Fosphenytoin sodium solid composition, freeze-drying method, and uses thereof

Abstract

The present invention relates to a solid composition of fosphenytoin sodium, a method for freeze-drying fosphenytoin sodium, and uses of the solid composition. The solid composition of fosphenytoin sodium comprises fosphenytoin sodium and at least one carbohydrate. The resulting solid composition of fosphenytoin sodium has excellent stability and can be stored at room temperature. Furthermore, the freeze-drying method of fosphenytoin sodium has a short freeze-drying time, and the resulting product does not sink, has a short reconstitution time, and meets quality requirements for its moisture content. The solid composition of fosphenytoin sodium can be used to treat epilepsy or other convulsive conditions.

Description

[Technical Field]

[0001] The present invention relates to a solid composition of fosphenytoin sodium, a freeze-drying method, and uses thereof. [Background technology]

[0002] Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was approved for marketing by the U.S. FDA in September 1996 and is used to treat and control epilepsy and other types of seizure conditions. Prior to its conversion to phenytoin in the body, fosphenytoin sodium has no pharmacological activity; therefore, its pharmacological effects are due to phenytoin.

[0003] The development of fosphenytoin sodium aims to replace phenytoin. The commercially available formulations of phenytoin sodium injection contain excessive amounts of propylene glycol and a relatively high pH (12), which can cause severe pain at the injection site, hypotension, progressive limb ischemia distal to the infusion site, and other vascular complications, such as "purple glove syndrome." Fosphenytoin sodium, on the other hand, avoids the problems associated with phenytoin sodium.

[0004] Currently, the commercially available dosage form of fosphenytoin sodium is an injectable solution, which must be stored at 2-8°C and should not be stored at room temperature for more than 48 hours. Fosphenytoin sodium injection is unstable at room temperature and is prone to decomposition, resulting in degradation impurities such as diphenylglycine, diphenylhydantoin acid, and phenytoin, which affect its clinical efficacy. Furthermore, storage conditions of 2-8°C increase the transportation and storage costs of fosphenytoin sodium injection. The structures of the main degradation impurities that form during storage of fosphenytoin sodium are shown in Table 1.

[0005] [Table 1]

[0006] In view of this, there is a strong need to develop an alternative dosage form of fosphenytoin sodium that will solve the above problems.

[0007] US Patent Publication No. 4,925,860 discloses a pharmaceutical composition of fosphenytoin sodium. The patent publication states that fosphenytoin sodium is susceptible to decomposition, and that the decomposition products include formaldehyde, 5,5-diphenyl-4-imidazolinone (DIZ), diphenylglycinamide, benzophenone, impurity A, and impurity C. The patent publication explains that a decrease in pH increases the rate of phenytoin production, and that the solubility of impurity C decreases at relatively low pH. Because impurity C is insoluble in water, it precipitates in aqueous fosphenytoin sodium formulations, shortening the shelf life of fosphenytoin sodium and causing particulate matter problems. The patent document teaches that the pH can be maintained between 8.3 and 9.4 using an appropriate organic buffer, such as trometamol, to convert the decomposition product of fosphenytoin sodium primarily to diphenylglycinamide within this pH range, thereby minimizing the occurrence of impurity C and thereby extending the shelf life of fosphenytoin sodium. The pH range of the composition meets the requirements of the United States Pharmacopeia (USP 28). However, the patent does not teach how to avoid the decomposition of fosphenytoin sodium, nor how to obtain a fosphenytoin sodium formulation that can be stored at room temperature.

[0008] Through research by the present inventors, it was found that the pharmaceutical composition prepared according to the formulation described in patent document US Pat. No. 4,925,860 was unstable when stored at 25° C. and 40° C., resulting in the production of impurity B.

[0009] European Patent Publication EP2303228B1 discloses liquid formulations of fosphenytoin sodium containing different buffers. The invention claims aqueous pharmaceutical compositions containing fosphenytoin or a salt thereof and a buffer selected from sodium bicarbonate, sodium phosphate, boric acid, or glycine, and having a pH of less than 8.3. The invention does not teach whether these compositions are stable, nor whether they can be lyophilized to obtain lyophilized compositions stable at room temperature.

[0010] According to the research of the present inventors, it was found that fosphenytoin sodium liquid formulations prepared according to the formulation described in Patent Document EP2303228B1 were unstable when stored at 25°C and 40°C, resulting in the formation of impurity B. Furthermore, it was found that after freeze-drying these liquid formulations, they were still unstable when stored at 25°C and 40°C, resulting in the formation of impurity A.

[0011] Patent document US 6,133,248 describes a pharmaceutical composition with an extended shelf life, which contains fosphenytoin sodium, cyclodextrin, and a pharmaceutically acceptable carrier. According to the patent document, after 10 days at 37°C, approximately 10 μg / mL of impurity C is newly generated. Impurity C is insoluble in aqueous conditions, and in the patent document, cyclodextrin serves to improve the solubility of impurity C but does not affect the rate of generation of the impurity. Furthermore, the patent document does not describe a method for effectively reducing the generation of impurities C and other impurities.

[0012] Patent document WO 9904798A1 describes a freeze-dried fosphenytoin sodium composition that can be reconstituted by adding a pharmaceutically acceptable diluent (most preferably water). According to the patent document, a solubility of over 140 mg / mL is achieved when freeze-dried fosphenytoin sodium prepared in a 100 mM trometamol buffer is reconstituted. However, the patent document does not teach whether freeze-dried formulations of fosphenytoin sodium are stable. According to the inventor's research, impurity A was produced when freeze-dried fosphenytoin sodium compositions containing a buffer (including trometamol) were left at 25°C and 40°C for 14 days.

[0013] A typical freeze-drying process involves the following steps: 1) Product preparation (pretreatment) 2) Freezing the product (prefreezing): Freezing the product to a solid state. 3) First stage drying (sublimation drying): Ice crystals in the product are removed by sublimation. 4) Second stage drying (analysis drying): Part of the remaining moisture in the product is evaporated at a relatively high temperature, so that the remaining moisture can meet the specified requirements. 5) Sealed packaging.

