Indian Patents. 265990:"A BUTYLPHTHALIDE INTRAVENOUS EMULSION"

Title of Invention	"A BUTYLPHTHALIDE INTRAVENOUS EMULSION"
Abstract	The present invention discloses a butylphthalide intravenous emulsion for intravenous injection or infusion, containing butylphthalide as an active ingredient in an amount of 0.01~50Wt% and an excipient in an amount of 50-99.99wt%, based on the total weight of the emulsion.

Full Text	BUTYLPHTHALIDE INTRAVENOUS EMULSION AND APPLICATION THEREOF FIELD OF INVENTION The present invention relates to a butylphthalide preparation, and specifically to a butylphthalide intravenous emulsion and application thereof. BACKGROUND OF THE INVENTION dl-3-n-Butylphthalide (NBP) also called butylphthalide is dl-3-butylisobenzofuran-l(3H)-one, which is a raceme. 1-3-n-Butylphthalid is extracted from celery seeds. NBP acts on multiple steps of cerebral ischemia procedure, such as reducing infarct area after focal cerebral ischemia, increasing cerebral blood flow in ischemic area and improving microcirculation in cerebral ischemic area, protecting mitochondrial function, alleviating damage to nerve function, and improving cerebral energy metabolism after total cerebral ischemia. Chinese Patent Nos. 98125618.X, 03137457.3, 200310100222.2 and 200410001748.X respectively disclose the applications of butylphthalide in anti-thrombus and anti-platelet aggregation, the application of 1-n-butylphthalide in prevention and treatment of dementia, cerebral infarction and in manufacture of medicaments for treatment of cerebral ischemia. Currently butylphthalide preparations available in market are only soft capsules. Since butylphthalide is of an oily liquid form, it can be dissolved in an oil phase or directly processed to form an emulsion, then can be packaged in hard capsules or soft capsules, or can be orally administered directly. However, butylphthalide has a relatively apparent first pass effect which leads to a relatively low bioavailability. In addition, cerebral ischemia patients usually are companied with dysphagia or coma, so that capsules cannot meet the clinical requirements for these patients. For cerebral ischemia patients, time is life. Therefore, it is vital to develop a new delivery system suitable for clinical application. SUMMARY OF THE INVENTION Since butylphthalide is an oily liquid and hardly dissoluble in water, a specific manufacture technology is employed in the present invention to process butylphthalide into an emulsion for intravenous administration. The butylphthalide intravenous emulsion of the present invention has the following advantages: the drug directly enters into systemic circulation, thus resulting in quick action; the solubility of butylphthalide is improved, resulting in a reduced dosage; and/or the targeting of butylphthalide to brain tissue is improved, thus reducing its toxic side-effects. The emulsion of the present invention has a particle size of between 10 and 2000 nm, and may be administered via intravenous injection or infusion in order to achieve quick action and brain targeting effect. The butylphthalide intravenous emulsion of the present invention comprises butylphthalide or derivatives thereof as an active ingredient in an amount of 0.01~50wt%, preferably 0.01~20wt%, more preferably 0.01-10wt%, and an excipient in an amount of 50~99.99wt%, preferably 80~99.9wt%, more preferably 90-99.5%, based on the total weight of the emulsion. The excipient comprises an oil phase, an aqueous phase, an emulsifier, a stabilizer and/or an osmoregulation agent. Butylphthalide or derivatives thereof may be either a raceme of butylphthalide or derivatives thereof, or /-butylphthalide or derivatives thereof. The excipient may comprise an oil phase in an amount of 0~50wt%, preferably 0.1~40wt%, an aqueous phase in an amount of 50~98wt%, preferably 60~97wt%, an emulsifier in an amount of 0.01~50wt%, preferably 0.5~10wt%, a stabilizer in an amount of 0~50wt%, preferably 0~15wt%, and an osmoregulation agent in an amount of 0~10wt%, all based on the total weight of the excipient. The process for manufacture of the butylphthalide intravenous emulsion of the present invention comprises the steps of, such as preparing a primary emulsion, homogenizing, sterilizing and quality controlling. The step of preparing the primary emulsion is carried out by utilizing ultrasonic method or high-speed shearing method (FA25 Model High Shear Emulsifying Machine, FLUKO Equipment Shanghai Co., Ltd.). The step of homogenizing is carried out by utilizing a two-stage high pressure emulsifying and homogenizing method (Niro-Soavi NS1001L Model High Pressure Homogenizer and Avestin EmulsiFlex-C5 High Pressure Homogenizer) or microfluidizing technology. The step of sterilizing is carried out by using high pressure sterilizing under rotation. The quality controlling is mainly carried out by measuring particle size. DETAILED DESCRIPTION OF THE INVENTION (1) Selection of oil phase In the emulsion of the present