconazole eye drop, and the process is complex. In addition, the background art of the patent document mentions the influence of pH on the solubility of voriconazole, but the pH is not measured in examples, and it is not considered whether the pH of the prepared eye drops is suitable for ophthalmic use.
Patent document CN113509436a discloses a preparation method of an eye drop, which adopts sulfobutyl-beta-cyclodextrin as a solubilizer, takes HCl and NaOH as pH regulators, takes NaCl as an osmotic pressure regulator, and also adds a thickening agent and a bacteriostat, and has complex formula and preparation process and high cost.
In order to make voriconazole suitable for ophthalmology, the voriconazole eye drops which have simple formula and preparation process, good solubility of voriconazole, pH and osmotic pressure suitable for ophthalmology, good stability, low irritation, good curative effect and low cost are required to be developed.
Disclosure of Invention
The invention aims to solve the technical problems
The invention aims to provide the voriconazole eye drops, which have the advantages of simple formula and preparation process, good voriconazole solubility, pH and osmotic pressure suitable for ophthalmology, good stability, low irritation, good curative effect and low cost.
The invention also aims at providing a preparation method of the voriconazole eye drops.
The invention also aims to provide the application of the voriconazole eye drops in preparing an eye medicine for treating fungal infection.
Technical means for solving the technical problems
The present invention has been accomplished by intensive studies with respect to the above-mentioned technical problems.
In particular, the invention is realized by:
1. a voriconazole eye drop comprising, in mass concentration (w/v):
0.5 to 1.5 percent of voriconazole,
15 to 25 percent of hydroxypropyl-beta-cyclodextrin,
sodium dihydrogen phosphate in an amount of 0.20 to 0.40% based on the amount of sodium dihydrogen phosphate monohydrate, and
and (3) water.
2. The voriconazole eye drop according to item 1, wherein voriconazole is present at a mass concentration (w/v) of 0.8% to 1.2%.
3. The voriconazole eye drops according to any one of claims 1 to 2, wherein voriconazole is present at a mass concentration (w/v) of 0.9% to 1.1%.
4. The voriconazole eye drops according to any one of claims 1 to 3, wherein voriconazole is present in a mass concentration (w/v) of 1.0 to 1.1%.
5. The voriconazole eye drops according to any one of claims 1 to 4, wherein hydroxypropyl- β -cyclodextrin is present at a concentration of 18% to 22% by mass (w/v).
6. The voriconazole eye drops according to any one of claims 1 to 5, wherein hydroxypropyl- β -cyclodextrin is present at a concentration (w/v) of 19% to 21%.
7. The voriconazole eye drops according to any one of claims 1 to 6, wherein hydroxypropyl- β -cyclodextrin is present at a concentration (w/v) of 20 to 21% by mass.
8. Voriconazole eye drops according to any one of claims 1 to 7, wherein sodium dihydrogen phosphate is present at a mass concentration (w/v) of 0.25% to 0.35% as sodium dihydrogen phosphate monohydrate.
9. The voriconazole eye drops according to any one of claims 1 to 8, wherein sodium dihydrogen phosphate is present at a mass concentration (w/v) of 0.28% to 0.32% as sodium dihydrogen phosphate monohydrate.
10. The voriconazole eye drops according to any one of claims 1 to 9, wherein sodium dihydrogen phosphate is present in a mass concentration (w/v) of 0.30 to 0.31% as sodium dihydrogen phosphate monohydrate.
11. The voriconazole eye drops according to any one of claims 1-10, wherein the water is water for injection, purified water, tap water, or any combination thereof.
12. The voriconazole eye drops according to any one of claims 1 to 11, wherein the water is water for injection.
13. The voriconazole eye drops according to any one of items 1 to 12, which does not comprise at least one of the following: osmotic pressure regulators, preservatives, and additional pH regulators.
14. The voriconazole eye drops according to any one of claims 1 to 13, which does not comprise an osmotic pressure regulator, a preservative, and an additional pH regulator;
15. the voriconazole eye drop according to any one of claims 1 to 14, which consists of voriconazole, hydroxypropyl- β -cyclodextrin, sodium dihydrogen phosphate, and water.
16. The voriconazole eye drop according to any one of items 1 to 15, which consists of the following components in mass concentration (w/v): 1% voriconazole, 18-22% hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate in an amount of 0.20-0.40% of sodium dihydrogen phosphate monohydrate, based on sodium dihydrogen phosphate monohydrate, and water.