[0014] In the first stage of drying, the material must absorb heat. If the chemical is not heated or if heat is insufficient, the moisture will absorb the chemical's own heat as it sublimes, lowering its temperature and vapor pressure, slowing the sublimation rate, extending the overall drying time, and reducing productivity. If the chemical is overheated, the chemical's sublimation rate will increase, but after offsetting the heat absorbed by the chemical's sublimation, the excess heat will raise the temperature of the frozen chemical itself, causing some or even all of the chemical to melt, resulting in drying collapse and blisters, resulting in overall drying failure. Therefore, in the first stage of drying, it is necessary to provide appropriate heat and maintain the freeze-dried layer below the product's eutectic point to prevent the ice crystals from melting.

[0015] The second stage of drying is also called analytical drying. After the first stage of drying, some moisture remains adsorbed on the capillary walls and polar groups of the dried material, and this moisture is not frozen. When this moisture reaches a certain content, it creates conditions for the growth and reproduction of microorganisms and certain chemical reactions. Experiments have shown that even a low moisture content adsorbed to a monolayer can form a solution of certain compounds, exhibiting mobility and reactivity similar to that of an aqueous solution. Therefore, to improve the storage stability of a product and extend its shelf life, it is necessary to remove as much of this moisture as possible.

[0016] In the general freeze-drying process, the freeze-drying time is extended to remove more moisture from the product, but this prolongs the total freeze-drying time of the product, increasing the time cost of freeze-drying and reducing the efficiency of freeze-drying. Currently, no research has been reported on an efficient freeze-drying method for fosphenytoin sodium. Summary of the Invention

[0017] The present invention aims to provide a solid composition of fosphenytoin sodium that can solve the problem that the fosphenytoin sodium formulations in the prior art are prone to decomposition and cannot be stored at room temperature. Another object of the present invention is to provide an efficient method for freeze-drying fosphenytoin sodium.

[0018] The present invention provides a solid composition of fosphenytoin sodium, characterized by comprising fosphenytoin sodium and at least one carbohydrate.

[0019] Preferably, the solid composition can be stored at room temperature.

[0020] Preferably, the solid composition is a freeze-dried composition.

[0021] Preferably, the carbohydrate is at least one selected from sugars and oligosaccharides.

[0022] Preferably, the sugar is at least one selected from monosaccharides, disaccharides, and sugar alcohols.

[0023] Preferably, the monosaccharide is at least one selected from glucose, galactose, and fructose.

[0024] Preferably, the disaccharide is at least one selected from sucrose, lactose, trehalose, maltose, and isomaltose.

[0025] Preferably, the sugar alcohol is at least one selected from sorbitol, mannitol, xylitol, and maltitol.

[0026] Preferably, the oligosaccharide is at least one selected from raffinose, stachyose, isomaltooligosaccharide, oligofructose, oligomannose, and soybean oligosaccharide.

[0027] Preferably, before freeze-drying, the weight-to-volume ratio of the carbohydrate in the composition is 1 to 20%, preferably 3 to 15%, more preferably 5 to 10%.

[0028] Preferably, the solid composition further comprises a buffering agent.

[0029] Preferably, the buffer is one or more selected from the group consisting of phosphate buffers, hydrogen phosphate buffers, dihydrogen phosphate buffers, bicarbonate buffers, carbonate buffers, borate buffers, borate buffers, amino acid buffers, trialkylamine buffers, trometamol buffers, pyrophosphate buffers, and glycylglycine buffers. Preferably, the phosphates, hydrogen phosphates, dihydrogen phosphates, bicarbonates, carbonates, borates, and pyrophosphates are each independently a sodium salt and / or a potassium salt, and the trialkylamine is trimethylamine.

[0030] Preferably, the concentration of the buffer before freeze-drying is 10 to 150 mM, more preferably 20 to 100 mM.

[0031] Preferably, the solid composition of fosphenytoin sodium has a pH of 8 to 10, preferably 8 to 9.3, and more preferably 8 to 9 before lyophilization or after reconstitution.

[0032] Preferably, the concentration of the fosphenytoin sodium before lyophilization is 75 mg / mL to 150 mg / mL, preferably 75 mg / mL to 100 mg / mL, and more preferably 75 mg / mL or 100 mg / mL.

[0033] Preferably, after reconstitution, the concentration of the fosphenytoin sodium is 75 mg / mL to 150 mg / mL, preferably 75 mg / mL to 100 mg / mL, and more preferably 75 mg / mL.

[0034] Preferably, the fosphenytoin sodium solid composition does not produce impurities A, B and C after 14 days at 25° C. and 60% relative humidity.

[0035] Preferably, the fosphenytoin sodium solid composition does not produce impurities A, B and C after aging at 25° C. and 60% relative humidity for 3 months.

[0036] Preferably, the fosphenytoin sodium solid composition does not produce impurities A, B and C upon standing at 40° C. and 75% relative humidity for 14 days.

[0037] Preferably, the fosphenytoin sodium solid composition does not produce impurities A, B and C when left at 40° C. and 75% relative humidity for 3 months.

[0038] Preferably, the solid composition is a freeze-dried composition, the freeze-dried composition comprising fosphenytoin sodium, a buffer, and at least one carbohydrate, the buffer being selected from trometamol, the carbohydrate being selected from trehalose, sucrose, mannitol, or lactose, and the freeze-dried composition having a pH of 8 to 9 before freeze-drying or after reconstitution.

[0039] Preferably, before lyophilization, the concentration of the fosphenytoin sodium is 75 mg / mL or 100 mg / mL, the concentration of the buffer is 20 to 100 mM, and the weight-to-volume ratio of the carbohydrate in the composition is 5 to 10%.

[0040] In another aspect, the present invention further provides a method for lyophilizing fosphenytoin sodium, wherein the total lyophilization time is reduced by at least 60%, preferably at least 70%, compared to the total lyophilization time of conventional lyophilization methods.

[0041] Preferably, the freeze-drying method includes: (1) a step of preparing a fosphenytoin sodium solution; (2) a step of pre-freezing the fosphenytoin sodium solution; and (3) a step of directly increasing the temperature of a drying plate to a predetermined temperature at a constant temperature increase rate, without separately providing a sublimation drying step and an analytical drying step.