invention, the oil phase generally has an amount in mass of 0-50% (w/v). It is required in the present invention that a therapeutically effective amount of drug should be dissolved in a relatively small amount of oil phase, no drug precipitate occurs or no layer separation occurs under cryogenic storage condition, and in the meantime a stable emulsion is able to be formed with an aqueous phase in the presence of an emulsifier. The oil phase as used in the present invention may be a natural vegetable oil with long chain fatty acid ester groups or a vegetable oil or fatty acid ester being subjected to structure modification and hydrolysis. The examples of those may be one of or a mixture of soybean oil (especially in injection grade), castor oil, tea-seed oil, peanut oil, cottonseed oil, sesame oil, rape oil, safflower oil, olive oil, coconut oil, palm oil and cacao oil; or may be a glyceride with a chain length of C6-C12 fatty acid, such as but not limited to Arlacel 80, Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, glyceride oleate, glyceride linoleate, macrogol glyceryl laurate, ethyl oleate, ethyl linoleate, caprylocaproyl triglyceride, and a mixture thereof; or may be a mixture of the above long chain fatty acid esters and medium-chain fatty acid esters. During the manufacture of an injection emulsion, a preferred oil phase has relatively little haemolysis effect and is refined. Besides generally used vegetable oils, the following oils may also be used in the present invention: Arlacel 80 (HLB=4.3) Sorbitan monooleate Arlacel 86 (HLB=2.8) Glyceride oleate: propylene glycol (90:10) Capmul MCM (HLB=5.5-6.0) Coconut oil C8/C10 monoglyceride or diglyceride Captex 200 (oil) Coconut oil C8/C10 propylene glycol diester Captex 355 (oil) Coconut oil C8/C10 triglyceride Miglyol812(oil) Coconut oil C8/C10 triglyceride Myvacet (oil) Purified and acetylated monoglyceride Myverol 18-92 (HLB-3-7) Purified sunflower oil monoglyceride (containing 90% of glyceride linoleate) Peceol (HLB=3) Glyceride oleate Maisine (HLB=3) Glyceride linoleate Gelucire 44/14 (HLB=14) Macrogol glyceryl laurate (2) Selection of emulsifier The emulsifier as used in the present invention may be one of or a mixture of nonionic surfactants and anionic surfactants.. The preferred emulsifier may be but not limited to one of or a mixture of soybean lecithin or modified soybean lecthin (natural or synthesized), ovolecithin or modified ovolecithin (natural or synthesized), Ophase 31, Poloxamer 108, Poloxamer 188, Poloxamer 407, polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG-400 monostearate, PEG-1750 monostearate, Tween-80, Tween-20, and Span-20. It is preferred to use a mixture of these emulsifiers. During the manufacture of an injection emulsion, the preferred emulsifier has relatively little haemolysis effect and is refined. Besides the above emulsifiers, the following may also be used in the butylphthalide emulsion of the present invention: Ophase 31 (HLB=4) Liquid lecithin Soybean lecithin (HLB=4/7/9) Soybean lecithin Cremophor EL (HLB= 13.5) Polyoxyethylene castor oil Poloxamer 108 (HLB=30.5) Polyoxyethylene polyoxypropylene ether F-38 Poloxamer 188 (HLB=29) Polyoxyethylene polyoxypropylene ether F-68 Poloxamer 407 (HLB=21.5) Polyoxyethylene polyoxypropylene ether F-127 Tween 80 (HLB=15) Polyoxyethylene sorbitan monoleate Tween 20 (HLB=16.7) Polyoxyethylene sorbitan monolaurate Span20(HLB=8.6) Sorbitan monolaurate (3) Selection of stabilizer Suitable stabilizer as used in the present invention may be but not limited to one of or a mixture of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and sodium salt thereof, vitamin A, vitamin C, and vitamin E. (4) Selection of osmoregulation agent Suitable osmoregulation agent as used in the present invention may be but not limited to one of or a mixture of sodium chloride, glucose, sorbitol, xylitol, mannitol, and glycerol. (5) Basic formulation of butylphthalide intravenous emulsion In the butylphthalide intravenous emulsion of the present invention, the ratio of butylphthalide : oil phase : emulsifier : aqueous phase : stabilizer : osmoregulation agent is any ratio (by weight) within the range of 0.01~50wt% : 0~50wt% : 0.01~50wt% : 50~98wt% : 0~50wt% : 0~10wt%. In one embodiment, the butylphthalide intravenous emulsion of the present invention has the following composition: Butylphthalide lOg Oil phase lOOg Emulsifier 50g Stabilizer 50g Aqueous phase Added to 1000ml DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 10 Soybean lecithin 12 Soybean oil 100 Vitamin E 1 Sorbitol 25 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and sorbitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121 °C for 15min. Nitrogen gas is fed for protection during the whole process. Example 2: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 15 Castor oil 100 Soybean lecithin 12 Poloxamer 188 6 Glycerol 25 Oleic acid 10 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and castor oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 3: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 20 Soybean lecithin 12 Olive oil 100 Cholic acid 1 Mannitol 20 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, cholic acid and olive oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and mannitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was treated with ultrasonic waves for 10 times (10 seconds for each time, power: 400W). Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 4: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 25 Cottonseed oil 100 Ovolecithin 12 Poloxamer 188 20 Glycerol 25 Sodium oleate 10 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and cottonseed oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 5: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 30 Soybean lecithin 12 Soybean oil 200 Tween 80 6 Vitamin E 8 Xylitol 100 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, Tween 80, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and xylitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 6: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 40 Caprylocaproyl triglyceride 200 Soybean lecithin 12 Poloxamer 188 20 Glycerol 25 Oleic acid 10 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and caprylocaproyl triglyceride were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 7: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 50 Soybean lecithin 15 Sesame oil 100 Vitamin E 8 Glycerol 22.5 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, vitamin E and sesame oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 8: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 20 Soybean oil 100 Ovolecithin 12 Poloxamer 188 20 Glycerol 25 Sodium oleate 10 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 9: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 100 Ovolecithin 20 Poloxamer 188 20 Glycerol 25 Sodium oleate 30 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, ovolecithin and sodium oleate were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 10: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 0.1 Soybean oil 100 Ovolecithin 19 Poloxamer 188 25 Glycerol 25 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, ovolecithin and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. Example 11: Preparation of butylphthalide intravenous emulsion Formula composition (g) Butylphthalide 5 Soybean oil 100 Ovolecithin 12 Poloxamer 188 20 Sodium oleate 3 Water for injection Added to 1000ml The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 was weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process. We claim: 1. A butylphthalide intravenous emulsion comprising butylphthalide as an active ingredient in an amount of 0.01~50wt% and an excipient in an amount of 50~99.99wt%, based on the total weight of the emulsion, wherein the excipient comprises an oil phase in an amount of 0.1-40wt%, an aqueous phase in an amount of 50-98wt%, an emulsifier in an amount of 0.01-50wt%, a stabilizer in an amount of 0-50wt%, and an osmoregulation agent in an amount of 0-10wt%, based on the total weight of the excipient, provided that the sum of the composition in the excipient does not exceed 100%; the oil phase comprises a natural vegetable oil with long chain fatty acid ester groups, or a vegetable oil or fatty acid ester being subjected to structure modification and hydrolysis, or glyceride with a chain length of C6~C12 fatty acid, or a mixture thereof. 2. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the butylphthalide is a raceme of butylphthalide, or /-butylphthalide. 3.The butylphthalide intravenous emulsion as claimed in claim 1, wherein the oil phase is one of or a mixture of soybean oil, castor oil, tea-seed oil, peanut oil, cottonseed oil, sesame oil, rape oil, safflower oil, olive oil, coconut oil, palm oil, cacao oil, Arlacel 80, Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, glyceride oleate, glyceride linoleate, macrogol glyceryl laurate, ethyl oleate, ethyl linoleate, and caprylocaproyl triglyceride,. 4. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the emulsifier comprises one of or a mixture of nonionic surfactants and anionic surfactants. 5. The butylphthalide intravenous emulsion as claimed in claim 4, wherein the emulsifier is one of or a mixture of soybean lecithin or modified soybean lecthin, ovolecithin or modified ovolecithin, Ophase 31, Poloxamer 108, Poloxamer 188, Poloxamer 407, polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG-400 monostearate, PEG-1750 monostearate, Tween-80, Tween-20, and Span-20. 6. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the stabilizer is one of or a mixture of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and sodium salt thereof, vitamin A, vitamin C, and vitamin E. 7. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the osmoregulation agent is one of or a mixture of sodium chloride, glucose, sorbitol, xylitol, mannitol, and glycerol.

