Fosphenytoin sodium injection and preparation method thereof

Abstract

The present invention relates to the field of medical technology, and the present invention discloses a fosphenytoin sodium injection and a preparation method thereof, which is composed of fosphenytoin sodium, tromethamine, vitamin E succinate polyethylene glycol ester and a pH regulator, and comprises the following steps: (1): dissolving fosphenytoin sodium in a buffer solution containing tromethamine, hydrochloric acid and / or sodium hydroxide; (2): adding vitamin E succinate polyethylene glycol ester solution to the mixed solution of step (1) to slowly include fosphenytoin sodium; (3): adjusting the pH value of the solution to constant volume, pre-filtering and sterilizing filtration, and then filling the liquid into a medium borosilicate glass tube injection bottle or a medium borosilicate glass ampoule to obtain fosphenytoin sodium injection. The stability of fosphenytoin sodium injection is significantly improved by using vitamin E succinate polyethylene glycol ester to include fosphenytoin sodium, and the preparation process is efficient, rapid and energy-saving; the storage conditions are milder and closer to the pH of human tissue fluid, and more suitable for use.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and more specifically, relates to fosphenytoin sodium injection and a preparation method thereof. Background Art

[0002] The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.

[0003] Phenytoin sodium was first synthesized in 1908 by Heinrich Biltz, a chemistry professor at the University of Kiel in Germany. In 1937, phenytoin sodium was used successfully in animal models of epilepsy and was launched in 1938 under the name of Dilantin, which is effective for almost all types of epilepsy. In 1953, phenytoin sodium injection was launched in the United States as a drug for acute treatment of symptomatic epilepsy. However, as an emergency drug, local pain, redness and swelling at the injection site are unbearable. In 1997, the US FDA discontinued the use of phenytoin sodium injection. Fosphenytoin sodium is a prodrug of phenytoin sodium, which is rapidly hydrolyzed by phosphoesterase in the body and completely converted into phenytoin. The water solubility of fosphenytoin sodium is 4,000 times that of phenytoin sodium, and the pH value of the aqueous solution is 8.6-12, thus overcoming the adverse reactions caused by the clinical use of phenytoin sodium, and thus becoming a new anti-epileptic drug with good efficacy, high safety and low irritation.

[0004] Fosphenytoin sodium, chemical name: Disodium (2,5-dioxo-4,4-diphenylimidazolidin-1-yl) methyl phosphate heptahydrate, molecular formula: C 16 H 13 N2Na2O6P, molecular weight: 406.24.

[0005] In the United States, the FDA approved the marketing of fosphenytoin sodium injection in 1966, with the trade name CEREBYX (stored at 2℃~8℃), the specification is 50mg PE / mL, and the licensee is Parke Davis Div Warner Lambert Co. This product has RLD status and is one of the reference preparations announced by NMPA. In November 2020, the FDA approved the marketing of fosphenytoin sodium injection, with the trade name SESQUIENT (stored at room temperature of 20℃~25℃), the specification is 50mg PE / mL, and the licensee is LUPIN INC. This product has RLD status and is one of the reference preparations announced by NMPA.

[0006] Fosphenytoin sodium contains phosphate and amide groups, which are prone to acid-catalyzed hydrolysis reactions. The lower the pH value, the more obvious the hydrolysis. The original product CEREBYX listed in the United States reduces the hydrolysis rate through low temperature and high pH value. The higher pH value and harsh storage conditions of the original product CEREBYX cause inconvenience in drug storage, transportation and clinical use.

[0007] Chinese patent CN106265501B reports a stable fosphenytoin sodium composition and its preparation. In the invention, sulfobutyl B-cyclodextrin is used to encapsulate the easily hydrolyzed fosphenytoin sodium and adjust the pH value. Compared with the original product at 2 to 8°C, the stability of the drug solution is greatly improved and it can be stored at room temperature (25°C).