[0042] Preferably, the fosphenytoin sodium solution comprises fosphenytoin sodium and at least one carbohydrate; Preferably, the carbohydrate is at least one selected from a sugar and an oligosaccharide, and the sugar is at least one selected from a monosaccharide, a disaccharide, and a sugar alcohol; Preferably, the monosaccharide is at least one selected from glucose, galactose, and fructose; Preferably, the disaccharide is at least one selected from sucrose, lactose, trehalose, maltose, and isomaltose; Preferably, the sugar alcohol is at least one selected from sorbitol, mannitol, xylitol, and maltitol; Preferably, the oligosaccharide is at least one selected from raffinose, stachyose, isomaltooligosaccharide, oligofructose, oligomannose, and soybean oligosaccharide; Preferably, the weight-to-volume ratio of the carbohydrate is 1 to 20%, preferably 3 to 15%, more preferably 5 to 10%; Preferably, the pH of the fosphenytoin sodium solution is 8 to 10, preferably 8 to 9.3, more preferably 8 to 9; Preferably, the fosphenytoin sodium solution further comprises a buffering agent; Preferably, the buffer is one or more selected from a phosphate buffer, a hydrogen phosphate buffer, a dihydrogen phosphate buffer, a hydrogen carbonate buffer, a carbonate buffer, a borate buffer, a borate buffer, an amino acid buffer, a trialkylamine buffer, a trometamol buffer, a pyrophosphate buffer, and a glycylglycine buffer, and preferably, the phosphate, hydrogen phosphate, dihydrogen phosphate, hydrogen carbonate, carbonate, borate, and pyrophosphate are each independently a sodium salt and / or a potassium salt, and the trialkylamine is trimethylamine, Preferably, the concentration of the buffer is 10 to 150 mM, more preferably 20 to 100 mM, Preferably, the concentration of the fosphenytoin sodium is 75 mg / mL to 150 mg / mL, more preferably 75 mg / mL to 100 mg / mL, and even more preferably 75 mg / mL or 100 mg / mL.

[0043] Preferably, in the freeze-drying method, the preliminary freezing temperature in step (2) is -40 to -60°C, preferably -45 to -55°C, and more preferably -45 to -50°C.

[0044] Preferably, the rate of temperature reduction to the pre-freezing temperature is 0.5 to 6°C / min, preferably 1 to 5°C / min, and more preferably 1 to 1.5°C / min.

[0045] Preferably, in the step (3), the temperature rise rate is 0.01 to 5°C / min, preferably 0.025 to 3°C / min, and more preferably 0.05 to 1.5°C / min.

[0046] Preferably, the temperature of the drying plate is directly raised to 5 to 25°C, more preferably to 10 to 25°C, and even more preferably to 20 to 25°C.

[0047] Preferably, the fosphenytoin sodium solid composition is used for the treatment of epilepsy or other convulsive conditions.

[0048] In another aspect, there is further provided the use of the fosphenytoin sodium solid composition for the manufacture of a medicament for the treatment of epilepsy or other convulsive conditions.

[0049] In another aspect, there is further provided a method for treating epilepsy or other convulsive conditions, comprising administering to a patient in need thereof a therapeutically effective dose of the above-described fosphenytoin sodium solid composition for treating epilepsy or other convulsive conditions.

[0050] In the present specification and claims, unless otherwise specified, the scientific and technical terms used in the present invention have the meanings commonly understood by those skilled in the art. However, to facilitate a better understanding of the present invention, the following definitions and interpretations of some related terms are provided.

[0051] The classification of carbohydrates in the present invention is based on the document "Carbohydrates in human nutrition: Report of a joint FAO / WHO expert consultation, Rome, April 14-18, 1997." Among these, "sugar" refers to saccharides with a degree of polymerization of 1 to 2, including monosaccharides, disaccharides, and sugar alcohols, such as glucose, galactose, fructose, sucrose, lactose, trehalose, maltose, isomaltose, sorbitol, mannitol, xylitol, and maltitol. "Oligosaccharide" refers to saccharides with a degree of polymerization of 3 to 9, including raffinose, stachyose, isomaltooligosaccharide, oligofructose, oligomannose, and soybean oligosaccharide.

[0052] The carbohydrate percentage (%) in the present invention is a weight-to-volume ratio, and the "weight-to-volume ratio" is the weight (unit: g) of the component contained in 100 mL of a liquid system, i.e., g / 100 mL.

[0053] In the present invention, the concentration unit mM of the buffer is a millimolar concentration, and the "millimolar concentration" is the number of millimoles (unit: mmol) of the component contained in 1 L of a liquid system, that is, mmol / L.

[0054] All stability studies in this invention are conducted at 25°C and 60% relative humidity, and at 40°C and 75% relative humidity.

[0055] In the present invention, RP-HPLC stands for reversed-phase high-performance liquid chromatography.

[0056] The detection limit in the present invention is the minimum amount at which an analyte can be detected in a sample. In particular, the detection limit for impurity A in the present invention is 11.0 pg, the detection limit for impurity B is 6.3 pg, and the detection limit for impurity C is 4.5 ng.

[0057] In the present invention, the above-mentioned expressions such as "does not produce impurities," "does not produce impurities A, B, and C," "impurities A, B, and C were not detected, and other impurities were not detected," "does not produce impurities A, B, and C, and other impurities," "no impurities found," and similar expressions all mean that the corresponding impurities in the test sample are below the detection limit.

[0058] In the present invention, the term "undetected" means that the corresponding impurity in the test sample is below the detection limit.

[0059] In the present invention, the impurity content of 0 in FIGS. 2 and 3 means that the corresponding impurity is not detected, that is, the impurity is below the detection limit.

[0060] In the present invention, "N / A" means not applicable.

[0061] In the present invention, the term "PES" means polyethersulfone.

[0062] The water content in the present invention is measured by Karl Fischer titration.

[0063] In the present invention, freeze-drying is carried out using an FTS Lyotar II freeze-dryer.

