A kind of phenylephrine hydrochloride eye drops and preparation method thereof

Abstract

The present invention relates to the technical field of ophthalmic medication, and in particular to a kind of phenylephrine hydrochloride eye drops and a preparation method thereof. A preparation method of phenylephrine hydrochloride eye drops comprises the following steps: nitrogen is filled into the water for injection of 30%-90% of the total volume, a buffer solution, a prescription amount of phenylephrine hydrochloride and a preservative are added in sequence, and the solution is stirred and dissolved to obtain a concentrated solution of phenylephrine hydrochloride; water for injection is added to the concentrated solution of phenylephrine hydrochloride to the total amount of preparation, the pH is adjusted to 4.0-5.8, filtered, filled with nitrogen, and phenylephrine hydrochloride eye drops are obtained; the dissolved oxygen in the water for injection after nitrogen filling is within 1ppm, and the residual oxygen content of the phenylephrine hydrochloride eye drops is controlled within 5%. By controlling the oxygen content in the solution during preparation and filling, and controlling the pH of the diluted solution to 4.0-5.8, the prepared eye drops have high stability, low impurity content, and long shelf life.

Description

Technical Field

[0001] The invention relates to the technical field of ophthalmic medication, and in particular to phenylephrine hydrochloride eye drops and a preparation method thereof. Background Art

[0002] Phenylephrine hydrochloride is (R)-(-)-α-[(methylamino)methyl]-3-hydroxybenzyl alcohol hydrochloride, with the molecular formula C 9 H 13 NO 2 ·HCl, this product is white or off-white crystalline powder; odorless. This product is easily soluble in water or ethanol, and insoluble in chloroform or ether. It can excite the α receptors of the radiating muscles of the eye, i.e., the pupil dilator muscles, causing the radiating muscles to contract and dilate the pupil. It has a short action time, does not increase intraocular pressure, and does not cause accommodation paralysis. It is a fast and short-acting mydriatic drug and is clinically suitable for mydriasis.

[0003] However, phenylephrine hydrochloride eye drops will be affected by light and temperature, causing the eye drops to generate impurities as the storage time increases, thus affecting the effectiveness of the eye drops. Summary of the invention

[0004] In view of the above technical problems, the present invention provides a phenylephrine hydrochloride eye drops and a preparation method thereof. Compared with the traditional preparation method, the eye drops prepared by the present method are less affected by light and temperature, have less impurities, are more stable, and can be stored for a longer time.

[0005] To solve the above technical problems, the embodiments of the present invention adopt the following technical solutions:

[0006] In a first aspect, an embodiment of the present invention provides a method for preparing phenylephrine hydrochloride eye drops, comprising the following steps:

[0007] S1: nitrogen is added to 30%-90% of the total amount of water for injection, and then a buffer solution, a prescribed amount of phenylephrine hydrochloride and a preservative are added in sequence, and stirred to dissolve to obtain a concentrated solution of phenylephrine hydrochloride;

[0008] S2: adding water for injection to the concentrated solution of phenylephrine hydrochloride to the total amount of preparation, adjusting the pH to 4.0-5.8, filtering, and filling with nitrogen to obtain phenylephrine hydrochloride eye drops;

[0009] The dissolved oxygen in the injection water after nitrogen filling is within 1 ppm, and the residual oxygen content of the phenylephrine hydrochloride eye drops is controlled within 5%.

[0010] Phenylephrine hydrochloride is sensitive to oxygen. The oxygen and residual oxygen content of the solution should be strictly controlled during the production process. Therefore, when preparing a concentrated solution of phenylephrine hydrochloride, the water needs to be nitrogen-filled to control the dissolved oxygen in the water within 1ppm after nitrogen filling. Nitrogen filling is performed during filling to control the residual oxygen in the eye drops below 5%. The pH of the diluted solution needs to be adjusted to 4.0-5.8. The prepared eye drops have high stability, low impurity content and long shelf life.

[0011] Not adding activated carbon in the preparation process of the present invention can reduce production costs, reduce pollution in the production clean area, alleviate environmental pressure, further reduce impurities and insoluble particles that may be introduced when adding activated carbon, and help further improve the effectiveness, safety and stability of product quality.

