CN114272216B - Freeze-dried preparation of 2-oxo-1-pyrrolidine derivative and preparation thereof - Google Patents
Freeze-dried preparation of 2-oxo-1-pyrrolidine derivative and preparation thereof Download PDFInfo
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- CN114272216B CN114272216B CN202111182589.8A CN202111182589A CN114272216B CN 114272216 B CN114272216 B CN 114272216B CN 202111182589 A CN202111182589 A CN 202111182589A CN 114272216 B CN114272216 B CN 114272216B
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Abstract
The invention discloses a 2-oxo-1-pyrrolidine derivative freeze-dried preparation and a preparation method thereof, and relates to the field of pharmaceutical preparations. The freeze-dried preparation is used for epileptic patients incapable of oral administration, and has the advantages of quick response and high bioavailability; secondly, the freeze-dried preparation has simple process, is convenient to manufacture and is easy to store and transport; in addition, the freeze-dried preparation provided by the invention can be clinically matched with 0.9% sodium chloride injection, sodium lactate ringer injection and 5% glucose injection for use, and has a good application prospect.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a freeze-dried preparation of a 2-oxo-1-pyrrolidine derivative and a preparation method thereof.
Background
Epilepsy is a second major neurological disorder next to headache, and epileptic seizures are a neurological disorder that leads to a sudden electrical discharge in the brain, and can be caused by a variety of causes, but in actual cases about 60% -75% of causes are unknown. Currently, drug therapy remains the primary means of controlling epilepsy.
The European drug administration (EMA) was approved for marketing in 1 month 14 and the American FDA was approved for marketing in 19 month 2016, and the product was available under the trade name Briviact for adjuvant treatment of partial seizures or non-secondary complications in adults, adolescents and children with epilepsy older than 4 years. The affinity of the brivaracetam is 15-30 times of that of the levetiracetam, so that the dosage of the brivaracetam is reduced by about 10 times, and the brivaracetam is safer.
It is known that the stability of freeze-dried powder is superior to injection solutions, oral solutions, and the like stored in a solution state for a long period of time. The brivaracetam is a new generation antiepileptic drug brivaracetam, and the effect of controlling epileptic attacks can be achieved by adjusting the balance of an excitatory transmitter and an inhibitory transmitter in the brain, and no brivaracetam freeze-dried preparation exists in the market at present.
In view of the above, the present inventors have conducted extensive and intensive studies, and have provided, through a large number of screening and experiments, a lyophilized preparation of brivaracetam and derivatives thereof which can be used for patients who cannot be orally administered, and which is fast in onset of action and high in bioavailability.
Disclosure of Invention
The invention aims to provide a 2-oxo-1-pyrrolidine derivative freeze-dried preparation and a preparation method thereof, wherein the freeze-dried preparation is used for epileptic patients incapable of oral administration, and has the advantages of quick response and high bioavailability; the freeze-dried preparation of the invention has simple process, convenient manufacture and easy preservation and transportation; in addition, the freeze-dried preparation of the invention has good compatibility stability with 0.9% sodium chloride injection, sodium lactate ringer injection and 5% glucose injection, is convenient for clinical application and has good application prospect.
In order to achieve the above object, the present invention has the following technical scheme:
in the present invention,
the term "about" is a modifier to an amount, and is meant to include within +or-5% of the modified amount.
In one aspect, the present invention provides a lyophilized formulation comprising a 2-oxo-1-pyrrolidine derivative and a lyophilization excipient.
The structural formula of the 2-oxo-1-pyrrolidine derivative is shown as the formula (I):
wherein the method comprises the steps of
R1 is C1-20 alkyl or C2-8 alkenyl;
r2 is C1-20 alkyl or C2-8 alkenyl;
x is-CONH 2 or-C n ONH 2 (n≤20)；
Preferably, the 2-oxo-1-pyrrolidine derivative is (2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butyramide shown in formula II or pharmaceutically acceptable salt thereof,
preferably, the 2-oxo-1-pyrrolidine derivative accounts for 1-90%, more preferably 5-60%, and preferably 10-30% of the total weight of the lyophilized preparation.
Further preferably, the 2-oxo-1-pyrrolidine derivative is (2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide.
The (2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butyramide is the brivaracetam.
The freeze-drying excipient is selected from one or more of mannitol, lactose, glucose, sorbitol, hydroxypropyl betacyclodextrin, sucrose, maltose, galactose, sulfobutyl betacyclodextrin and trehalose;
preferably, the freeze-drying excipient is selected from one or more of mannitol, trehalose, hydroxypropyl betacyclodextrin and sulfobutyl-betacyclodextrin.
In some preferred embodiments, the lyophilization excipient is a mixture of mannitol and sulfobutyl-betacyclodextrin, wherein the mass ratio of mannitol to sulfobutyl-betacyclodextrin is 3:13;
in some preferred embodiments, the freeze-drying excipient is a mixture of trehalose and hydroxypropyl betacyclodextrin, wherein the mass ratio of the trehalose to the hydroxypropyl betacyclodextrin is 3:2;
the water content of the freeze-dried powder is less than 5%, preferably, the water content of the freeze-dried powder is less than 3%.