[0064] The term "reconstitution" in the present invention means dissolving each component of a lyophilized formulation using an aqueous solution (including, but not limited to, ethanol, water, a buffer solution, a sodium chloride solution, an aqueous glucose solution, or a mixture thereof, such as water for injection or physiological saline) to obtain a reconstituted pharmaceutical formulation. The reconstitution of a lyophilized formulation in the present invention can be carried out using technical means generally known to those skilled in the art. Therefore, a reconstituted formulation is obtained after reconstitution of the lyophilized formulation. [Effects of the Invention]

[0065] The fosphenytoin sodium solid composition of the present invention has excellent stability and can be stored at room temperature, whereas commercially available fosphenytoin sodium injections must be stored at 2 to 8°C, and even when stored at such low temperatures, impurities are inevitably generated in the commercially available product.

[0066] The solid composition of fosphenytoin sodium provided as one aspect of the present invention does not produce impurities A, B, or C when left for 14 days under conditions of 25°C and 60% humidity, or 40°C and 75% humidity.

[0067] The solid composition of fosphenytoin sodium provided as another aspect of the present invention does not produce impurities A, B, or C when stored at 2 to 8°C, 25°C and 60% humidity, or 40°C and 75% humidity for 1 month, 2 months, or 3 months.

[0068] In addition, the freeze-drying method of fosphenytoin sodium according to the present invention does not adopt the general freeze-drying method, and does not have separate sublimation drying and analytical drying steps. Instead, the temperature of the drying plate is directly raised to a predetermined temperature (e.g., 20°C) at a constant temperature-rising rate to perform freeze-drying. This ensures that the water content meets the quality requirements, significantly shortens the freeze-drying time, and the resolubility of the freeze-dried product is relatively good, being completely resolubilized within 1 minute, making it convenient for clinical use.

[0069] The freeze-drying process provided as another aspect of the present invention provides a freeze-dried product with stable quality, and does not produce impurities A, B, or C when left for 14 days under conditions of 25°C and 60% humidity or 40°C and 75% humidity.

[0070] The freeze-drying process provided as another aspect of the present invention stabilizes the quality of the freeze-dried product, and does not produce impurities A, B, or C when left at 2 to 8°C, 25°C and 60% humidity, or 40°C and 75% humidity for 1 month, 2 months, or 3 months. [Brief explanation of the drawings]

[0071] [Figure 1] 1 shows histograms of the content of impurity B in the liquid formulations in Test 1 after being left to stand at 25°C and 40°C for 14 days. The histograms on the left corresponding to each sample are graphs of sample data after being left to stand at 25°C for 14 days, and the histograms on the right are graphs of sample data after being left to stand at 40°C for 14 days. [Figure 2] 1 shows histograms of the content of impurity A in the freeze-dried formulations in Test 1 after standing at 25°C and 40°C for 14 days. The histograms on the left corresponding to each sample are graphs of sample data after standing at 25°C for 14 days, and the histograms on the right are graphs of sample data after standing at 40°C for 14 days. [Figure 3] 1 is a histogram of the percentage of total impurities for the liquid and lyophilized formulations in Study 1 after storage at 25° C. and 40° C. for 14 days. [Figure 4] 1 is a chromatogram of the freeze-dried formulation containing glycine in Test 1 after it was left at 40° C. for 14 days. [Figure 5] 1 is an enlarged chromatogram of the freeze-dried formulation containing glycine in Test 1 after being left at 40° C. for 14 days. [Figure 6] This shows the freeze-drying pressure curve (fill volume 1.5 mL) obtained using scale-up freeze-drying process #7-1 in Test 5. The CM line indicates the pressure setting value of the freeze-drying machine, and the Pirani line indicates the pressure monitoring value of the freeze-drying machine. [Figure 7] This is a freeze-drying temperature curve (fill volume 1.5 mL) obtained by freeze-drying using scale-up freeze-drying process #7-1 in Test 5. In this curve, the SHELF SETPT line indicates the temperature setting value of the drying plate, the Left line indicates the temperature monitoring value of the left probe in the freeze-drying machine, and the Right line indicates the temperature monitoring value of the right probe in the freeze-drying machine. [Figure 8]This shows the freeze-drying pressure curve (fill volume 7.5 mL) obtained using scale-up freeze-drying process #7-2 in Test 5. The CM line indicates the pressure setting value of the freeze-drying machine, and the Pirani line indicates the pressure monitoring value of the freeze-drying machine. [Figure 9] This is a freeze-drying temperature curve (fill volume 7.5 mL) obtained by freeze-drying using scale-up freeze-drying process #7-2 in Test 5. In this curve, the SHELF SETPT line indicates the drying plate temperature setting value, the Left line indicates the temperature monitoring value of the left probe in the freeze-drying machine, and the Right line indicates the temperature monitoring value of the right probe in the freeze-drying machine. [Figure 10] 1 is a photograph of the appearance of a representative sample (fill volume: 1.5 mL) of a freeze-dried formulation obtained by freeze-drying using scale-up freeze-drying process #7-1 in Test 5. [Figure 11] 1 is a photograph of the bottom of a representative sample bottle (fill volume 1.5 mL) of a freeze-dried formulation obtained by freeze-drying using scale-up freeze-drying process #7-1 in Test 5. [Figure 12] 1 is a photograph of the appearance of a representative sample (fill volume 7.5 mL) of a freeze-dried formulation obtained by freeze-drying using scale-up freeze-drying process #7-2 in Test 5. [Figure 13] 1 is a photograph of the bottom of a representative sample bottle (fill volume 7.5 mL) of a freeze-dried formulation obtained by freeze-drying using scale-up freeze-drying process #7-2 in Test 5. DETAILED DESCRIPTION OF THE INVENTION

[0072] The following examples are provided to explain the embodiments of the present invention in detail, but these examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0073] Materials and Methods Analytical detection methods The analytical detection method in the present invention is the same as the analytical detection method for fosphenytoin sodium injection described in the United States Pharmacopoeia (USP 42). The specific detection method is reversed-phase high performance chromatography, and the detection conditions are as follows: Chromatography conditions: Instrument: High-performance liquid chromatography Agilent 1290 Infinity Chromatography column: ZORBAX Eclipse SB 80Å Phenyl, 4.6x150mm, 3.5μm Mobile phase: methanol:acetonitrile:buffer (8.2 g / L potassium dihydrogen phosphate solution adjusted to pH 6.5 with 6 mol / L potassium hydroxide solution) = 25:2:73 Elution method: isocratic elution Detection wavelength: 214 nm Sample concentration: 0.15 mg / mL Flow rate: 1.25mL / min Sample injection volume: 40 μL System applicability: Impurity A, Impurity B, Impurity C Separation: The separation between impurities A and B is 4.0 or more. Tailing factor: The tailing factor of the fosphenytoin sodium peak is 1.8 or less %RSD: The relative standard deviation of the peak area of fosphenytoin sodium is 1.0% or less. Theoretical plate number: 2250 or more calculated for the fosphenytoin sodium peak

[0074] (2) Preparation of solutions: Preparation of buffer solution: An 8.2 g / L aqueous solution of potassium dihydrogen phosphate was prepared, and the pH was adjusted to 6.5±0.05 with 6N potassium hydroxide solution.