17. The voriconazole eye drops according to any one of items 1 to 16, comprising, in terms of mass concentration (w/v):
1% of voriconazole,
20% of hydroxypropyl-beta-cyclodextrin,
sodium dihydrogen phosphate in an amount of 0.30% based on the amount of sodium dihydrogen phosphate monohydrate, and
water for injection.
18. A method for preparing voriconazole eye drops according to any one of claims 1 to 17, comprising the steps of:
dissolving hydroxypropyl-beta-cyclodextrin in water for injection to obtain a solution;
adding sodium dihydrogen phosphate and/or hydrate thereof into the solution and dissolving;
voriconazole is added to the above solution and dispersed, optionally supplemented with water for injection.
19. Use of voriconazole eye drops according to any one of claims 1 to 18 in the manufacture of an ophthalmic medicament for the treatment of a fungal infection.
20. The use according to item 19, wherein,
the fungal infection comprises keratitis.
21. The use according to claim 19 or 20, wherein the fungal infection is an infection caused by fusarium solani and/or aspergillus fumigatus.
Technical effects
According to the voriconazole eye drop disclosed by the invention, the voriconazole, the sodium dihydrogen phosphate and the hydroxypropyl-beta-cyclodextrin are used in a combination manner, so that the perfect balance of the solubility, the pH and the osmotic pressure of the voriconazole in the preparation can be realized under the condition of normal temperature preparation, an osmotic pressure regulator, a preservative and other pH regulator or other auxiliary materials are not required to be added, the formula is simple, the preparation process is simple, the cost is low, the stability and the irritation are low, the curative effect is good, freeze-drying and preservation are not required, and the voriconazole eye drop can be directly prepared, and the use is convenient.
Detailed Description
When describing the present invention, all terms (including technical and scientific terms) used in the disclosure of the invention have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs unless otherwise defined.
In the following paragraphs, the various aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner as would be apparent to one of ordinary skill in the art from this disclosure in one or more embodiments. Furthermore, while some embodiments described herein include some features included in other embodiments, but not others included in the other embodiments, combinations of features of different embodiments are intended to be within the scope of the invention, and form different embodiments, as will be appreciated by those of skill in the art. For example, any of the embodiments may be used in any combination in the appended claims and in the following claims.
The term "comprising" as used herein is synonymous with "comprising" or "containing" and is inclusive or open-ended and does not exclude additional, unrecited members, elements, or method steps. It will be appreciated that the term "comprising" as used herein includes the term "consisting of … …".
Recitation of numerical ranges by endpoints includes all integers subsumed within that range as well as fractions (e.g. 1 to 5 may include 1, 2, 3, 4 when referring to the number of elements, for example, and may also include 1.5, 2, 2.75, and 3.80 when referring to a metric, for example) as appropriate. The enumeration of endpoints also includes the endpoint values themselves (e.g., 1.0-5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein.
The term "sodium dihydrogen phosphate" as used herein refers to a compound represented by NaH2PO4 unless otherwise specified.
The term "calculated on sodium dihydrogen phosphate monohydrate" as used herein refers to equivalent molar amounts of sodium dihydrogen phosphate monohydrate as calculated for the content unless otherwise specified.
Where a numerical value is referred to herein, unless specifically stated otherwise, reference to the numerical value is to be understood as disclosing the numerical value itself and also covering variations of +/-10% or less, preferably +/-5% or less, more preferably +/-1% or less, of the numerical value and of the numerical value as long as such variations are suitable for being made in the disclosed invention.
The present invention will be specifically described below. Each claim and embodiment of the invention so defined may be combined with any other claim and/or embodiment unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. In this regard, the invention is achieved in particular by any one of the following numbered claims and embodiments or any combination of one or more of them with any other aspect and/or embodiment.
The first aspect of the present invention relates to voriconazole eye drops comprising, in mass concentration (w/v): 0.5 to 1.5 percent of voriconazole, 15 to 25 percent of hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate (the amount of which is 0.20 to 0.40 percent when counted by sodium dihydrogen phosphate monohydrate), and water.
In one embodiment, the voriconazole content may be in terms of mass concentration (w/v): 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, or a range defined by any two thereof.