[0008] However, the inclusion of sulfobutyl B-cyclodextrin has the problems of long inclusion time and high inclusion temperature, low preparation efficiency and large energy consumption. Summary of the invention

[0009] The purpose of the present invention is to provide a fosphenytoin sodium injection and a preparation method thereof in view of the problems existing in the current prior art, so as to solve the problem that the storage conditions of fosphenytoin sodium injection do not match the safety requirements of actual use scenarios. The provided fosphenytoin sodium injection can be stored at room temperature, and the storage pH is suitable for the physiological pH of the human body, making the transportation and use of the injection easier and safer.

[0010] The technical solution of the present invention is as follows:

[0011] In one aspect, the present invention provides a method for preparing fosphenytoin sodium injection, comprising the following steps:

[0012] Step (1): dissolving fosphenytoin sodium in a buffer solution containing tromethamine, hydrochloric acid and / or sodium hydroxide to form a mixed solution;

[0013] Step (2): adding vitamin E polyethylene glycol succinate (TPGS1000) to the mixed solution of step (1) to slowly include fosphenytoin sodium;

[0014] Step (3): After adjusting the pH value of the solution, the volume is fixed, and after pre-filtration and sterilization filtration, the drug solution is sealed in a medium-borosilicate glass tube injection bottle or a medium-borosilicate glass ampoule to obtain fosphenytoin sodium injection.

[0015] According to a preferred embodiment, the method of adding vitamin E polyethylene glycol succinate (TPGS1000) in step (2) includes a first method and a second method, wherein the first method is to directly add anhydrous vitamin E polyethylene glycol succinate (TPGS1000), and the second method is to add an aqueous solution of vitamin E polyethylene glycol succinate (TPGS1000).

[0016] According to a preferred embodiment, the vitamin E polyethylene glycol succinate (TPGS1000) aqueous solution is prepared by taking an injection amount not exceeding the total preparation amount, adding a prescribed amount of TPGS1000, and stirring to dissolve.

[0017] According to a preferred embodiment, in step (2), when the first method is used for adding, the inclusion time is 1.5 h to 4 h; when the second method is used, the inclusion time is 0.5 h to 3 h.

[0018] According to a preferred embodiment, in the step (3), hydrochloric acid and / or sodium hydroxide may be used to adjust the pH value; in the step (3), pre-filtration and sterilization filtration may be performed using a microporous filter.

[0019] Preferably, the pore size of the microporous filter for pre-filtration is 0.45 μm, and the pore size of the microporous filter for sterilization filtration is 0.22 μm.

[0020] Preferably, the microporous filter includes any one of a polyethersulfone microporous filter, a polyvinylidene fluoride microporous filter, a polytetrafluoroethylene microporous filter, a cellulose acetate microporous filter, and a cellulose nitrate microporous filter.

[0021] According to a preferred embodiment, the buffer solution in step (1) comprises tromethamine, water for injection and hydrochloric acid and / or sodium hydroxide, and the amount of hydrochloric acid and / or sodium hydroxide added is such that the pH value of the tromethamine buffer solution is increased to 6.5 to 7.5.

[0022] According to a preferred embodiment, the amount of water for injection added to the buffer solution in step (1) is 50% to 90%, and the amount of tromethamine added is 1.21 mg / ml to 3.63 mg / ml, preferably 2.42 mg / ml.

[0023] According to a preferred embodiment, the amount of fosphenytoin sodium added in step (2) is 60 mg / ml to 90 mg / ml.

[0024] According to a preferred embodiment, the amount of vitamin E succinate polyethylene glycol ester added in step (2) is 0.1 mg / ml to 20 mg / ml, preferably 0.5 mg / ml to 10 mg / ml, and more preferably 2 mg / ml to 8 mg / ml.

[0025] According to a preferred embodiment, adjusting the pH value of the solution in step (3) is specifically adjusting the pH value of the solution to 7.0-8.5.

[0026] According to a preferred embodiment, the liquid preparation temperature in step (1) and step (2) is not more than 30°C.

[0027] According to a preferred embodiment, the preparation temperature of the vitamin E polyethylene glycol succinate (TPGS1000) aqueous solution is no more than 80° C., and after preparation, the temperature is cooled to below 30° C. for standby use.