[0075] Reference sample stock solution A: An appropriate amount of the fosphenytoin sodium reference sample was taken and dissolved in a small amount of methanol, and then diluted with the mobile phase to give a solution containing approximately 0.75 mg of fosphenytoin sodium per mL.

[0076] Reference sample stock solution B: Appropriate amounts of the diphenylglycine (impurity A) reference sample, the diphenylhydantoic acid (impurity B) reference sample, and the phenytoin reference sample (impurity C) were taken, dissolved in methanol, and quantitatively diluted to give a solution containing approximately 7.5 μg of impurity A, approximately 15 μg of impurity B, and approximately 7.5 μg of impurity C per mL.

[0077] Reference sample solution: An appropriate amount of reference sample stock solution A and reference sample stock solution B was taken and quantitatively diluted with buffer solution to obtain a solution containing 150 μg of fosphenytoin sodium, approximately 0.75 μg of impurity A, approximately 1.5 μg of impurity B, and approximately 0.75 μg of impurity C per mL.

[0078] Sample solution (liquid preparation): 7.5 μL of a 100 mg / mL fosphenytoin sodium liquid preparation was taken and diluted to 5 mL with a buffer solution (pH 6.5) containing 10% methanol to obtain a solution containing approximately 150 μg of fosphenytoin sodium per mL.

[0079] Sample solution (lyophilized formulation): 10 μL of the reconstituted solution of 75 mg / mL lyophilized fosphenytoin sodium formulation was taken and diluted to 5 mL with a buffer solution (pH 6.5) containing 10% methanol to obtain a solution containing approximately 150 μg of fosphenytoin sodium per mL.

[0080] pH The pH of fosphenytoin sodium formulation samples was measured using a Thermo Scientific OrionStar Model A 211 pH meter equipped with a Ross PerpHecT microelectrode (model number 8220BNWP). For buffer solution formulations, pH was measured using a triode electrode (Thermo Scientific US Gel-filled Ultra Triode Electrodes). The instrument was calibrated with buffer solutions of pH 4, 7, and 10 before each use.

[0081] Karl Fischer Moisture content was measured using a Mettler Toledo DL36 KF Coulometer and a Mettler Toledo DO305 Drying Oven. The KF-Oven (Sigma, 34784, Lot# SZBD 226AV) instrument was calibrated using Hydranal water standards. Approximately 50 mg of lyophilized powder was transferred to a 3 mL 13 mm vial and capped. The vial containing the lyophilized powder was heated to 100 °C in a drying oven. The remaining water vapor in the sample was bubbled through Hydranal (Sigma, 34836, Lot# SZBE 2830V) containing the catholyte and anolyte reservoirs, and the evolved water vapor was titrated using the Coulomb method.

[0082] Study 1: Stability study of 75 mg / mL fosphenytoin sodium formulations containing different buffers The inventors evaluated the stability of liquid and lyophilized formulations of 75 mg / mL fosphenytoin sodium with and without different buffers at 25°C and 40°C for 14 days.

[0083] [Table 2]

[0084] Preparation method: (1) Add the blended amount of buffer to water for injection, adjust the pH to 8.8 with a pH adjuster, add water for injection to make up to 100 mL, prepare a 100 mM buffer solution, and filter it through a 0.2 μm PES filter membrane. (2) Fosphenytoin sodium was added to the buffer solution prepared in step (1) to prepare a liquid formulation with a concentration of 75 mg / mL of fosphenytoin sodium. This was then poured into a 5 mL syringe in 2 mL portions and freeze-dried using a freeze-drying process to prepare a freeze-dried formulation of fosphenytoin sodium. The freeze-drying parameters of the freeze-dried formulation are shown in Table 3.

[0085] [Table 3]

[0086] Table 4 shows the RP-HPLC analysis results of the concentration and content on day 0 of the liquid formulations of fosphenytoin sodium containing different buffers before lyophilization and the lyophilized formulations after reconstitution. The data showed that the concentrations of both the pre- and post-lyophilization formulations were within the target range. According to the United States Pharmacopeia (USP-42), the allowable content limit for fosphenytoin sodium is 90-110%. The content of the formulation containing glycylglycine (Formulation 5) was slightly higher, at 111-112%.

[0087] [Table 4]

[0088] Tables 5 and 6 show the concentrations and contents of the liquid and lyophilized formulations after leaving them at 25° C. and 40° C. for 14 days. The data show that the liquid and lyophilized formulations were almost at the target concentrations.

[0089] [Table 5]

[0090] [Table 6]

[0091] Tables 7 and 8 show the change in purity of fosphenytoin sodium formulations containing different buffer solutions before and after lyophilization after being left for 14 days.

[0092] [Table 7]

[0093] [Table 8]

[0094] As shown in Table 7 and Figure 1, impurity B was formed in the liquid formulation after standing at 25°C and 40°C for 14 days. As shown in Table 8 and Figure 2, impurity A was formed in the lyophilized formulation after 14 days of storage at 25°C and 40°C. Figure 3 shows the total impurity content of the liquid formulation and the freeze-dried formulation after being left at 25°C and 40°C for 14 days. 4 and 5 show chromatograms of a representative freeze-dried formulation (a freeze-dried formulation containing glycine), which show that impurity A was produced after standing at 40° C. for 14 days.