In one embodiment, the hydroxypropyl-beta-cyclodextrin may be present in an amount, in terms of mass concentration (w/v), of: 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, or a range defined by any two thereof.
In one embodiment, the sodium phosphate monobasic, as measured by sodium phosphate monobasic, may be: 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, or a range defined by any two thereof.
In one embodiment, the water is water for injection, purified water, tap water, or any combination thereof.
In one embodiment, the water is water for injection.
In one embodiment, the voriconazole ophthalmic solution may be free of at least one of the following: osmotic pressure regulators, preservatives, and additional pH regulators. The osmolality adjusting agent, preservative, and additional pH adjusting agent described herein refer to agents functioning as an osmolality adjusting agent, preservative, and pH adjusting agent, respectively, in addition to voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water.
In one embodiment, the voriconazole ophthalmic solution is free of an osmotic pressure regulator. As noted above, the osmolality adjusting agents described herein refer to agents other than voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water that act as osmolality adjusting agents.
In one embodiment, the voriconazole ophthalmic solution is preservative-free. As described above, the preservative as described herein refers to an agent that functions as a preservative other than voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water.
In one embodiment, the voriconazole ophthalmic solution does not contain an additional pH adjustor. As noted above, the additional pH adjusting agents described herein refer to agents other than voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water that act as pH adjusting agents.
In one embodiment, the voriconazole ophthalmic solution is free of osmotic pressure modifiers, preservatives, and additional pH modifiers.
In one embodiment, the voriconazole ophthalmic solution consists of voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water. In other words, it contains no other excipients other than voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water, including but not limited to osmotic pressure regulator, preservative, and additional pH regulator.
In one embodiment, the voriconazole ophthalmic solution comprises, in terms of mass concentration (w/v): 1% voriconazole, 20% hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate in an amount of 0.30% based on the amount of sodium dihydrogen phosphate monohydrate, and water for injection.
In one embodiment, the voriconazole eye drops consist of the following components in mass concentration (w/v): 1% voriconazole, 18-22% hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate in an amount of 0.25-0.35% of sodium dihydrogen phosphate monohydrate, based on the amount of sodium dihydrogen phosphate monohydrate, and water.
In one embodiment, the voriconazole eye drops consist of the following components in mass concentration (w/v): 1% voriconazole, 20% hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate in an amount of 0.30% based on the amount of sodium dihydrogen phosphate monohydrate, and water for injection.
The second aspect of the present invention relates to a method for preparing the voriconazole eye drops, comprising the following steps:
dissolving hydroxypropyl-beta-cyclodextrin in water for injection to obtain a solution;
adding sodium dihydrogen phosphate and/or hydrate thereof into the solution and dissolving;
voriconazole is added to the above solution and dispersed, optionally supplemented with water for injection.
In one embodiment, the process in the preparation method is performed at normal temperature.
In one embodiment, the sodium dihydrogen phosphate hydrate comprises sodium dihydrogen phosphate monohydrate and/or sodium dihydrogen phosphate dihydrate. For example, the sodium dihydrogen phosphate hydrate may be sodium dihydrogen phosphate monohydrate.
In one embodiment, the dissolving and dispersing in the process is performed by stirring.
The third aspect of the invention relates to the use of the voriconazole ophthalmic solution described above for the preparation of an ophthalmic medicament for the treatment of a fungal infection.
In one embodiment, the fungal infection comprises keratitis. Preferably, the fungal infection is an infection caused by fusarium solani and/or aspergillus fumigatus.
The inventor finds that when voriconazole, sodium dihydrogen phosphate and hydroxypropyl-beta-cyclodextrin are used in combination, good voriconazole solubility in the preparation can be realized under the condition of normal temperature preparation, pH and osmotic pressure suitable for ophthalmology are realized, an osmotic pressure regulator, a preservative and other pH regulator or other auxiliary materials are not needed to be added, the formula is simple, the preparation process is simple, the cost is low, the stability is good, the irritation is low, the curative effect is good, freeze-drying preservation is not needed, and the preparation method can be directly used for preparing eye drops, and the use is convenient.
What has been described above is merely an exemplary embodiment of the present invention. It should be noted herein that modifications can be made by those skilled in the art without departing from the inventive concept, and these are intended to be within the scope of the present invention.