[0028] Another aspect of the present invention provides a fosphenytoin sodium injection, which is prepared by the preparation method of fosphenytoin sodium injection as described in the preceding claims.

[0029] On the other hand, the present invention provides an aqueous solution for preparing fosphenytoin sodium medicine, which comprises fosphenytoin sodium, tromethamine, vitamin E succinate polyethylene glycol ester, a pH regulator and water for injection, wherein the content of fosphenytoin sodium is 50-100 mg / ml, the content of tromethamine is 1.21 mg / ml-3.63 mg / ml, the content of vitamin E succinate polyethylene glycol ester is 0.1 mg / ml-20 mg / ml, the pH regulator adjusts the pH value of the medicine solution to 7.0-8.5, and the initial addition amount of water for injection is 50%-90%.

[0030] According to a preferred embodiment, the content of fosphenytoin sodium is 60 mg / ml to 90 mg / ml.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. A fosphenytoin sodium injection and a preparation method thereof. The preparation method of the present application adopts vitamin E succinate polyethylene glycol ester (TPGS1000) to include fosphenytoin sodium injection, the inclusion time is short and the inclusion efficiency is high, and the obtained fosphenytoin sodium injection can be stably stored at a pH value suitable for the human body and room temperature, the stability is greatly improved, the steps of storage, transportation and actual use of fosphenytoin sodium injection are greatly simplified, and the storage stability and convenience of use of fosphenytoin sodium injection are taken into account;

[0033] 2. A fosphenytoin sodium injection and a preparation method thereof. The preparation method of the present application also ensures the stability of fosphenytoin sodium, polyethylene glycol succinate (TPGS1000) and tromethamine after being compatible with each other by adjusting the preparation process and the amount of substances used. By innovatively improving the inclusion substance and the inclusion process, while achieving the improvement of the stability of the injection, the efficiency of the preparation process and the reduction of energy consumption are also ensured. That is, the fosphenytoin sodium injection of the present application achieves the effects of improving the preparation efficiency, reducing the preparation cost, improving the stability of the injection and improving the convenience of the injection, and has the excellent effect of killing four birds with one stone. DETAILED DESCRIPTION

[0034] The specific embodiments listed in the present invention are only examples of the present invention, and the present invention is not limited to the specific embodiments described below. For those skilled in the art, any equivalent modifications and substitutions to the embodiments described below are also within the scope of the present invention. Therefore, the equal transformations and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturers are not specified for all reagents or instruments, they are all conventional products that can be purchased commercially. In order to better illustrate the present invention, numerous specific details are given in the specific embodiments below. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details. In other embodiments, the methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the purport of the present invention.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. Unless otherwise specified, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0036] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0037] Example 1 Preparation of Fosphenytoin Sodium Injection

[0038] The steps include:

[0039] Step (1): taking about 90% of the total amount of injection water, adding a prescribed amount of tromethamine, stirring and dissolving, obtaining a tromethamine buffer solution, controlling the temperature to below 25° C., and setting aside; taking a prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, obtaining a tromethamine buffer solution containing fosphenytoin sodium, and setting aside;

[0040] Step (2): The solution in step (1) is adjusted to pH 8.5 to 9.5 using hydrochloric acid or sodium hydroxide, and then the volume is fixed to 1 ml. After pre-filtration and sterilization filtration using a microporous filter, the liquid is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0041] The formula used in this embodiment is shown in Table 1 below:

[0042] Table 1 Example 1 Formula

[0043]

[0044]

[0045] The performance test results of the fosphenytoin sodium injection prepared in this example are shown in Table 2:

[0046] Table 2 Performance test of fosphenytoin sodium injection prepared in Example 1

[0047]

[0048]

[0049] Example 2 Preparation of Fosphenytoin Sodium Injection

[0050] In this example, the effect of the amount of TPGS1000 added on the stability of fosphenytoin sodium injection was studied by adjusting different amounts of TPGS1000 added.

