Single-dose fenpropenyl phthalmic solution and preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical preparations, and particularly relates to a single-dose anilineprofen eye drop and its preparation method. The single-dose anilineprofen eye drop comprises anilineprofen, an osmotic pressure regulator, a metal ion chelating agent, and a pH adjuster, wherein the pH adjuster is selected from at least one of phosphate, boric acid, and borax. This single-dose anilineprofen eye drop does not contain antibacterial agents, thus avoiding secondary microbial contamination during the use of multi-dose eye drops and the toxic side effects of antibacterial agents on the eyes; it also exhibits stable quality and good efficacy.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a single-dose aniprofen eye drop and a preparation method thereof. Background Art

[0002] From the perspective of chemical structure, anilineprofen belongs to the aromatic alkanoic acid class of non-steroidal anti-inflammatory analgesics. It is a non-steroidal analgesic and anti-inflammatory drug that is metabolized to felbinac in the body to exert its effects. Its mechanism of action is to inhibit the activity of cyclooxygenase (COX), block the synthesis of eicosatetraenoic acid derivatives, inhibit the synthesis of prostaglandins, and relieve inflammatory reactions. It is clinically used for conditions related to analgesia and anti-inflammatory effects, such as pain after surgical treatment, pain from various cancers, pain from trauma, low back pain, gout, neuralgia, kidney and urinary stone pain, etc. After felbinac and tromethamine are salified, the water solubility and safety of anilineprofen injection are greatly increased, and it can be further prepared into eye drops for use.

[0003] Existing aniline profen eye drops are multi-dose packages and are repeatedly used. Once the preparation is unsealed, it is easy to be contaminated by microorganisms in tears and air during use and storage, which then causes potential safety hazards. Therefore, in order to prevent the secondary pollution of ophthalmic preparations after unsealing, antibacterial agents are generally required to be added to ophthalmic preparations. However, long-term use of eye drops containing antibacterial agents may cause epithelial cell damage, shedding, and degeneration of cornea and conjunctiva, leading to membrane ulcers or erosion, and bring certain potential safety hazards to medication patients, such as the occurrence of symptoms such as decreased vision and congestion of eyes, and even loss of vision in severe cases. In addition, the irrationality of the amount of eye drops causes the remaining eye drops in the hands of patients to be discarded, which not only wastes resources and increases the pollution of medical waste, but also causes patients to suffer certain economic losses. Therefore, multi-dose packaged eye drops are increasingly unable to meet the needs of long-term medication patients.

[0004] Single-dose eye drops are disposable eye drops that can be used immediately after opening and discarded after use. They do not require the addition of antibacterial agents, effectively preventing damage to the eyes caused by antibacterial agents. At the same time, single-dose eye drops are more portable than multi-dose eye drops. Therefore, single-dose anilineprofen eye drops are an advantageous eye drop for treating eye inflammation in combination with the trend of eye medication. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a single-dose aniline profen eye drops and a preparation method thereof, wherein the single-dose aniline profen eye drops do not require the addition of an antibacterial agent, can avoid secondary microbial contamination of multi-dose eye drops during use and the toxic side effects of the antibacterial agent on the eyes; and have stable quality and good efficacy.

[0006] The first aspect of the present invention provides a single-dose fenpropenyl eye drops, comprising fenpropenyl eye drops, an osmotic pressure regulator, a metal ion complexing agent, and a pH regulator;

[0007] The single-dose fenprofen eye drops do not contain an antibacterial agent;

[0008] The pH regulator is selected from at least one of phosphate, boric acid and borax.

[0009] According to some embodiments of the present invention, the single-dose of fenpropenyl alcohol eye drops comprises the following components in mass volume concentrations:

[0010] Aniprofen: 0.1-0.4%,

[0011] Osmotic pressure regulator: 0.7% to 1.5%,

[0012] Metal ion complexing agent: 0.01% to 0.02%,

[0013] pH adjuster: adjust the pH value of the single-dose aniprofen eye drops to 6.0-8.0.

[0014] According to some embodiments of the present invention, the mass volume concentration of aniprofen is 0.1-0.4%, including but not limited to: 0.1-0.3%, 0.1-0.2%, 0.4%, 0.2%, 0.1%; preferably 0.1-0.2%.

[0015] According to some embodiments of the present invention, the mass volume concentration of the osmotic pressure regulator is 0.7% to 1.5%, including but not limited to: 0.7% to 1.3%, 0.8% to 1.5%, 0.8% to 1.3%.

[0016] According to some embodiments of the present invention, the osmotic pressure regulator is sodium chloride.