Examples
1. Determination of formulation ingredients and content
1. Preparation of eye drops
According to the formulations shown in table 1 below, eye drops of examples 1 to 9 and comparative examples 1 to 9 were obtained by performing the preparation in the following steps (1) to (3).
Step (1): mixing proper amount of water for injection and hydroxypropyl-beta-cyclodextrin in the formula amount, stirring and dissolving to obtain a solution.
Step (2): adding the sodium dihydrogen phosphate monohydrate with the formula amount into the solution, and stirring for dissolution;
step (3): at room temperature, voriconazole is added into the solution, stirred and dispersed, and the injection water is supplemented until the total amount of the injection water is 1L, and the mixture is continuously stirred to be uniform, so that the eye drops are obtained.
TABLE 1
The percentages (%) shown in table 1 are: (solute mass/solution volume) ×100%
2. Solubility of voriconazole in solution, pH, and osmotic pressure.
For the eye drops of examples 1 to 9 and comparative examples 1 to 9 prepared by the above steps, solubility of voriconazole in the solution was observed and recorded, and pH and osmotic pressure of the eye drops were measured, and the results are shown in table 2 below.
TABLE 2
According to ophthalmic clinical pharmacology (third edition) (3) As mentioned therein, "the eye has a relatively high tolerance to osmotic pressure, and normal ocular tolerance corresponds to 0.8%Osmotic pressure of 1.2% NaCl solution, and most eye drops recorded in the second part of Chinese pharmacopoeia are referred to, wherein the term of osmotic pressure molar concentration is specified in the following terms, and the molar concentration ratio of osmotic pressure (1) Should be 0.9 to 1.1. As can be seen from the combination of the above two parts, the osmotic pressure range of the eye drops needs to be set to be 0.8% -1.0% of the osmotic pressure of NaCl solution (2) That is, the osmolality is required to be 257 to 323.
From the above table 2, it can be seen that in the case of the eye drops of examples 1 to 9, both good solubility of voriconazole and osmotic pressure suitable for ophthalmic use were achieved. In contrast, in the case of the eye drops of comparative examples 1 to 9, there are problems in that the solubility of voriconazole is insufficient and/or the osmotic pressure is not suitable for ophthalmic use. Thus, the formulations of examples 1-9 are superior to comparative examples 1-9 in terms of the solubility of voriconazole and the osmotic pressure of the solution.
Remarks:
(1) The osmolality ratio of the eye drops to the 0.9% (g/ml) NaCl standard solution is called osmolality ratio.
(2) Typically, the osmolality of a 0.9% NaCl solution (i.e., normal saline) is about 290.
(3) Ophthalmic clinical pharmacology (third edition), main code Chen Zuji, zhang Junjie, beijing: chemical industry Press 2021:60.
3. Eye irritation of eye drops.
The eye drops of voriconazole of examples 1, 5 and 9 and comparative examples 1, 5 and 9 were examined for the irritation of rabbit eyes.
Test purpose: whether the administration of the voriconazole eye drops can generate a stimulating response and the reversibility of stimulation to animal eyes is examined, and a basis is provided for the safety of clinical application.
The test method comprises the following steps: 6 groups were designed, each group used 4 Japanese white rabbits, male and female halves. The self contrast of the left side and the right side of the same body is adopted. The administration was continued for 14 days, 12 times per day. Each animal was given 0.1mL of eye drops for the right eye and the control was given the same volume of 0.9% sodium chloride injection for the left eye. Animal body weight was weighed once at the day of introduction, day of first dosing, and end of observation, respectively. All animals tested were subjected to a general state observation once daily during the test period. Animals were examined by slit lamps for both eyes 1h, 2h, 4h, 24h, 48h, 72h before and after the first and last dosing daily, and the whole procedure was followed for sodium fluorescein corneal staining. The stimulus response scores of the cornea, iris and conjunctiva of each animal at each observation time are added to obtain total integral, and the integral sum of one group is divided by the animal number to obtain final score so as to judge the stimulus degree.
Test animals: white rabbits of Japanese big ears, ordinary grade.
The source is as follows: qingdao Kangda Biotechnology Co., ltd.
Weight of: the weight range is 1596.2 g-1603.1 g (male parent), 1583.1 g-1662.5 g (female parent) when the Chinese medicinal composition is introduced; when in use, the weight range is 1657.6 g-1683.7 g (female parent), 1642.6 g-1708.9 g (male parent).