[0012] Preferably, in step S2, the pH regulator is selected from one or more of phosphoric acid, hydrochloric acid, boric acid or sodium hydroxide.

[0013] In the present invention, the pH regulator is not limited to phosphoric acid, hydrochloric acid, boric acid and sodium hydroxide, and any solution that can adjust the pH value of the solution to 4.0-5.8 can be used as the pH regulator of the present invention.

[0014] Preferably, in step S2, the filter element used for filtration is selected from one or more of polyethersulfone, polytetrafluoroethylene or polyvinylidene fluoride filter elements; the filter element is a multi-stage filter element. Furthermore, the multi-stage filter element is a three-stage filter element; the pore sizes of the three-stage filter element are 0.45 μm, 0.2 μm and 0.2 μm respectively.

[0015] In the present invention, a specific three-stage filter element is used for sequential filtration, and the second and third stage filter elements are connected in series for redundant filtration. Such a design can not only ensure that the microbial limit of the product is qualified and reduce the introduction of impurities from the raw materials, but also further improve the quality stability of the product.

[0016] Preferably, in step S1, the buffer is a phosphate buffer, and the phosphate buffer is sodium dihydrogen phosphate and disodium hydrogen phosphate; the preservative is selected from one or more of benzalkonium chloride, benzalkonium bromide, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate or sodium sorbate.

[0017] In the present invention, adding a buffer to the raw material can maintain the stability of the pH value of the product, which is beneficial to improving clinical adaptability. Adding a preservative to the raw material can effectively ensure the quality of the product. When the preservative in the raw material is benzalkonium chloride, the material of the filter element does not include polyether sulfone.

[0018] Preferably, the concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.025-0.1 g / mL. Preferably, when the concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.025 g / mL, each 1000 drops of eye drops include the following components: 4-15 g of sodium dihydrogen phosphate, 3-10 g of disodium hydrogen phosphate, 50 g of phenylephrine hydrochloride, 0.2-0.5 g of benzalkonium chloride, and the total volume of the prepared eye drops is 2000 mL; or, each 1000 drops of eye drops include the following components: 30-120 g of sodium dihydrogen phosphate, 20-80 g of disodium hydrogen phosphate, 375 g of phenylephrine hydrochloride, 1.5-3.8 g of benzalkonium chloride, and the total volume of the prepared eye drops is 15000 mL.

[0019] Preferably, when the concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.1 g / mL, each 1000 tubes of eye drops include the following components: 10-40 g of sodium dihydrogen phosphate, 7-30 g of disodium hydrogen phosphate, 500 g of phenylephrine hydrochloride, and 0.4-1.3 g of benzalkonium chloride, and the total volume of the prepared eye drops is 5000 mL.

[0020] In the present invention, low-density polyethylene eye drop bottles are used to fill the eye drops, and a special high-barrier bag is used as an outer bag after nitrogen filling, which can further ensure product quality. Furthermore, colorants are added to the low-density polyethylene eye drop bottles during the production process, and the high-barrier bag is made of opaque material, which can prevent the influence of light on the eye drops.

[0021] In a second aspect, an embodiment of the present invention further provides a phenylephrine hydrochloride eye drops prepared by the above-mentioned preparation method.

[0022] In the present invention, the phenylephrine hydrochloride contained in each 1 mL of phenylephrine hydrochloride eye drops should be 95%-105% of the labeled amount. For example: taking 1 mL of the phenylephrine hydrochloride eye drops as a benchmark, when the mass of the phenylephrine hydrochloride is 0.025 g, each 1000 tubes of eye drops include the following components: 4-15 g of sodium dihydrogen phosphate, 3-10 g of disodium hydrogen phosphate, 47.5-52.5 g of phenylephrine hydrochloride, 0.2-0.5 g of benzalkonium chloride, and the total volume of the prepared eye drops is 2000 mL; or, each 1000 tubes of eye drops include the following components: 30-120 g of sodium dihydrogen phosphate, 20-80 g of disodium hydrogen phosphate, 356.25-393.75 g of phenylephrine hydrochloride, 1.5-3.8 g of benzalkonium chloride, and the total volume of the prepared eye drops is 15000 mL.