[0051] The steps include:

[0052] Step (1): taking about 80% of the total amount of water for injection, adding the prescribed amount of tromethamine and hydrochloric acid, stirring and dissolving, obtaining a tromethamine buffer solution for standby use; taking the prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, obtaining a tromethamine buffer solution containing fosphenytoin sodium, for standby use;

[0053] Step (2): Take a prescribed amount of TPGS1000 anhydrous, add it to the tromethamine buffer solution containing phenytoin sodium fos ...

[0054] Step (3): The solution obtained in step (2) is adjusted to pH 8.0 using hydrochloric acid and then fixed to volume. After pre-filtration and sterilization filtration using a microporous filter, the drug solution is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0055] In this embodiment, five groups of formulas were used to prepare five fosphenytoin sodium injections, and the formulas are shown in Table 3 below:

[0056] Table 3 Formulation of Example 2

[0057]

[0058] The performance test results of fosphenytoin sodium injection in experimental groups 2-1 to 2-5 of this embodiment are shown in Table 4 below:

[0059] Table 4 Performance test results of injection solutions prepared by experimental groups 2-1 to 2-5 of Example 2

[0060]

[0061]

[0062]

[0063] According to the data of experimental groups 2-1 to 2-5 in Table 4, the following conclusions can be drawn:

[0064] (1) When the dosage of vitamin E succinate polyethylene glycol ester was within the range of 0.1 mg / ml to 20 mg / ml and under the stability condition of 2 to 8°C, the properties, pH value and related substances of the product did not change significantly and met the internal control standards.

[0065] (2) When the dosage of vitamin E succinate polyethylene glycol ester was in the range of 0.1 mg / ml to 20 mg / ml, under the stability condition of 25°C, the properties and pH value of the product did not change significantly and met the internal control standards; impurity B increased slowly, but the levels of each impurity and total impurities were far below the limit.

[0066] (3) When the dosage of vitamin E succinate polyethylene glycol ester was in the range of 0.1 mg / ml to 20 mg / ml, under the stability condition of 40°C, the properties of the product did not change significantly and met the internal control standards, the pH value decreased slightly and met the internal control standards, and the impurity B and phenytoin increased rapidly, among which phenytoin exceeded the internal control standard at 40°C for 30 days, indicating that under this inclusion method at 40°C, the phenytoin impurity will increase rapidly as the storage time increases within the storage period of 10 to 30 days. This indicates that the sodium fosphenytoin injection prepared in this application is not suitable for long-term storage at a temperature of 40°C or above, and the temperature and holding time need to be controlled.

[0067] Compared with Table 2 above, it can be seen that the prescription of Example 1 does not add vitamin E succinate polyethylene glycol ester to include fosphenytoin sodium, and the pH value of fosphenytoin sodium injection is much different from the pH value of human tissue fluid, which has exceeded the acceptance standard for fosphenytoin sodium injection. In addition, the stability of fosphenytoin sodium at room temperature 25°C and 2-8°C is significantly worse than the stability of fosphenytoin sodium injection in experimental groups 1-5 of Example 2.

[0068] Example 3 Preparation of Fosphenytoin Sodium Injection

[0069] In this example, the pH of fosphenytoin sodium injection was adjusted to study the effect of pH on the stability of fosphenytoin sodium injection.

[0070] The steps include:

[0071] Step (1): taking about 80% of the total amount of water for injection, adding the prescribed amount of tromethamine and hydrochloric acid, stirring and dissolving, obtaining a tromethamine buffer solution for standby use; taking the prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, obtaining a tromethamine buffer solution containing fosphenytoin sodium, for standby use;

[0072] Step (2): Take a prescribed amount of TPGS1000 anhydrous, add it to the tromethamine buffer solution containing phenytoin sodium fos ...