Week-old: 84-126 days old (female); 90-132 days old (female) when administration.
Eyes of each animal were examined within 24 hours prior to the test to ensure that rabbit eyes had no irritating symptoms, no corneal defects and no conjunctival lesions.
Judgment standard: the stimulatory response scores of the cornea, iris and conjunctiva of each animal were obtained according to the criteria of table 3 below, added to obtain total scores, the total score of a group was divided by the number of animals to obtain final scores, the stimulation degree was judged according to the criteria of table 4 below, and the test results are shown in table 5.
TABLE 3 eye irritation response score criteria
TABLE 4 evaluation criteria for eye irritation
TABLE 5 eye irritation of voriconazole eye drops to test rabbits
As is clear from Table 5, in examples 1, 5 and 9, no eye irritation reaction was observed in the cornea, iris and conjunctiva of all rabbits at 1h, 2h, 4h, 24h, 48h and 72h before and after the administration of each day. In contrast, in the cases of comparative examples 1, 5, and 9, scattered or diffuse turbidity was found when the cornea of both eyes of the rabbit was observed, and/or conjunctival congestion, conjunctival edema, and conjunctival secretion were found when the conjunctiva was observed. Thus, the formulations of examples 1, 5, 9 are superior to comparative examples 1, 5, 9 in terms of eye irritation.
2. Consideration of pH
1. Preparation of eye drops
According to the formulations shown in Table 6 below, eye drops of comparative examples 10 to 13 were prepared in the following procedures (1) to (4).
Step (1): mixing proper amount of water for injection and hydroxypropyl-beta-cyclodextrin in the formula amount, stirring and dissolving to obtain a solution.
Step (2): adding the sodium dihydrogen phosphate monohydrate with the formula amount into the solution, and stirring for dissolution;
step (3): at room temperature, voriconazole was added to the above solution and dispersed with stirring.
Step (4): adding appropriate amount of sodium hydroxide and hydrochloric acid to adjust towards target pH value, supplementing injectable water to total amount of 1L, and stirring to obtain eye drop.
TABLE 6
2. The solubility of voriconazole in solution, the actual pH, and the osmotic pressure.
The solubility of voriconazole in the solution was observed and recorded for the eye drops of comparative examples 10 to 13 prepared by the above procedure, and the actual pH value and osmotic pressure of the eye drops were measured, and the results are shown in table 7 below.
TABLE 7
3. Stability of voriconazole in solution.
The voriconazole eye drops of examples 1, 5, 9 and comparative examples 10 to 13 were left at 40℃for 5 days, 10 days and 30 days, and the voriconazole content and the related substance content in the voriconazole eye drops of days 0, 5, 10 and 30 were measured, wherein the detection method of the voriconazole content and the related substance content (impurity content) was performed with reference to "voriconazole" item in the second section of the "chinese pharmacopoeia of 2020 edition, and the results are shown in table 8 below.
The voriconazole eye drops of examples 1, 5, 9 and comparative examples 10 to 13 were left at 25℃for 6 months, and the voriconazole content and the content of the relevant substances in the voriconazole eye drops of day 0, month 3, and month 6 were measured, wherein the detection methods of the voriconazole content and the content of the relevant substances (impurity content) were the same as above, and the results are shown in Table 9 below.
The voriconazole eye drops of examples 1, 5, 9 and comparative examples 10 to 13 were left at 2 to 8 ℃ for 24 months, and the voriconazole content and the related substance content in the voriconazole eye drops on day 0, month 6, month 12, and month 24 were measured, wherein the detection methods of the voriconazole content and the related substance content (impurity content) were the same as above, and the results are shown in table 10.
Table 8: stability of voriconazole in solution at 40℃
Table 9: stability of voriconazole in solution at 25℃
Table 10: stability of voriconazole in solution at 2-8℃
During actual production, storage, transportation, and use, it is desirable that the eye drops remain stable at temperatures as close as possible to the surrounding environment (e.g., typical temperatures of 2-8 ℃ (refrigeration temperatures that are relatively readily available), 25 ℃ (room temperature), or 40 ℃ (high temperatures that may be encountered daily). Furthermore, during actual production, storage, transportation and use, it is desirable to meet the following limit requirements: the sum of all impurities is not more than 0.5%.