[0023] Preferably, based on 1 mL of the phenylephrine hydrochloride eye drops, when the mass of the phenylephrine hydrochloride is 0.1 g, each 1000 tubes of eye drops include the following components: 10-40 g of sodium dihydrogen phosphate, 7-30 g of disodium hydrogen phosphate, 475-525 g of phenylephrine hydrochloride, and 0.4-1.1 g of benzalkonium chloride, and the total volume of the prepared eye drops is 5000 mL.

[0024] Compared with the prior art, the present invention has one of the following beneficial effects:

[0025] The present invention controls the dissolved oxygen in the water after nitrogen filling to be within 1ppm by nitrogen filling treatment, controls the residual oxygen in the eye drops to be below 5% by nitrogen filling during filling, and adjusts the pH of the diluted concentrated solution to 4.0-5.8. The prepared eye drops have high stability, low impurity content and long storage time. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0027] The present invention adjusts the preparation process of phenylephrine hydrochloride eye drops, and controls the oxygen content in the solution by nitrogen filling during the preparation of the concentrated solution and the filling process, thereby preventing the oxygen in the solution from affecting the properties of the eye drops. In addition, by adjusting the pH of the traditional eye drops from 6-8 to 4.0-5.8, the stability of the eye drops can be further improved and the storage period of the eye drops can be extended.

[0028] The pH regulator of the present invention can be selected from one or more of phosphoric acid, hydrochloric acid, boric acid or sodium hydroxide. Preferably, the regulator can be any two of phosphoric acid, hydrochloric acid, boric acid or sodium hydroxide. The present invention has no particular limitation on the amount relationship of any two of the regulators, for example, the weight ratio can be 0.5-2:1, and the present invention is not limited thereto.

[0029] The present invention has no particular limitation on the filter element material used for filtration, and any one or more of polyethersulfone, polytetrafluoroethylene or polyvinylidene fluoride filter elements may be used; there is no particular limitation on the number of filter elements, as long as there are more than two stages. There is no particular limitation on the pore size of the second-stage filter element, as long as it is smaller than the pore size of the first-stage filter element.

[0030] In the present invention, the preservative may be selected from one or more of benzalkonium chloride, benzalkonium bromide, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate or sodium sorbate. Preferably, the preservative may be any two of benzalkonium chloride, benzalkonium bromide, chlorobutanol, methyl parahydroxybenzoate, propyl parahydroxybenzoate or sodium sorbate. The present invention has no particular limitation on the amount of any two of the preservatives, for example, the weight ratio may be 0.5-2:1, but the present invention is not limited thereto.

[0031] In the following examples and comparative examples, the residual oxygen content is detected by using a desktop headspace gas analyzer (the manufacturer of the equipment is AMETEK Trading Co., Ltd., model number is Dansensor CheckMate 3) to detect the residual oxygen.

[0032] The technical solution of the present invention is described below with specific embodiments.

[0033] Example 1

[0034] This embodiment provides a method for preparing phenylephrine hydrochloride eye drops, comprising the following steps:

[0035] The total amount of the eye drops prepared in Example 1 is 50 L, and 25,000 bottles are prepared.

[0036] S1: Add 50% of the total volume of water for injection into the dilution tank, fill with nitrogen to control the dissolved oxygen within 1ppm, add 100g of sodium dihydrogen phosphate, 250g of disodium hydrogen phosphate, 1.25kg of phenylephrine hydrochloride, and 10g of benzalkonium chloride in sequence, stir and dissolve in sequence to obtain a concentrated solution of phenylephrine hydrochloride eye drops.

[0037] S2: Add injection water to the concentrated solution to the total preparation amount, adjust the pH value to 4.0 with 2M hydrochloric acid solution, filter through polyvinylidene fluoride filter elements with pore sizes of 0.45 μm, 0.2 μm, and 0.2 μm in sequence, fill with nitrogen, control the residual oxygen content to 2%, and bag to obtain phenylephrine hydrochloride eye drops.

[0038] Embodiment 2-5

[0039] The preparation method of the phenylephrine hydrochloride eye drops provided in Examples 2-5 is the same as that in Example 1, and the total amount of eye drops prepared is 50 L, and 25,000 drops are prepared. The components and process parameters are shown in Table 1.