Full Text

BUTYLPHTHALIDE INTRAVENOUS EMULSION AND APPLICATION THEREOF
FIELD OF INVENTION
The present invention relates to a butylphthalide preparation, and specifically to a butylphthalide intravenous emulsion and application thereof.
BACKGROUND OF THE INVENTION
dl-3-n-Butylphthalide (NBP) also called butylphthalide is
dl-3-butylisobenzofuran-l(3H)-one, which is a raceme. 1-3-n-Butylphthalid is extracted from celery seeds. NBP acts on multiple steps of cerebral ischemia procedure, such as reducing infarct area after focal cerebral ischemia, increasing cerebral blood flow in ischemic area and improving microcirculation in cerebral ischemic area, protecting mitochondrial function, alleviating damage to nerve function, and improving cerebral energy metabolism after total cerebral ischemia. Chinese Patent Nos. 98125618.X, 03137457.3, 200310100222.2 and 200410001748.X respectively disclose the applications of butylphthalide in anti-thrombus and anti-platelet aggregation, the application of 1-n-butylphthalide in prevention and treatment of dementia, cerebral infarction and in manufacture of medicaments for treatment of cerebral ischemia.
Currently butylphthalide preparations available in market are only soft capsules. Since butylphthalide is of an oily liquid form, it can be dissolved in an oil phase or directly processed to form an emulsion, then can be packaged in hard capsules or soft capsules, or can be orally administered directly. However, butylphthalide has a relatively apparent first pass effect which leads to a relatively low bioavailability. In addition, cerebral ischemia patients usually are companied with dysphagia or coma, so that capsules cannot meet the clinical requirements for these patients. For cerebral ischemia patients, time is life. Therefore, it is vital to develop a new delivery system suitable for clinical application.