[0073] Step (3): The solution obtained in step (2) is adjusted to a pH of 7.0-8.5 using hydrochloric acid and / or sodium hydroxide, and then the volume is fixed. After pre-filtration and sterilization filtration using a microporous filter, the liquid is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0074] The pH values ​​were adjusted to different values ​​to form experimental groups 3-1 to 3-4, and 4 fosphenytoin sodium injections were prepared. The formulas are shown in Table 5:

[0075] Table 5 Formula of fosphenytoin sodium injection in Example 3

[0076]

[0077] The performance test results of Fosphenytoin Sodium Injection in experimental groups 3-1 to 3-4 are as follows:

[0078] Table 6 Performance test results of fosphenytoin sodium injection in experimental groups 3-1 to 3-4 of Example 3

[0079]

[0080]

[0081]

[0082] As can be seen from Table 6 above:

[0083] (1) Under the stability condition of 2-8°C, the properties, pH value and impurities of the formulations with different pH values ​​did not change significantly and met the internal control standards;

[0084] (2) Under stability conditions of 25°C and 40°C, for formulations with different pH values, the lower the pH value, the slower the growth of impurity B and the faster the growth of phenytoin impurities; on the contrary, the higher the pH value, the faster the growth of impurity B and the slower the growth of phenytoin. The formulation with a pH value of about 8.0 has the best product quality;

[0085] (3) When the pH value of the formulation was 7.0, phenytoin exceeded the internal control standard at 40°C for 10 days, indicating that the pH of this product should not be adjusted to below 7.0.

[0086] In summary, it is proposed to add hydrochloric acid and / or sodium hydroxide as pH adjusters in the prescription of this product to adjust the pH value of the prepared solution to within the range of 7.5 to 8.5, which can ensure that the quality of the drug solution during the stability period meets the internal control standards.

[0087] Example 4 Preparation of Fosphenytoin Sodium Injection

[0088] In this example, different amounts of tromethamine were adjusted to study the effects of different tromethamine contents on the stability of the prepared fosphenytoin sodium injection.

[0089] The steps include:

[0090] Step (1): taking about 80% of the total amount of water for injection, adding the prescribed amount of tromethamine and hydrochloric acid, stirring and dissolving, obtaining a tromethamine buffer solution for standby use; taking the prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, obtaining a tromethamine buffer solution containing fosphenytoin sodium, for standby use;

[0091] Step (2): Take a prescribed amount of TPGS1000 anhydrous, add it to the tromethamine buffer solution containing phenytoin sodium fos ...

[0092] Step (3): The solution obtained in step (2) is adjusted to pH 8.0 using hydrochloric acid and then fixed to volume. After pre-filtration and sterilization filtration using a microporous filter, the drug solution is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0093] The addition amount of tromethamine was adjusted to different experimental groups 4-1 to 4-3, and three fosphenytoin sodium injections were prepared. The formulas are shown in Table 7:

[0094] Table 7 Formula of Fosphenytoin Sodium Injection of Experimental Groups 4-1 to 4-3 in Example 4

[0095]

[0096] The performance test results of fosphenytoin sodium injection in experimental groups 4-1 to 4-3 are shown in Table 8 below:

[0097] Table 8 Performance test results of fosphenytoin sodium injection in experimental groups 4-1 to 4-3 in Example 4

[0098]

[0099]

[0100] It can be seen from Table 8 above that there is no significant difference in product quality for 1.21 mg / ml to 3.63 mg / ml of tromethamine and it meets the internal control standards. Based on risk control, the proposed dosage of 1.21 mg / ml to 3.63 mg / ml of tromethamine can ensure that the product quality meets the requirements.

[0101] Example 5 Preparation of Fosphenytoin Sodium Injection

[0102] In this example, different ways of adding TPGS1000 anhydrate were adjusted to study the effects of different feeding methods on the stability of the prepared fosphenytoin sodium injection; and the effects of different feeding times under the same feeding method on the stability of the prepared fosphenytoin sodium injection.