[0040] Table 1 Components and process parameters of Examples 2-5

[0041]

[0042]

[0043] Examples 6-10

[0044] The preparation method of the phenylephrine hydrochloride eye drops provided in Examples 6-10 is the same as that in Example 1, and the total amount of eye drops prepared is 150 L, and 10,000 drops are prepared. The components and process parameters are shown in Table 2.

[0045] Table 2 Components and process parameters of Examples 6-10

[0046]

[0047] Examples 11-15

[0048] The preparation method of the phenylephrine hydrochloride eye drops provided in Examples 11-15 is the same as that in Example 1, and the total amount of eye drops prepared is 150 L, and 30,000 drops are prepared. The components and process parameters are shown in Table 3.

[0049] Table 3 Components and process parameters of Examples 11-15

[0050]

[0051]

[0052] Example 16

[0053] This embodiment provides a method for preparing phenylephrine hydrochloride eye drops, comprising the following steps:

[0054] The total amount of eye drops prepared in Example 16 is 50 L, and 25,000 bottles are prepared.

[0055] S1: Add 70% of the total volume of water for injection into the dilution tank, fill with nitrogen to control the dissolved oxygen within 1ppm, add 750g of sodium dihydrogen phosphate, 300g of disodium hydrogen phosphate, 3.93kg of phenylephrine hydrochloride, and 30g of benzalkonium chloride in sequence, stir and dissolve in sequence to obtain a concentrated solution of phenylephrine hydrochloride eye drops;

[0056] S2: Add injection water to the concentrated solution to the total preparation amount, adjust the pH value to 4.0 with 2M boric acid solution, filter through polytetrafluoroethylene filter elements with pore sizes of 0.45 μm, 0.2 μm, and 0.2 μm in sequence, fill with nitrogen, control the residual oxygen content to 3%, and bag to obtain phenylephrine hydrochloride eye drops.

[0057] Comparative Examples 1-9

[0058] In order to investigate the effect of pH value on phenylephrine hydrochloride eye drops, eye drops with other pH values ​​were also prepared, wherein the components and process parameters are shown in Table 4.

[0059] Table 4 Components and process parameters of Comparative Examples 1-9

[0060]

[0061]

[0062] Comparative Examples 10-15

[0063] In order to investigate the effect of nitrogen filling on phenylephrine hydrochloride eye drops, eye drops without nitrogen filling and nitrogen filling only during the preparation stage were prepared, and the components and process parameters are shown in Table 5.

[0064] Table 5 Components and process parameters of Comparative Examples 10-15

[0065]

[0066]

[0067] Test example

[0068] The phenylephrine hydrochloride eye drops prepared in Examples 1-3, Examples 6-8, Examples 11-13 and Comparative Examples 1-9 were exposed to light (the light conditions were: total illumination ≥ 1.2 × 10 6 Lux·hr, near-ultraviolet energy ≥200w·hr / m 2 ), the results are shown in Table 6.

[0069] Table 6 Properties of Examples 1-3, Examples 6-8, Examples 11-13 and Comparative Examples 1-9

[0070]

[0071] It can be seen from the above table that: with the extension of illumination time, the properties of eye drops with a pH value greater than 5.8 changed significantly, and the properties of eye drops with a pH value between 4.0-5.8 hardly changed. It can be seen that when the pH value of the eye drops is between 4.0-5.8, the eye drops are hardly affected by light.

[0072] The effect of temperature (temperature is 60° C.) on the phenylephrine hydrochloride eye drops prepared in Examples 1-3, Examples 6-8, Examples 11-13 and Comparative Examples 1-9 was examined. The results are shown in Table 7.

[0073] Table 7 Properties of Examples 1-3, Examples 6-8, Examples 11-13 and Comparative Examples 1-9

[0074]

[0075]

[0076] It can be seen from the above table that: as the eye drops are placed at a temperature of 60°C for longer time, the properties of the eye drops with a pH value greater than 5.8 change significantly, while the properties of the eye drops with a pH value between 4.0-5.8 remain almost unchanged. It can be seen that when the pH value of the eye drops is between 4.0-5.8, the eye drops are hardly affected by temperature.