[0095] Study 2: Study on the effect of carbohydrates on the stability of fosphenytoin sodium formulations This study investigated the effect of carbohydrates on the stability of fosphenytoin sodium formulations, the formulations of which are shown in Table 9.

[0096] [Table 9]

[0097] Preparation method: The fosphenytoin sodium, buffer, and carbohydrate in the above formulation were added to water for injection and stirred to dissolve, and then the pH was adjusted to 8.8±0.1 with a pH adjuster. Water for injection was added to make up to 100 mL, and the solution was filtered through a 0.2 μm PES filter membrane to prepare a liquid formulation of fosphenytoin sodium with the concentration indicated in the formulation. 1 mL of this formulation was poured into a 3 mL syringe and then freeze-dried using the process parameters listed in Table 10.

[0098] [Table 10]

[0099] The experimental results showed that the concentrations of each liquid formulation and freeze-dried formulation on days 0 and 14 were almost at the target concentrations. Based on the RP-HPLC results for each formulation, the RP-HPLC analytical purity on day 0 for both the liquid and lyophilized formulations was 100%. Table 11 shows the impurity status of the liquid and lyophilized formulations of fosphenytoin sodium after leaving them at 25°C and 40°C for 14 days.

[0100] [Table 11]

[0101] A commercially available liquid formulation of fosphenytoin sodium contains 100 mM trometamol and 75 mg / mL fosphenytoin sodium, and the specification discloses that the pH range of the formulation is 8.6 to 9.0. The storage condition of the formulation is 2 to 8°C. A liquid formulation of fosphenytoin sodium (Formulation 10) was prepared according to the commercially available formulation, and its stability was investigated. As shown in Table 11, when stored at 25°C and 40°C, the formulation produced a relatively high content of impurity B due to hydrolysis. Furthermore, when the liquid formulation was freeze-dried and then left at 40°C for 14 days, impurity A was produced.

[0102] Furthermore, after 75 mg / mL lyophilized formulations of fosphenytoin sodium containing water, sodium carbonate, lysine, arginine, or glycine (formulations 8, 10, 12, 14, 16, and 18) were left at 40°C for 14 days, all of them produced impurity A. Of these, the lyophilized formulations of fosphenytoin sodium containing sodium carbonate, lysine, or glycine (formulations 12, 14, and 18) produced impurity C.

[0103] Surprisingly, in the presence of 5% lactose, 5% mannitol, 10% trehalose, or 10% sucrose, no impurities A, B, or C were detected in any of the lyophilized formulations (formulations 9, 11, 13, 15, 17, 19, 20, 21, and 22) after storage at 25°C and 40°C for 14 days, and no other impurities were detected.

[0104] This indicates that no impurities are produced when 75 mg / mL freeze-dried formulations of fosphenytoin sodium containing water, trometamol, sodium carbonate, arginine, lysine, or glycine are left in the presence of carbohydrates at 25°C and 40°C for 14 days. This indicates that carbohydrates in freeze-dried formulations can stabilize fosphenytoin sodium and prevent the formulation from decomposing to produce various impurities such as impurity A.

[0105] Compared with liquid formulations, the freeze-dried formulation disclosed in the present invention has excellent stability without producing impurities after standing at 25°C and 40°C.

[0106] Study 3: Stability study of carbohydrate-containing 100 mg / mL fosphenytoin sodium lyophilized formulations Study 2 showed that a carbohydrate-containing 75 mg / mL lyophilized formulation of fosphenytoin sodium produced no impurities after storage at 40°C for 14 days.

[0107] In this study, the stability of carbohydrate-containing 100 mg / mL lyophilized formulations of fosphenytoin sodium (with or without trometamol) was investigated.

[0108] Generally, the fill volume is one of the important parameters for lyophilization, especially the height of the fill volume. Therefore, we tried to minimize the fill volume of a 500 mg dose by preparing the API at a higher concentration. Although the preparation concentration is higher, the effective dose is still the same or can be reconstituted as needed.

[0109] When the preparation concentration of fosphenytoin sodium was 112.5 mg / mL, the clarity of the formulation containing mannitol was superior to that of the formulations containing trehalose or sucrose, indicating that fosphenytoin sodium had better solubility in mannitol solution, and was completely dissolved in both when diluted to 100 mg / mL.

[0110] The pre-lyophilized solution formulations of 100 mg / mL fosphenytoin sodium with carbohydrate and with or without buffer are shown in Table 12.

[0111] [Table 12]

[0112] Preparation method: The carbohydrate, fosphenytoin sodium, and buffer in the above formulation were added to water for injection and stirred to dissolve, and then the pH was adjusted to 8.8±0.1 with a pH adjuster. Water for injection was added to make up to 100 mL, and the mixture was filtered through a 0.2 μm PES filter membrane to prepare a liquid formulation of fosphenytoin sodium with the concentration indicated in the formulation. 1 mL of this formulation was poured into a 3 mL syringe and then freeze-dried using the process parameters listed in Table 13.

[0113] [Table 13]

[0114] The results of the clarity test showed that the liquid formulation was clear both on day 0 and after being left at 40°C for 14 days, and the lyophilized formulation was clear both on day 0 and after being left at 40°C for 14 days.

[0115] The measured concentrations of each liquid formulation and lyophilized formulation containing 100 mg / mL of fosphenytoin sodium are shown in Table 14. After leaving each liquid formulation and lyophilized formulation at 40°C for 14 days, the concentrations were almost all within the target concentration range.

[0116] [Table 14]

[0117] Table 15 shows the purity of each liquid formulation and freeze-dried formulation after standing at 40°C for 14 days. The purity of each freeze-dried formulation after standing at 40°C for 14 days was 100%.

[0118] [Table 15]

[0119] Table 16 shows the impurity content of each liquid formulation and freeze-dried formulation after leaving them at 40°C for 14 days.

[0120] [Table 16]

[0121] As shown in Table 16, impurity B was observed in each liquid formulation. When 5% mannitol, 10% trehalose, or 10% sucrose was present, each lyophilized formulation of fosphenytoin sodium (100 mg / mL) was left at 40°C for 14 days, unexpectedly, no impurities A, B, or C, as well as other impurities, indicating that the carbohydrates in the lyophilized formulations stabilize fosphenytoin sodium and prevent its degradation.