SUMMARY OF THE INVENTION
Since butylphthalide is an oily liquid and hardly dissoluble in water, a specific manufacture technology is employed in the present invention to process butylphthalide into an emulsion for intravenous administration. The butylphthalide intravenous emulsion of the present invention has the following advantages: the drug directly enters into systemic circulation, thus resulting in quick action; the solubility of butylphthalide is improved, resulting in a reduced dosage; and/or the targeting of butylphthalide to brain tissue is improved, thus reducing its toxic side-effects.
The emulsion of the present invention has a particle size of between 10 and 2000 nm, and may be administered via intravenous injection or infusion in order to achieve quick action and brain targeting effect.
The butylphthalide intravenous emulsion of the present invention comprises butylphthalide or derivatives thereof as an active ingredient in an amount of 0.01~50wt%, preferably 0.01~20wt%, more preferably 0.01-10wt%, and an excipient in an amount of 50~99.99wt%, preferably 80~99.9wt%, more preferably 90-99.5%, based on the total weight of the emulsion. The excipient comprises an oil phase, an aqueous phase, an emulsifier, a stabilizer and/or an osmoregulation agent. Butylphthalide or derivatives thereof may be either a raceme of butylphthalide or derivatives thereof, or /-butylphthalide or derivatives thereof.
The excipient may comprise an oil phase in an amount of 0~50wt%, preferably 0.1~40wt%, an aqueous phase in an amount of 50~98wt%, preferably 60~97wt%, an emulsifier in an amount of 0.01~50wt%, preferably 0.5~10wt%, a stabilizer in an amount of 0~50wt%, preferably 0~15wt%, and an osmoregulation agent in an amount of 0~10wt%, all based on the total weight of the excipient.
The process for manufacture of the butylphthalide intravenous emulsion of the present invention comprises the steps of, such as preparing a primary emulsion, homogenizing, sterilizing and quality controlling. The step of preparing the primary emulsion is carried out by utilizing ultrasonic method or high-speed shearing method (FA25 Model High Shear Emulsifying Machine, FLUKO Equipment Shanghai Co., Ltd.). The step of homogenizing is

carried out by utilizing a two-stage high pressure emulsifying and homogenizing method (Niro-Soavi NS1001L Model High Pressure Homogenizer and Avestin EmulsiFlex-C5 High Pressure Homogenizer) or microfluidizing technology. The step of sterilizing is carried out by using high pressure sterilizing under rotation. The quality controlling is mainly carried out by measuring particle size.
DETAILED DESCRIPTION OF THE INVENTION
(1) Selection of oil phase
In the emulsion of the present invention, the oil phase generally has an amount in mass of 0-50% (w/v). It is required in the present invention that a therapeutically effective amount of drug should be dissolved in a relatively small amount of oil phase, no drug precipitate occurs or no layer separation occurs under cryogenic storage condition, and in the meantime a stable emulsion is able to be formed with an aqueous phase in the presence of an emulsifier. The oil phase as used in the present invention may be a natural vegetable oil with long chain fatty acid ester groups or a vegetable oil or fatty acid ester being subjected to structure modification and hydrolysis. The examples of those may be one of or a mixture of soybean oil (especially in injection grade), castor oil, tea-seed oil, peanut oil, cottonseed oil, sesame oil, rape oil, safflower oil, olive oil, coconut oil, palm oil and cacao oil; or may be a glyceride with a chain length of C6-C12 fatty acid, such as but not limited to Arlacel 80, Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, glyceride oleate, glyceride linoleate, macrogol glyceryl laurate, ethyl oleate, ethyl linoleate, caprylocaproyl triglyceride, and a mixture thereof; or may be a mixture of the above long chain fatty acid esters and medium-chain fatty acid esters.
During the manufacture of an injection emulsion, a preferred oil phase has relatively little haemolysis effect and is refined. Besides generally used vegetable oils, the following oils may also be used in the present invention:
Arlacel 80 (HLB=4.3) Sorbitan monooleate
Arlacel 86 (HLB=2.8) Glyceride oleate: propylene glycol (90:10)

Capmul MCM (HLB=5.5-6.0) Coconut oil C8/C10 monoglyceride or diglyceride

Captex 200 (oil)

Coconut oil C8/C10 propylene glycol diester

Captex 355 (oil)

Coconut oil C8/C10 triglyceride

Miglyol812(oil)

Coconut oil C8/C10 triglyceride

Myvacet (oil)

Purified and acetylated monoglyceride

Myverol 18-92 (HLB-3-7) Purified sunflower oil monoglyceride
(containing 90% of glyceride linoleate)

Peceol (HLB=3)

Glyceride oleate

Maisine (HLB=3)