[0017] According to some embodiments of the present invention, the mass volume concentration of the metal ion complexing agent is 0.01% to 0.02%, preferably 0.01%.

[0018] According to some embodiments of the present invention, the metal ion complexing agent is disodium edetate.

[0019] According to some embodiments of the present invention, the pH value of the single-dose aniprofen eye drops is adjusted by a pH adjuster to 6.0-8.0, including but not limited to: 6.0-7.5, 6.5-7.5, 6.6-7.4, 6.6-7.2, 6.9-7.1.

[0020] According to some embodiments of the present invention, the mass volume concentration of the pH regulator is 0.2% to 1.0%, including but not limited to: 0.2% to 0.9%, 0.2% to 0.3%, 0.8% to 0.9%.

[0021] According to some embodiments of the present invention, the pH adjuster is phosphate, and further, the mass volume concentration of the phosphate is 0.2% to 0.3%.

[0022] According to some embodiments of the present invention, the phosphate is a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate; wherein the mass ratio of disodium hydrogen phosphate to sodium dihydrogen phosphate is 4-8:1, including but not limited to: 4-7:1, 4-6:1, 5-8:1, 5-7:1, 5-6:1; preferably 5-6:1.

[0023] According to some embodiments of the present invention, the pH regulator is boric acid and borax, and further, the total mass volume concentration of the boric acid and borax is 0.8% to 0.9%.

[0024] According to some embodiments of the present invention, the mass ratio of boric acid to borax is 20 to 30:1, preferably 20 to 25:1.

[0025] According to some embodiments of the present invention, the osmotic pressure of the single-dose fenpropenyl alcohol eye drops is 260-320 mOsmol / kg.

[0026] According to some embodiments of the present invention, the single-dose fenpropenyl alcohol eye drops are independently packaged, and the volume range of the independently packaged container is 0.4 to 0.8 mL / vial.

[0027] The second aspect of the present invention provides a method for preparing the above-mentioned single-dose fenpropenyl alcohol eye drops, comprising the following steps:

[0028] The aniline profen, osmotic pressure regulator, metal ion complexing agent and pH regulator are mixed, sterilized and filtered to obtain the product.

[0029] According to some embodiments of the present invention, the sterilization is carried out by moist heat sterilization, and is sterilized by hot pressing at 121° C. for 8-30 minutes.

[0030] According to some embodiments of the present invention, the filtration is performed in a Class A clean area and terminally filtered through a 0.22 μm filter element.

[0031] According to some embodiments of the present invention, a filling step is further included after the filtration; the canning uses a "blow-fill-seal" integrated machine for single-dose filling, and the filling volume is 0.4mL to 0.8mL.

[0032] The third aspect of the present invention provides the use of the above-mentioned single-dose aniprofen eye drops in the preparation of a drug for treating inflammation of the external eye and anterior segment of the eye.

[0033] The external eye and anterior segment inflammation include at least one of blepharitis, conjunctivitis, keratitis, scleritis, superficial scleritis, iridocyclitis, and postoperative inflammation.

[0034] Beneficial effects:

[0035] The single-dose anilinoprofen eye drops provided by the present invention do not contain antibacterial agents, thus avoiding potential dangers and toxic side effects on eyes caused by antibacterial agents, and are produced by an aseptic filling process or a hot pressing sterilization process, thereby ensuring the aseptic requirements of the product, and providing patients with safer and more reliable anilinoprofen eye drops. In addition, after the single-dose anilinoprofen eye drops of the present invention are treated with high temperature and strong light, the anilinoprofen content and pH value are substantially unchanged, and the content of related substances is not detected, indicating that the single-dose anilinoprofen eye drops are stable in nature.

[0036] The mass volume concentration (%) of a certain component in the present invention refers to the mass (g) of the component contained in 100 mL of solution.

[0037] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0039] Figure 1 This is a graph of the scoring standard (refined standard) for rabbit conjunctival inflammation irritation symptoms according to an embodiment of the present invention. DETAILED DESCRIPTION

[0040] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0041] If there is a description of the first and the second, it is only for the purpose of distinguishing the technical features, and it cannot be understood as indicating or implying the relative importance or implicitly indicating the number of the indicated technical features or implicitly indicating the order of the indicated technical features. In the description of the present invention, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in combination with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0042] Example 1

[0043] This embodiment provides a single-dose of fenpropiprofen eye drops, and its formula composition is shown in Table 1.