[0103] The steps include:

[0104] Step (1): taking about 80% of the total amount of water for injection, adding the prescribed amount of tromethamine and hydrochloric acid, stirring and dissolving, obtaining a tromethamine buffer solution for standby use; taking the prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, obtaining a tromethamine buffer solution containing fosphenytoin sodium, for standby use;

[0105] Step (2) is to add TPGS1000 by the first method or the second method:

[0106] The first method is to take a prescribed amount of TPGS1000 anhydrous, add it to the tromethamine buffer solution containing fosphenytoin sodium in step (1), stir and dissolve for 1.5 to 4 hours to include fosphenytoin sodium, and set aside;

[0107] The second method is to take a prescribed amount of TPGS1000 anhydrous substance and dissolve it in advance, then add it to the tromethamine buffer solution containing fosphenytoin sodium in step (1), stir and dissolve it for 0.5 to 3 hours to include fosphenytoin sodium, and set it aside;

[0108] Step (3): The solution obtained in step (2) is adjusted to pH 8.0 using hydrochloric acid and / or sodium hydroxide, and then the volume is fixed. After pre-filtration and sterilization filtration using a microporous filter, the liquid is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0109] Different addition methods of TPGS1000 anhydrous were adjusted to form experimental group 5-1 and experimental group 5-2, and two fosphenytoin sodium injections were prepared. The formulas are shown in Table 9:

[0110] Table 9 Formula of Fosphenytoin Sodium Injection of Experimental Groups 5-1 to 5-2 in Example 5

[0111]

[0112] The performance test results of fosphenytoin sodium injection of experimental groups 5-1 to 5-2 at different time points during the inclusion process are shown in Table 10 below:

[0113] Table 10 Performance test results of fosphenytoin sodium injection in experimental groups 5-1 to 5-2 in Example 5

[0114]

[0115] It can be seen from Table 10 above that there is no significant difference in the quality of the final product obtained by the two feeding methods, but in the actual feeding process, the liquid preparation time of experimental group 5-2 is much less than that of experimental group 5-1, and the TPGS dissolution and inclusion time in experimental group 5-1 is more than 1h. Considering the efficiency of actual large-scale production, the feeding method experimental group 5-2 is proposed.

[0116] Example 6 Preparation of Fosphenytoin Sodium Injection

[0117] In this example, the pH values ​​of different tromethamine buffer solutions were adjusted to study the effect of tromethamine buffer solutions with different pH values ​​on the stability of the prepared fosphenytoin sodium injection.

[0118] The steps include:

[0119] Step (1): taking about 80% of the total amount of water for injection, adding the prescribed amount of tromethamine and hydrochloric acid, stirring and dissolving, adding different amounts of hydrochloric acid solution to adjust the pH value of the tromethamine buffer solution to 6.5-7.5, to obtain a tromethamine buffer solution for standby use; taking the prescribed amount of fosphenytoin sodium, adding it to the tromethamine buffer solution, stirring and dissolving, to obtain a tromethamine buffer solution containing fosphenytoin sodium, for standby use;

[0120] Step (2): Take a prescribed amount of TPGS1000 anhydrous, add it to the tromethamine buffer solution containing phenytoin sodium fos ...

[0121] Step (3): The solution obtained in step (2) is adjusted to pH 8.0 using hydrochloric acid and then fixed to volume. After pre-filtration and sterilization filtration using a microporous filter, the drug solution is filled into a medium borosilicate glass tube injection bottle to obtain fosphenytoin sodium injection.

[0122] The tromethamine buffer solutions adjusted to different pH values ​​were used to form experimental groups 4-1 to 4-3, and three fosphenytoin sodium injections were prepared. The formulas are shown in Table 11:

[0123] Table 11 Formula of Fosphenytoin Sodium Injection of Experimental Groups 6-1 to 6-3 in Example 6

[0124]

[0125] The performance test results of fosphenytoin sodium injection prepared by tromethamine buffer solutions with different pH values ​​were performed on experimental groups 6-1 to 6-3 of fosphenytoin sodium injection as shown in Table 12 below:

[0126] Table 12 Performance test results of fosphenytoin sodium injection in experimental groups 6-1 to 6-3 in Example 6

[0127]

[0128]

[0129]

[0130] It can be seen from Table 12 above that the growth levels of various impurities are basically the same under the same stability conditions after the preparation of the preparation by adjusting the pH value of the tromethamine buffer solution to 6.5-7.5. Therefore, the proposed adjustment of the pH value of the tromethamine solution to 6.5-7.5 can ensure that the API dissolves quickly and the product has good stability after preparation.