As can be seen from tables 8, 9 and 10, the voriconazole content of the solutions of examples 1, 5 and 9 was maintained at 98.6% or more even at 30 days under the respective conditions of 2 to 8 ℃, 25 ℃ or 40 ℃. In contrast, the solutions of comparative examples 10 to 13 all had significantly lower voriconazole content than examples 1, 5, and 9 under the same conditions under the above conditions, and the voriconazole content was reduced to 92.6% when left at 40 ℃ for 6 months. It can be seen that the stability of voriconazole in the solutions of examples 1, 5, 9 is significantly higher than that in the solutions of comparative examples 10 to 13 at higher temperatures of 25 ℃ or 40 ℃. Moreover, when left for 24 months under the storage condition of 2 to 8 ℃, the impurity contents in the solutions of comparative examples 10 to 13 do not meet the desired limit requirements (i.e., exceed 0.5%), whereas the impurity contents in the solutions of examples 1, 5, and 9 are only 0.06 to 0.12%, which is greatly superior to the desired limit requirements.
Thus, the formulations of examples 1, 5, 9 are significantly better than comparative examples 10-13 in terms of stability of voriconazole, with the test results of example 5 being optimal.
3. Comparison with other formulations
1. Preparation of eye drops
According to the formulations shown in Table 11 below, eye drops of comparative examples 14 to 20 were prepared in the following procedures (1) to (4).
Step (1): mixing proper amount of water for injection with hydroxypropyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin in the formula amount, and stirring for dissolving to obtain a solution.
Step (2): adding the rest adjuvants (sodium dihydrogen phosphate monohydrate, alcohol, hyaluronic acid, glycerol, glycine, and sodium chloride) into the above solution, stirring and dissolving;
step (3): at room temperature, voriconazole (if necessary, an appropriate amount of ethanol, and then volatilization) was added to the above solution, and the dispersion was stirred.
Step (4): adding appropriate amount of sodium hydroxide and hydrochloric acid, supplementing injectable water to total amount of 1L, and stirring to obtain eye drop.
TABLE 11
2. The solubility of voriconazole in solution, the actual pH, and the osmotic pressure.
The solubility of voriconazole in the solution was observed and recorded for the eye drops of comparative examples 14 to 20 prepared by the above procedure, and the actual pH value and osmotic pressure of the eye drops were measured, and the results are shown in table 12 below.
Table 12
As described above, the osmolality of the eye drops needs to be 257 to 323. As is clear from Table 12, in comparative examples 14 to 20, the osmolality of the eye drops of comparative examples 14 to 16, 18 and 20 does not meet the ophthalmic requirements.
3. Eye irritation of eye drops.
For voriconazole eye drops of representative example 5 and representative comparative examples 17, 19, a study of the irritation of rabbit eyes was performed.
Test purpose: whether the administration of the voriconazole eye drops can generate a stimulating response and the reversibility of stimulation to animal eyes is examined, and a basis is provided for the safety of clinical application.
The test method comprises the following steps: 3 groups were designed, each group used 4 Japanese white rabbits, male and female halves. The self contrast of the left side and the right side of the same body is adopted. The administration was continued for 14 days, 12 times per day. Each animal was given 0.1mL of eye drops for the right eye and the control was given the same volume of 0.9% sodium chloride injection for the left eye. Animal body weight was weighed once at the day of introduction, day of first dosing, and end of observation, respectively. All animals tested were subjected to a general state observation once daily during the test period. Animals were examined by slit lamps for both eyes 1h, 2h, 4h, 24h, 48h, 72h before and after the first and last dosing daily, and the whole procedure was followed for sodium fluorescein corneal staining. The stimulus response scores of the cornea, iris and conjunctiva of each animal at each observation time are added to obtain total integral, and the integral sum of one group is divided by the animal number to obtain final score so as to judge the stimulus degree.
Test animals: white rabbits of Japanese big ears, ordinary grade.
The source is as follows: qingdao Kangda Biotechnology Co., ltd.
Weight of: the weight range is 1596.2 g-1603.1 g (male parent), 1583.1 g-1662.5 g (female parent) when the Chinese medicinal composition is introduced; when in use, the weight range is 1657.6 g-1683.7 g (female parent), 1642.6 g-1708.9 g (male parent).
Week-old: 84-126 days old (female); 90-132 days old (female) when administration.