Glyceride linoleate

Gelucire 44/14 (HLB=14) Macrogol glyceryl laurate
(2) Selection of emulsifier
The emulsifier as used in the present invention may be one of or a mixture of nonionic surfactants and anionic surfactants.. The preferred emulsifier may be but not limited to one of or a mixture of soybean lecithin or modified soybean lecthin (natural or synthesized), ovolecithin or modified ovolecithin (natural or synthesized), Ophase 31, Poloxamer 108, Poloxamer 188, Poloxamer 407, polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG-400 monostearate, PEG-1750 monostearate, Tween-80, Tween-20, and Span-20. It is preferred to use a mixture of these emulsifiers. During the manufacture of an injection emulsion, the preferred emulsifier has relatively little haemolysis effect and is refined. Besides the above emulsifiers, the following may also be used in the butylphthalide emulsion of the present invention:

Ophase 31 (HLB=4)

Liquid lecithin

Soybean lecithin (HLB=4/7/9) Soybean lecithin
Cremophor EL (HLB= 13.5) Polyoxyethylene castor oil

Poloxamer 108 (HLB=30.5) Polyoxyethylene polyoxypropylene ether F-38
Poloxamer 188 (HLB=29) Polyoxyethylene polyoxypropylene ether F-68
Poloxamer 407 (HLB=21.5) Polyoxyethylene polyoxypropylene ether F-127
Tween 80 (HLB=15) Polyoxyethylene sorbitan monoleate
Tween 20 (HLB=16.7) Polyoxyethylene sorbitan monolaurate
Span20(HLB=8.6) Sorbitan monolaurate
(3) Selection of stabilizer
Suitable stabilizer as used in the present invention may be but not limited to one of or a mixture of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and sodium salt thereof, vitamin A, vitamin C, and vitamin E.
(4) Selection of osmoregulation agent
Suitable osmoregulation agent as used in the present invention may be but not limited to one of or a mixture of sodium chloride, glucose, sorbitol, xylitol, mannitol, and glycerol.
(5) Basic formulation of butylphthalide intravenous emulsion
In the butylphthalide intravenous emulsion of the present invention, the ratio of butylphthalide : oil phase : emulsifier : aqueous phase : stabilizer : osmoregulation agent is any ratio (by weight) within the range of 0.01~50wt% : 0~50wt% : 0.01~50wt% : 50~98wt% : 0~50wt% : 0~10wt%.
In one embodiment, the butylphthalide intravenous emulsion of the present invention has the following composition:
Butylphthalide lOg
Oil phase lOOg
Emulsifier 50g
Stabilizer 50g

Aqueous phase Added to 1000ml
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Example 1: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 10
Soybean lecithin 12
Soybean oil 100
Vitamin E 1
Sorbitol 25
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and sorbitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121 °C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 2: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 15
Castor oil 100

Soybean lecithin 12
Poloxamer 188 6
Glycerol 25
Oleic acid 10
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and castor oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 3: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 20
Soybean lecithin 12
Olive oil 100
Cholic acid 1
Mannitol 20
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, cholic acid and olive oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C

water bath. Soybean lecithin and mannitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was treated with ultrasonic waves for 10 times (10 seconds for each time, power: 400W). Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 4: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 25
Cottonseed oil 100
Ovolecithin 12
Poloxamer 188 20
Glycerol 25
Sodium oleate 10
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and cottonseed oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for

protection during the whole process.
Example 5: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 30
Soybean lecithin 12
Soybean oil 200
Tween 80 6
Vitamin E 8
Xylitol 100
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, Tween 80, vitamin E and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Soybean lecithin and xylitol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 6: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 40
Caprylocaproyl triglyceride 200