[0077] The effect of temperature (temperature is 60° C.) on the phenylephrine hydrochloride eye drops prepared in Example 2, Example 7, Example 12 and Comparative Examples 10-15 was examined. The results are shown in Table 8.

[0078] Table 8 Property results of Example 2, Example 7, Example 12 and Comparative Examples 10-15

[0079]

[0080]

[0081] From the table above, we can see that if the oxygen content in the eye drops is not controlled during the preparation and filling stages, more impurities will be generated as the time at 60°C increases. It can be seen that controlling the oxygen content in the solution during the preparation and filling stages can improve the quality of the eye drops.

[0082] The properties and impurity content of the phenylephrine hydrochloride prepared in Example 1-2 and Comparative Example 1-3 were tested after being stored at 30° C. for 5 months. The results are shown in Table 9.

[0083] Table 9 Properties and impurity content results of Examples 1-2 and Comparative Examples 1-3 after 5 months of storage

[0084]

[0085] It can be seen from the above table that controlling the pH value of eye drops between 4.0-5.8 can improve the quality of eye drops.

[0086] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing phenylephrine hydrochloride eye drops, characterized in that: It consists of the following steps: S1: nitrogen is added to 30%-90% of the total volume of water for injection, and then a buffer solution, a prescribed amount of phenylephrine hydrochloride and a preservative are added in sequence, and stirred to dissolve to obtain a concentrated phenylephrine hydrochloride solution; S2: adding water for injection to the concentrated phenylephrine hydrochloride solution to the total amount of preparation, adjusting the pH to 4.0-5.8, filtering, and filling with nitrogen to obtain phenylephrine hydrochloride eye drops; Wherein, the dissolved oxygen in the water for injection after nitrogen filling is within 1 ppm, and the residual oxygen content of the phenylephrine hydrochloride eye drops is controlled within 5%; In step S1, the preservative is benzalkonium chloride; In step S2, the filter element used for filtration is selected from one or more of polyethersulfone, polytetrafluoroethylene or polyvinylidene fluoride filter elements, and the filter element is a three-stage filter element, and the pore sizes of the three-stage filter element are 0.45 μm, 0.2 μm and 0.2 μm respectively; The concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.025-0.1 g / mL; The buffer is a phosphate buffer.

2. The method for preparing phenylephrine hydrochloride eye drops according to claim 1, characterized in that: In step S2, the pH adjusting agent is selected from one or more of phosphoric acid, hydrochloric acid, boric acid or sodium hydroxide.

3. The method for preparing phenylephrine hydrochloride eye drops according to claim 1, characterized in that: In step S1, the phosphate buffer is sodium dihydrogen phosphate and disodium hydrogen phosphate.

4. The method for preparing phenylephrine hydrochloride eye drops according to claim 1, characterized in that: When the concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.025 g / mL: Each 1000 tubes of eye drops contain the following components: 4-15 g of sodium dihydrogen phosphate, 3-10 g of disodium hydrogen phosphate, 50 g of phenylephrine hydrochloride, 0.2-0.5 g of benzalkonium chloride, and the total volume of the prepared eye drops is 2000 mL; Or, each 1000 tubes of eye drops include the following components: 30-120 g of sodium dihydrogen phosphate, 20-80 g of disodium hydrogen phosphate, 375 g of phenylephrine hydrochloride, 1.5-3.8 g of benzalkonium chloride, and the total volume of the prepared eye drops is 15000 mL.

5. The method for preparing phenylephrine hydrochloride eye drops according to claim 1, characterized in that: When the concentration of phenylephrine hydrochloride in the phenylephrine hydrochloride eye drops is 0.1 g / mL: Every 1000 tubes of eye drops include the following components: 10-40 g of sodium dihydrogen phosphate, 7-30 g of disodium hydrogen phosphate, 500 g of phenylephrine hydrochloride, and 0.4-1.1 g of benzalkonium chloride. The total volume of the prepared eye drops is 5000 mL.

6. A phenylephrine hydrochloride eye drop prepared by the method for preparing phenylephrine hydrochloride eye drop according to any one of claims 1 to 5.

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