[0122] Test 4: Study of the freeze-drying process A solution containing 100 mg / mL fosphenytoin sodium, 5% mannitol, and 100 mM trometamol at pH 8.8 was studied with different freeze-drying processes.

[0123] The composition of the fosphenytoin sodium liquid formulation used for lyophilization is shown in Table 17.

[0124] [Table 17]

[0125] Preparation method: Fosphenytoin sodium was dissolved in water for injection at 25°C, and trometamol and mannitol were added to the solution. After stirring to dissolve, the pH was adjusted to 8.8 with 1N HCl or NaOH. Water for injection was added to make up to 100 mL, and the mixture was filtered through a 0.2 μm PES filter membrane to prepare the fosphenytoin sodium liquid formulation shown in the formula. 7.5 mL of the formulation was injected into a 15 mL syringe.

[0126] Each of the liquid formulations prepared by the above methods was freeze-dried using the process parameters listed in Table 18.

[0127] [Table 18]

[0128] The moisture content, reconstitution time and stability of the freeze-dried samples obtained through different freeze-drying processes are shown in Table 19.

[0129] [Table 19]

[0130] The results in Tables 18 and 19 show that the freeze-dried products obtained from the freeze-drying process were all cake-like products with a moisture content of 2.5-3.6%. None of the freeze-dried products produced any impurities even after storage at 2-8°C, 25°C, and 40°C for 14 days.

[0131] The reconstitution times of the freeze-dried products obtained by freeze-drying processes #2 to #6 were all within one minute, while the reconstitution time of the freeze-dried product obtained by freeze-drying process #1 was relatively long. The total freeze-drying time for the conventional freeze-drying processes (freeze-drying processes #1 to #4) is approximately four to six days. Surprisingly, the freeze-drying times for freeze-drying processes #5 and #6 of the present invention were very fast, shortening the freeze-drying time to approximately two days. Compared to the freeze-drying times of the conventional freeze-drying processes (#2, #3, #4), which were at least 141 hours, the freeze-drying times of the freeze-drying processes of the present invention (#5 and #6) were reduced by at least 60%, with freeze-drying process #5 reducing the freeze-drying time by approximately 64% and freeze-drying process #6 reducing the freeze-drying time by approximately 69%. (Time reduction for freeze-drying process #5 = {[(freeze-drying time for freeze-drying process #4 - freeze-drying time for freeze-drying process #5) / freeze-drying time for freeze-drying process #4] x 100% and time reduction for freeze-drying process #6 = [(freeze-drying time for freeze-drying process #4 - freeze-drying time for freeze-drying process #6) / freeze-drying time for freeze-drying process #4] x 100%.

[0132] Table 20 shows the appearance, reconstitution time, and pH of the freeze-dried samples obtained by freeze-drying process #6 on day 0 and after 14 days of storage under different conditions.

[0133] [Table 20]

[0134] The results in Table 20 show that the lyophilized product prepared according to the #6 lyophilization process showed no change in appearance on day 0 compared to samples stored at 2-8°C, 25°C, and 40°C for 14 days. All samples were white and cake-like, without any pitting. The lyophilized product was reconstituted in a 75 mg / mL fosphenytoin sodium solution using water for injection, and the reconstitution time for all products was less than one minute. After reconstitution, the lyophilized product was clear, colorless, and free of particles, with a pH of 8.8-9.0, which was the target value.

[0135] Table 21 shows the RP-HPLC analysis results of the freeze-dried samples obtained in freeze-drying process #6 on day 0 and after 14 days of storage under different conditions.

[0136] [Table 21]

[0137] The results in Table 21 show that the formulations before and after lyophilization did not produce any impurities on day 0, and the concentrations and contents all met the requirements of the United States Pharmacopoeia (USP 42). The lyophilized formulations left at 2-8°C, 25°C, and 40°C for 14 days all had 100% purity, and did not produce impurities A, B, C, or other impurities.

[0138] Test 5: Scale-up freeze-drying study The composition of the fosphenytoin sodium liquid formulation used for lyophilization is shown in Table 22.

[0139] [Table 22]

[0140] Preparation of solutions before lyophilization: Fosphenytoin sodium was dissolved in water for injection at 40°C, and trometamol and mannitol were added to the solution. After stirring to dissolve, the pH was adjusted to 8.8 with 1N HCl or NaOH, and the solution was made up to 1 L with water for injection. The solution was then filtered through a 0.2 μm PES filter membrane to prepare a liquid formulation of fosphenytoin sodium at the concentration indicated in the formulation.

[0141] Scale-up Freeze-Drying Process #7-1 1.5 mL of the solution before freeze-drying was poured into a 5 mL syringe and freeze-dried using the process parameters shown in Table 23.

[0142] [Table 23]

[0143] Environmental temperature: 20℃ Scale-up Freeze-Drying Process #7-2 7.5 mL of the solution before freeze-drying was poured into a 15 mL syringe and freeze-dried using the process parameters shown in Table 24.

[0144] [Table 24]

[0145] The freeze-drying process operation is as follows: Samples were placed at 20°C and pre-frozen by ramping the drying plate temperature to -50°C at a rate of 1.5°C / min. The formulations were frozen at -50°C for 3 hours. The freeze-dryer pressure was set to 75 mTorr, and the drying plate temperature was increased to 20°C at a rate of 1.5°C / min. Once the Pirani pressure reached the set pressure, the drying plate temperature was increased to 30°C at a rate of 1.5°C / min. Data showed that samples prepared according to scale-up freeze-drying process #7-1 (1.5 mL fill volume) completed the freeze-drying process in less than 2 days. Samples prepared according to scale-up freeze-drying process #7-2 (7.5 mL fill volume) completed the freeze-drying process in less than 3 days.

[0146] Temperature and pressure curves for scaled-up freeze-drying processes The temperature and pressure curves of the scaled-up freeze-drying processes #7-1 and #7-2 are shown in Figures 6 to 9.

[0147] The 1.5 mL packed volume sample reached a Pirani pressure of 75 mTorr after 20 hours and was dried for 30 hours before secondary drying at 30°C. More water was released during the secondary drying process at 30°C, as evidenced by the increase in Pirani pressure.