[0131] Example 7 Different formulas of fosphenytoin sodium injection and sodium chloride injection (0.9%)

[0132] The compatibility stability of different formulas of fosphenytoin sodium injection and sodium chloride injection (0.9%) is shown in Table 13 below:

[0133] Table 13 Compatibility stability of different formulations of fosphenytoin sodium injection and sodium chloride injection (0.9%)

[0134]

[0135]

[0136] The compatibility stability of different formulas of fosphenytoin sodium injection and glucose injection (5%) is shown in Table 14:

[0137] Table 14 Compatibility stability of different formulas of fosphenytoin sodium injection and glucose injection (5%)

[0138]

[0139] From Table 14 we can see that:

[0140] After using the SESQUIENT reference prescription preparation and the homemade preparation with 0.9% sodium chloride injection and 5% glucose injection respectively, they have good stability at room temperature within 24 hours, and the content of single impurities and total impurities of related substances has almost no change. This shows that the stability of the homemade preparation meets the requirements and is better than that of the SESQUIENT reference prescription preparation.

[0141] In summary, the proposed dosage of vitamin E succinate polyethylene glycol ester is 5 mg / ml for product improvement of fosphenytoin sodium injection, which can improve the stability of the product.

[0142] The above-mentioned embodiments only express the specific implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the protection scope of the present application. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the technical solution concept of the present application, and these all belong to the protection scope of the present application.

Claims

1. An aqueous solution for preparing a fosphenytoin sodium drug, characterized in that: The invention comprises fosphenytoin sodium, tromethamine, vitamin E succinate polyethylene glycol ester, a pH regulator and water for injection, wherein the content of fosphenytoin sodium is 50-100 mg / ml, the content of tromethamine is 1.21 mg / ml-3.63 mg / ml, the content of vitamin E succinate polyethylene glycol ester is 0.1 mg / ml-20 mg / ml, the pH regulator is used to adjust the pH value of the liquid medicine to 7.0-8.5, and the initial addition amount of water for injection is 50%-90%.

2. The aqueous solution for preparing fosphenytoin sodium medicine according to claim 1, characterized in that: The content of fosphenytoin sodium is 60 mg / ml to 90 mg / ml.

3. A method for preparing fosphenytoin sodium injection, characterized in that: The steps include: Step (1): dissolving fosphenytoin sodium in a buffer solution containing tromethamine, hydrochloric acid and / or sodium hydroxide to form a mixed solution; Step (2): adding the vitamin E succinate polyethylene glycol solution to the mixed solution of step (1) to slowly include fosphenytoin sodium; Step (3): After adjusting the pH value of the solution, the volume is fixed, and after pre-filtration and sterilization filtration, the drug solution is sealed in a medium-borosilicate glass tube injection bottle or a medium-borosilicate glass ampoule to obtain fosphenytoin sodium injection.

4. The method for preparing fosphenytoin sodium injection according to claim 3, characterized in that: The method of adding vitamin E polyethylene glycol succinate in step (2) includes a first method and a second method. The first method is to directly add anhydrous vitamin E polyethylene glycol succinate, and the second method is to add an aqueous solution of vitamin E polyethylene glycol succinate.

5. The method for preparing fosphenytoin sodium injection according to claim 4, characterized in that: In the step (3), the pre-filtration and sterilization filtration can be performed using a microporous filter; the pore size of the microporous filter for pre-filtration is 0.45 μm, and the pore size of the microporous filter for sterilization filtration is 0.22 μm.

6. A fosphenytoin sodium injection, characterized in that: The fosphenytoin sodium injection is prepared by the composition and preparation method of any one of claims 2 to 5.

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