Soybean lecithin 12
Poloxamer 188 20
Glycerol 25
Oleic acid 10
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, soybean lecithin, oleic acid and caprylocaproyl triglyceride were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 7: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 50
Soybean lecithin 15
Sesame oil 100
Vitamin E 8
Glycerol 22.5
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, vitamin E and sesame oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C

water bath. Soybean lecithin and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 8: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 20
Soybean oil 100
Ovolecithin 12
Poloxamer 188 20
Glycerol 25
Sodium oleate 10
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for

protection during the whole process.
Example 9: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 100
Ovolecithin 20
Poloxamer 188 20
Glycerol 25
Sodium oleate 30
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, ovolecithin and sodium oleate were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 10: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 0.1
Soybean oil 100
Ovolecithin 19

Poloxamer 188 25
Glycerol 25
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, ovolecithin and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 and glycerol were weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.
Example 11: Preparation of butylphthalide intravenous emulsion
Formula composition (g)
Butylphthalide 5
Soybean oil 100
Ovolecithin 12
Poloxamer 188 20
Sodium oleate 3
Water for injection Added to 1000ml
The preparation process comprises the steps of: butylphthalide, ovolecithin, sodium oleate and soybean oil were weighed and mixed to form an oil phase, and the oil phase was pre-heated in a 60°C water bath. Poloxamer 188 was weighed and dispersed in water to form an aqueous phase, and the aqueous phase was pre-heated in a 60°C water bath. The oil phase

was slowly poured into the aqueous phase, and the mixture was dispersed by using a high shear emulsifying machine under 10,000 rpm for 5 min. Then the mixture was circulated in a high pressure homogenizer for 5 times, in which the first stage pressure is lOOMPa and the second stage pressure is lOMPa. Then the emulsion was regulated to have a pH of 8, filtered, subpackaged and sterilized at 121°C for 15min. Nitrogen gas is fed for protection during the whole process.

We claim:
1. A butylphthalide intravenous emulsion comprising butylphthalide as an active ingredient in an amount of 0.01~50wt% and an excipient in an amount of 50~99.99wt%, based on the total weight of the emulsion, wherein the excipient comprises an oil phase in an amount of 0.1-40wt%, an aqueous phase in an amount of 50-98wt%, an emulsifier in an amount of 0.01-50wt%, a stabilizer in an amount of 0-50wt%, and an osmoregulation agent in an amount of 0-10wt%, based on the total weight of the excipient, provided that the sum of the composition in the excipient does not exceed 100%; the oil phase comprises a natural vegetable oil with long chain fatty acid ester groups, or a vegetable oil or fatty acid ester being subjected to structure modification and hydrolysis, or glyceride with a chain length of C6~C12 fatty acid, or a mixture thereof.
2. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the butylphthalide is a raceme of butylphthalide, or /-butylphthalide.
3.The butylphthalide intravenous emulsion as claimed in claim 1, wherein the oil phase is one of or a mixture of soybean oil, castor oil, tea-seed oil, peanut oil, cottonseed oil, sesame oil, rape oil, safflower oil, olive oil, coconut oil, palm oil, cacao oil, Arlacel 80, Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, glyceride oleate, glyceride linoleate, macrogol glyceryl laurate, ethyl oleate, ethyl linoleate, and caprylocaproyl triglyceride,.
4. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the emulsifier
comprises one of or a mixture of nonionic surfactants and anionic surfactants.
5. The butylphthalide intravenous emulsion as claimed in claim 4, wherein the emulsifier is one of or a mixture of soybean lecithin or modified soybean lecthin, ovolecithin or modified ovolecithin, Ophase 31, Poloxamer 108, Poloxamer 188, Poloxamer 407, polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG-400 monostearate, PEG-1750 monostearate, Tween-80, Tween-20, and Span-20.
6. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the stabilizer is one of or a mixture of oleic acid, sodium oleate, sodium caprylate, cholesterol, cholic acid, deoxycholic acid and sodium salt thereof, vitamin A, vitamin C, and vitamin E.

7. The butylphthalide intravenous emulsion as claimed in claim 1, wherein the osmoregulation agent is one of or a mixture of sodium chloride, glucose, sorbitol, xylitol, mannitol, and glycerol.

"A BUTYLPHTHALIDE INTRAVENOUS EMULSION"

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