[0148] The 7.5 mL packed volume sample reached a Pirani pressure of 75 mTorr after 30 hours and was dried for 38 hours before secondary drying at 30°C. More water was released during the secondary drying process at 30°C, as evidenced by the increase in Pirani pressure.

[0149] According to the temperature curve data of the scaled-up freeze-drying processes 7-1 and 7-2, during the drying process, the product with a 1.5 ml filling volume was kept at -20°C for about 4 hours, and the product with a 7.5 mL filling volume was kept at -20°C for about 10 hours.

[0150] In the scaled-up freeze-drying process, freeze-dried samples on day 0 were white, slightly cracked cakes with no collapse (Figures 10-13), with reconstitution times of approximately 56-70 seconds and moisture contents of approximately 2-3%. After storing the freeze-dried samples at 2-8°C, 25°C, and 40°C for 1 month, they remained white, slightly cracked cakes, with moisture contents of approximately 3% for 7.5 mL fill volumes and approximately 3-6% for 1.5 mL fill volumes, and with reconstitution times of approximately 31-88 seconds for 7.5 mL fill volumes (Table 25).

[0151] [Table 25]

[0152] The lyophilized preparation was reconstituted with water for injection to prepare a 75 mg / mL fosphenytoin sodium solution. After reconstitution of the samples on day 0 and those left standing for 1 month at 2 to 8°C, 25°C, and 40°C, the pH was 8.8 to 8.9, with no significant changes (Table 26).

[0153] [Table 26]

[0154] Table 27 shows the RP-HPLC analysis results of the formulations obtained in the scaled-up lyophilization processes #7-1 and #7-2. The liquid and lyophilized formulations on day 0 were free of impurities A and B. The formulations were at the target concentrations.

[0155] [Table 27]

[0156] Tables 28 to 30 show the RP-HPLC analysis results of the lyophilized formulations after storage for 1 month, 2 months, and 3 months at 2 to 8°C, 25°C, and 40°C. The data show that no impurities were generated after storage of the lyophilized formulations at 2 to 8°C, 25°C, and 40°C for 3 months.

[0157] [Table 28]

[0158] [Table 29]

[0159] [Table 30]

Claims

1. A solid composition of fosphenytoin sodium comprising fosphenytoin sodium and at least one carbohydrate selected from monosaccharides, disaccharides, and sugar alcohols, the monosaccharide is at least one selected from glucose, galactose, and fructose; the disaccharide is at least one selected from sucrose, lactose, trehalose, maltose, and isomaltose; The sugar alcohol is at least one selected from sorbitol, mannitol, xylitol, and maltitol; The fosphenytoin sodium solid composition is a lyophilized composition, A solid composition of fosphenytoin sodium, characterized in that the carbohydrate is present in an amount of 5-10% by weight to volume of the composition prior to freeze-drying.

2. 2. The fosphenytoin sodium solid composition of claim 1, wherein the fosphenytoin sodium solid composition can be stored at room temperature.

3. The solid composition of fosphenytoin sodium according to claim 1 or 2, further comprising a buffering agent.

4. 4. The solid composition of fosphenytoin sodium according to claim 3, wherein the buffer is one or more selected from the group consisting of phosphate buffers, hydrogen phosphate buffers, dihydrogen phosphate buffers, bicarbonate buffers, carbonate buffers, borate buffers, borate buffers, amino acid buffers, trialkylamine buffers, trometamol buffers, pyrophosphate buffers, and glycylglycine buffers.

5. The solid composition of fosphenytoin sodium according to any one of claims 1 to 4, wherein the solid composition of fosphenytoin sodium has a pH of 8 to 10 before lyophilization or after reconstitution.

6. 6. The solid composition of fosphenytoin sodium according to claim 1, wherein the concentration of fosphenytoin sodium before lyophilization is 75 mg / mL to 150 mg / mL.

7. 7. The solid composition of fosphenytoin sodium according to claim 1, wherein the concentration of fosphenytoin sodium after reconstitution is 75 mg / mL to 150 mg / mL.

8. The solid composition of fosphenytoin sodium according to any one of claims 1 to 7, wherein the solid composition of fosphenytoin sodium does not produce impurities A, B, or C after standing at 25°C and 60% relative humidity for 14 days. 【Chemical 1】

9. The solid composition of fosphenytoin sodium according to any one of claims 1 to 7, wherein the solid composition of fosphenytoin sodium does not produce impurities A, B, or C after being left at 40°C and 75% relative humidity for 14 days. 【Chemistry 2】

10. The solid composition of fosphenytoin sodium according to any one of claims 1 to 9, wherein the solid composition is a freeze-dried composition comprising fosphenytoin sodium, a buffer, and at least one carbohydrate, wherein the buffer is selected from trometamol, the carbohydrate is selected from trehalose, sucrose, mannitol, or lactose, and the freeze-dried composition has a pH of 8 to 9 before freeze-drying or after reconstitution.

11. 11. The solid composition of fosphenytoin sodium according to claim 10, wherein, before lyophilization, the concentration of the fosphenytoin sodium is 75 mg / mL or 100 mg / mL, the concentration of the buffer is 20-100 mM, and the weight-to-volume ratio of the carbohydrate in the composition is 5-10%.

12. 2. The freeze-drying method for a solid composition of fosphenytoin sodium according to claim 1, comprising: (1) a step of preparing a fosphenytoin sodium solution; (2) a step of pre-freezing the fosphenytoin sodium solution; and (3) a step of directly raising the temperature of a drying plate to a predetermined temperature at a constant temperature increase rate, without separately providing a sublimation drying step and an analytical drying step, wherein the total freeze-drying time is reduced by 60% or more compared to the total freeze-drying time of conventional freeze-drying methods.

13. 13. The freeze-drying method of claim 12, wherein the fosphenytoin sodium solution comprises fosphenytoin sodium and at least one carbohydrate.

14. The freeze-drying method according to claim 12 or 13, wherein the preliminary freezing temperature in the step (2) is −40 to −60° C.

15. A solid composition of fosphenytoin sodium according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of epilepsy or other convulsive conditions.

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