Eyes of each animal were examined within 24 hours prior to the test to ensure that rabbit eyes had no irritating symptoms, no corneal defects and no conjunctival lesions.
Judgment standard: the stimulatory response scores of the cornea, iris and conjunctiva of each animal were obtained according to the criteria of table 3 above, added to obtain total scores, the total score of a group was divided by the number of animals to obtain final scores, the stimulation degree was judged according to the criteria of table 4 above, and the test results are shown in table 13.
Table 13 Furiconazole eye drops with stimulating effect on the eyes of the rabbits tested
As is clear from Table 13, in the case of example 5, no eye irritation reaction was observed in the cornea, iris and conjunctiva of all rabbits at 1h, 2h, 4h, 24h, 48h and 72h before and after the administration of each day. In contrast, in the case of comparative examples 17, 19, the wrinkles were found to be significantly deepened, engorged, swollen, slightly engorged around the cornea when the irises of both eyes of the rabbits were observed, and conjunctival engorged, conjunctival oedema, and conjunctival secretions were found when the conjunctiva was observed. Thus, the formulation of example 5 is significantly better than comparative examples 17 and 19 in terms of eye irritation.
4. Pharmacodynamic test
Pharmacodynamic tests were performed on voriconazole eye drops of examples 1, 5, 9 and comparative examples 17, 19.
Test purpose: the therapeutic effect of voriconazole eye drops on Fusarium solani and aspergillus fumigatus keratitis of rabbits is observed.
Test animals: japanese white rabbits, weighing 2.0-2.5 kg, both male and female, provided by the university of Shenyang pharmacopoeia test animal center, have no inflammatory response and eye injury.
Establishing a rabbit keratitis model: healthy adult Japanese white rabbits were selected and randomly divided into three major groups (group I, group II and group III), each of which was an vaccinated eye. Group I inoculated with Fusarium solani (5X 10) 5 CFu/mL), group II were inoculated with Aspergillus fumigatus (5X 10) 2 CFU/mL), group iii is blank (without any surgery). All eyes tested were started three days prior to surgery with tobramycin dexamethasone eye drops four times a day. Inoculating: the test Japanese white rabbits were anesthetized by 30% Ulatan solution for otic margin intravenous injection, conventionally sterilized before surgery, procaine hydrochloride for surface anesthesia, eyelid speculum, and 25. Mu.L of the two bacterial liquids were injected with a lmL syringe having a 30G cosmetic needleEntering the central shallow stroma of the cornea to a depth of about 1/3 of the cornea thickness; the ofloxacin eye ointment is used for eye drops after operation. After keratitis has formed, the cornea is scraped and simultaneously stained with gram stain and Giemsa, and the cultured fungus positive inclusion group is identified by microbiome. There were 4 animals per group of samples per model. The animals were grouped and the doses are shown in Table 14.
TABLE 14 grouping of animals and dosing amounts
All animals were examined and recorded under a slit lamp after the start of dosing, and slit lamp photographs and scoring were performed on days 1, 8, 15, and 22 of dosing. The stroma of the eye was recorded for corneal edema, ulcer diameter and margin, ulcer depth, time and height of appearance of the pus in the anterior chamber, time of corneal perforation, time of ulcer healing, and corresponding scores were given. Clinical scoring criteria are shown in table 15. The statistics of keratitis conditions were carried out on animals of each group according to the scoring criteria of table 15, and the results are shown in tables 16 and 17.
TABLE 15 clinical score criteria for keratitis
Table 16 table of the evaluation of the eye drops of voriconazole for the treatment of infection of rabbit keratitis with fusarium solani
| Time | 1d | 8d | 15d | 22d |
| Example 1 | 6.63±1.30 | 6.63±2.33 | 5.38±3.60 ** | 4.63±3.25 * |
| Example 5 | 6.65±1.12 | 6.60±1.99 | 5.04±3.40 ** | 3.17±3.13 * |
| Example 9 | 6.56±1.41 | 6.56±2.43 | 5.12±2.67 ** | 4.44±2.25 * |
| Comparative example 17 | 6.77±1.09 | 6.53±2.41 | 5.81±2.56 * | 4.97±3.15 * |
| Comparative example 19 | 6.98±1.12 | 6.63±2.33 | 5.80±3.71 * | 4.87±2.31 * |
| Positive drug | 6.62±1.26 | 6.83±2.12 | 5.11±3.20 ** | 3.24±3.01 * |
| Model (blank) | 6.68±1.13 | 8.33±1.32 | 9.11±1.22 | 7.33±3.26 |
Comparison to model set: * ，P<0.05； ** ，P<0.01
table 17 table of the evaluation of voriconazole eye drops for the treatment of aspergillus fumigatus infection in rabbit keratitis
Comparison to model set: * ，P<0.05； ** ，P<0.01
from tables 16-17, it can be seen that differences (P < 0.1) occur between the scores of each of the example, comparative example and positive drug groups compared to the model group on day 15 and/or day 22 of dosing, wherein significant differences (P < 0.05) occur for examples 1, 5, 9, and clinical scores for examples 1, 5, 9 are significantly higher than for comparative examples 17, 19 on day 15 and day 22 of dosing. Thus, the formulations of examples 1, 5, 9 are superior to comparative examples 17, 19 in efficacy.