[0044] The preparation method of the single-dose anilinoprofen eye drops is as follows:

[0045] (1) Take about 60 mL of water for injection, add disodium hydrogen phosphate and sodium dihydrogen phosphate, and after complete dissolution, add sodium chloride, edetate disodium and anilinoprofen, and dilute to 100 mL with water for injection to obtain a drug solution;

[0046] (2) Add the drug solution into a pressure-resistant container and sterilize it with wet heat at 121°C for 15 minutes. After the sterilization is completed, cool the drug solution to below 40°C;

[0047] (3) Under a Class A environment, the drug solution is filtered through a 0.22 μm filter cartridge and filled in a single dose using a "blow-fill-seal" all-in-one machine with a filling volume of 0.4 mL.

[0048] Embodiment 2, 3

[0049] Examples 2 and 3 respectively provide a single-dose of aniprofen eye drops, the formulation composition of which is shown in Table 1, and the preparation method thereof is carried out with reference to that in Example 1.

[0050] Table 1 Formula composition of Examples 1 to 3 (g)

[0051]

[0052] Example 4

[0053] This embodiment provides a single-dose of fenpropenyl phthalmic solution, the formulation of which is as follows:

[0054] Aniprofen 0.10g,

[0055] Boric acid 0.83 g,

[0056] Borax 0.04g,

[0057] Edetate disodium 0.01g,

[0058] Sodium chloride 1.30g,

[0059] Add water for injection to make up to 100 mL.

[0060] The preparation method of the single-dose fenpropenyl amine eye drops is carried out with reference to Example 1.

[0061] Comparative Example 1

[0062] This comparative example provides a single-dose of fenpropenyl phthalmic solution, the formulation of which is as follows:

[0063] Aniprofen 0.1g,

[0064] Anhydrous citric acid 0.05g,

[0065] Sodium citrate 0.45g,

[0066] Edetate disodium 0.01g,

[0067] Sodium chloride 0.67g,

[0068] Add water for injection to make up to 100 mL.

[0069] The preparation method of the single-dose fenpropenyl amine eye drops is carried out with reference to Example 1.

[0070] Test Case

[0071] 1. Sample stability

[0072] The influencing factors of the single-dose aniline profen eye drops prepared in Examples 1 to 4 and Comparative Example 1 were studied. The effects of high temperature (60°C) for 5 days, 10 days, and 30 days, strong light (total illumination not less than 1.2×10 6 Lux·hr, near ultraviolet energy not less than 200w·hr / m 2 ) The content of aniprofen, the content of edetate disodium, related substances, pH value and osmotic pressure in the eye drops under the conditions of 5 days and 10 days.

[0073] Among them, the content determination method of aniprofen was carried out in accordance with the general rules 0512 of the fourth volume of the Chinese Pharmacopoeia 2020 edition;

[0074] The content determination method of edetate disodium was carried out according to the general rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia;

[0075] The content determination method of relevant substances is carried out in accordance with the general rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia;

[0076] The pH value was determined according to the General Rules 0631 of Part IV of the 2020 edition of the Chinese Pharmacopoeia;

[0077] The method for determining osmotic pressure is carried out in accordance with General Rules 0632 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia.

[0078] The test results of the single-dose anilinoprofen eye drops prepared in Examples 1 to 4 are shown in Table 2.

[0079] Table 2 Measurement results of eye drops of Examples 1 to 4

[0080]

[0081]

[0082] As can be seen from Table 2, the single-dose aniline profen eye drops prepared in Examples 1 to 3 were placed under strong light irradiation for 10 days and at high temperature for 30 days. The maximum single impurity and total impurities of the samples were not detected, the aniline profen content did not change significantly, the edetate disodium content did not change significantly, and the pH value and osmotic pressure did not change significantly, indicating that the samples have good stability.

[0083] The single-dose anilineprofen eye drops prepared in Example 4 were placed under strong light irradiation for 10 days and at high temperature for 30 days. There was no significant change in the anilineprofen content, the edetate disodium content, the pH value and the osmotic pressure. Related substances were detected but met the standards and did not increase, indicating that the sample had good stability.

[0084] The single-dose anilineprofen eye drops prepared in Comparative Example 1 are not suitable for use as the eye drops of the present invention because the citric acid / sodium citrate system is used as the pH regulator, which is incompatible with the system and floccules are precipitated when left standing.

[0085] 2. Pharmacodynamics test

[0086] The pharmacodynamics of the single-dose anilinoprofen eye drops prepared in Examples 1 to 3 were compared with the commercially available pranoprofen eye drops (Senju Pharmaceutical Co., Ltd.).