In conclusion, the invention can realize good solubility of voriconazole in the preparation, pH and osmotic pressure suitable for ophthalmology under the condition of normal temperature preparation by combining specific amounts of voriconazole, sodium dihydrogen phosphate and hydroxypropyl-beta-cyclodextrin, and has the advantages of simple formula, simple preparation process, low cost, good stability, low irritation, good curative effect, no need of freeze-drying preservation, direct preparation into eye drops, convenient use and excellent technical effect.
Claims (10)
1. A voriconazole eye drop comprising, in mass concentration (w/v):
0.5 to 1.5 percent of voriconazole,
15 to 25 percent of hydroxypropyl-beta-cyclodextrin,
sodium dihydrogen phosphate in an amount of 0.20 to 0.40% based on the amount of sodium dihydrogen phosphate monohydrate, and
and (3) water.
2. The voriconazole eye drops according to claim 1, wherein,
voriconazole is present in a mass concentration (w/v) of 0.8% to 1.2%, for example 0.9% to 1.1%, for example 1.0 to 1.1%.
3. The voriconazole ophthalmic solution according to any one of claims 1 to 2, wherein,
hydroxypropyl-beta-cyclodextrin is present in a mass concentration (w/v) of 18% to 22%, e.g. 19% to 21%, e.g. 20 to 21%.
4. The voriconazole eye drops according to any one of claims 1 to 3, wherein,
sodium phosphate monobasic is present in a mass concentration (w/v) of 0.25% to 0.35%, for example 0.28% to 0.32%, for example 0.30% to 0.31%, as measured by sodium phosphate monobasic monohydrate.
5. The voriconazole eye drops according to any one of claims 1 to 4, wherein,
the water is water for injection, purified water, tap water or any combination thereof;
preferably, the water is water for injection.
6. Voriconazole ophthalmic solution according to any one of claims 1 to 5, which does not comprise at least one of the following: osmotic pressure regulators, preservatives, and additional pH regulators;
preferably, it does not contain osmolality adjusting agents, preservatives, and additional pH adjusting agents;
preferably, it consists of voriconazole, hydroxypropyl-beta-cyclodextrin, sodium dihydrogen phosphate, and water.
7. Voriconazole ophthalmic solution according to any one of claims 1 to 6, comprising, in mass concentration (w/v):
1% of voriconazole,
20% of hydroxypropyl-beta-cyclodextrin,
sodium dihydrogen phosphate in an amount of 0.30% based on the amount of sodium dihydrogen phosphate monohydrate, and
water for injection.
8. A process for the preparation of voriconazole eye drops according to any one of claims 1 to 7, comprising the steps of:
dissolving hydroxypropyl-beta-cyclodextrin in water for injection to obtain a solution;
adding sodium dihydrogen phosphate and/or hydrate thereof into the solution and dissolving;
voriconazole is added to the above solution and dispersed, optionally supplemented with water for injection.
9. Use of voriconazole eye drops according to any one of claims 1 to 7 in the manufacture of an ophthalmic medicament for the treatment of fungal infections.
10. The use according to claim 9, wherein,
the fungal infection comprises a keratitis and,
preferably, the fungal infection is an infection caused by fusarium solani and/or aspergillus fumigatus.
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| CN116570558B (en) * | 2023-06-21 | 2023-12-26 | 广州仁恒医药科技股份有限公司 | Voriconazole ophthalmic nanometer slow-release composition and preparation method and application thereof |
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