[0087] 44 New Zealand rabbits were selected. Except for the blank control group, the remaining groups were used to prepare the animal model of conjunctivitis induced by croton oil in New Zealand rabbits. The specific groups were: blank group, model group, pranoprofen eye drops group, anilineprofen eye drops A (0 mg / mL), B (1 mg / mL), C (2 mg / mL), D (4 mg / mL), a total of 7 groups, 4 rabbits (8 eyes) in each group. The first administration time was taken as the start time of administration, and the conjunctival congestion, edema, and secretion scores of the animals were observed at 1, 2, 4, 6, 8, 12, and 24 hours after administration (scoring criteria as shown in Figure 1 The detailed scores and total scores were calculated respectively. The results are shown in Tables 3 to 6.

[0088] Table 3 Effects of different concentrations of aniprofen eye drops on conjunctivitis induced by croton oil in New Zealand rabbits

[0089]

[0090] Note: Compared with the blank group, △ It means P≤0.05, △△ Indicates P ≤ 0.01.

[0091] Table 4 Effects of different concentrations of aniprofen eye drops on conjunctivitis induced by croton oil in New Zealand rabbits

[0092]

[0093] Note: Compared with the blank group, △ It means P≤0.05, △△ Indicates P≤0.01; compared with the solvent group, # It means P≤0.05, ## Indicates P≤0.01; compared with the model group, * It means P≤0.05, ** Indicates P ≤ 0.01.

[0094] Table 5 Effects of different concentrations of aniprofen eye drops on conjunctivitis induced by croton oil in New Zealand rabbits

[0095]

[0096]

[0097] Note: Compared with the blank group, △ It means P≤0.05, △△ Indicates P≤0.01; compared with the solvent group, # It means P≤0.05, ## Indicates P≤0.01; compared with the model group, * It means P≤0.05, ** Indicates P ≤ 0.01.

[0098] Table 6 Effects of different concentrations of aniprofen eye drops on conjunctivitis induced by croton oil in New Zealand rabbits

[0099]

[0100] Note: Compared with the blank group, △ It means P≤0.05, △△ Indicates P≤0.01; compared with the solvent group, # It means P≤0.05, ## Indicates P≤0.01; compared with the model group, * It means P≤0.05,** Indicates P ≤ 0.01.

[0101] The test results in Tables 3 to 6 indicate that different concentrations of aniprofen eye drops and pranoprofen eye drops have a certain improvement effect on acute conjunctivitis in rabbits induced by croton oil, and the order of effect strength is aniprofen 2 mg / mL > 1 mg / mL > pranoprofen (1 mg / mL) > 4 mg / mL > solvent (0 mg / mL).

[0102] The embodiments of the present invention are described in detail above, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A single-dose fenpropenyl phthalmic solution, characterized in that: The following components are included in mass volume concentrations: Aniprofen: 0.1-0.4%, Osmotic pressure regulator: 0.7% to 1.5%, Metal ion complexing agent: 0.01% to 0.02%, pH adjuster: for adjusting the pH value of the single-dose fenpropenyl phthalmic solution to 6.0-8.0; The single-dose fenprofen eye drops do not contain an antibacterial agent; The pH regulator is selected from phosphate, or boric acid and borax; The mass volume concentration of the pH regulator is 0.2% to 1.0%; The phosphate is a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate; wherein the mass ratio of disodium hydrogen phosphate to sodium dihydrogen phosphate is 4 to 8:1; The mass ratio of the boric acid to borax is 20-30:

1.

2. The single-dose fenpropenyl phthalmic solution according to claim 1, characterized in that: The osmotic pressure regulator is sodium chloride.

3. The single-dose fenpropenyl phthalmic solution according to claim 1, characterized in that: The metal ion complexing agent is disodium edetate.

4. The single-dose anilinoprofen eye drops according to claim 1, characterized in that: The osmotic pressure of the single-dose aniprofen eye drops is 260-320 mOsmol / kg.

5. The single-dose fenpropenyl phthalmic solution according to claim 1, characterized in that: The single-dose fenpropenyl phthalmic solution is independently packaged, and the volume range of the independently packaged container is 0.4 to 0.8 mL per vial.

6. The method for preparing the single-dose aniprofen eye drops according to any one of claims 1 to 5, characterized in that: The following steps are involved: The aniline profen, osmotic pressure regulator, metal ion complexing agent and pH regulator are mixed, sterilized and filtered to obtain the product.

7. Use of the single-dose anilinoprofen eye drops according to any one of claims 1 to 5 in the preparation of a medicament for treating conjunctivitis.

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