On the other hand, the invention also provides a preparation method of the freeze-dried preparation, which comprises the following steps:
dissolving 2-oxo-1-pyrrolidine derivative and excipient in water, filtering with a filter membrane, filling into a penicillin bottle, pre-freezing, primary drying, secondary drying, tamponading and capping, and packaging to obtain a freeze-dried preparation product;
or dissolving the 2-oxo-1-pyrrolidine derivative and the excipient in water, filtering by a filter membrane, pre-freezing, drying for the first time, drying for the second time to obtain freeze-dried powder, crushing, directly filling the freeze-dried powder into an ampoule bottle, further sealing the ampoule bottle in a melting way, and packaging to obtain a freeze-dried preparation product.
In still another aspect, the invention also provides application of the freeze-dried preparation in preparing medicines for preventing and/or treating epilepsy-related diseases.
The beneficial effects of the invention are as follows:
(1) The freeze-dried preparation is used for epileptic patients incapable of oral administration, and has the advantages of quick response and high bioavailability.
(2) The buvaracetam freeze-dried preparation prepared by the invention has simple process and is convenient for commercial production.
(3) The buvaracetam freeze-dried preparation prepared by the invention can be clinically matched with 0.9 percent sodium chloride injection, sodium lactate ringer injection and 5 percent glucose injection.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the claimed invention and those skilled in the art can make various changes and modifications to the invention of the present application in light of the disclosure, which should also fall within the scope of the claimed invention.
The invention is further illustrated by means of the following specific examples. The experimental methods for which specific conditions are not noted in the following examples are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The content and related substances in the examples are measured, and checked according to the rule 0512 (high performance liquid chromatography) of the fourth edition of the Chinese pharmacopoeia 2020, using octadecylsilane chemically bonded silica as filler (C18 column, 250×4.6mm, 5 μm or chromatographic column with equivalent efficacy); 0.02mol/L potassium dihydrogen phosphate solution (pH adjusted to 5.5 with 2% potassium hydroxide): acetonitrile=90:10 (v/v) as mobile phase a and acetonitrile as mobile phase B, gradient elution was performed according to the following table (table 1 below), flow rate was 1.0ml per minute, column temperature was 30 ℃, and detection wavelength was 210nm. Precisely measuring 10 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording related data.
TABLE 1
The insoluble particles are measured, the test is checked according to the rule 0903 (insoluble particle checking method) of the fourth edition of the Chinese pharmacopoeia 2020, 5 bottles of the test sample are taken, the outer wall of the container is cleaned by water, the bottle cap is carefully opened, 10ml of the water for checking the particles is precisely added, the bottle cap is carefully covered, the content is dissolved by slowly shaking, the test sample is carefully combined into a sampling cup, the sampling cup is placed for 2 minutes, and the sampling cup is placed on a sampler. Stirring is started to make the solution uniform, and the measurement is carried out for 4 times according to the method, and the sampling amount is not less than 5ml each time. And (3) counting out the first data, taking an average value of subsequent measurement results, and calculating the number of particles contained in each container according to the sampling volume and the marking device volume of each container. Limit: each sample container contains less than 3000 particles of more than 10 μm and less than 300 particles of more than 25 μm.
The method comprises the steps of inspecting visible foreign matters according to the rule 0904 (visible foreign matter inspection method) of the four parts of 2020 edition, taking 5 pieces (bottles) of test articles, adding a proper amount of water for injection to dissolve the medicinal powder completely, placing the test articles at the edge of a light shielding plate of a visible foreign matter tester, holding the neck of a container, slightly rotating and overturning the container (avoiding generating bubbles) at a visible distance, suspending the visible foreign matters possibly existing in the medicinal liquid, visually inspecting under black and white backgrounds respectively, and repeatedly observing, wherein the total inspection time limit is 20 seconds. No visible foreign matter such as metal chips, glass chips, fibers having a length of more than 2mm, lumps having a maximum particle diameter of more than 2mm, macroscopic aerosol particle deposits when rotated gently after standing, non-countable particle groups or shaking-free deposits, and protein flocs which are difficult to count within a prescribed time, can be detected in the sample.
Example 1
Using mannitol as excipient, preparing the buvaracetam into freeze-dried powder, carrying out drug loading (the ratio is about 5 percent (w/w percent)), and then crushing the freeze-dried powder and directly carrying out sterile filling.
The preparation method comprises the following steps:
weighing 5 g of buvaracetam, dissolving in 1000ml of water, uniformly mixing by ultrasonic, adding 95 g of mannitol, uniformly stirring, and filtering by a 0.22 mu m microporous filter; opening a freeze dryer, pouring a sample solution into a beaker, placing the beaker on a baffle plate of the freeze dryer, pre-freezing the sample solution at-45 ℃, drying the sample solution for 2 hours at-15 ℃ for the first time, drying the sample solution for 20 hours at 25 ℃ for the second time, and obtaining freeze-dried powder; pulverizing the lyophilized powder, directly filling into penicillin bottles, and preparing about 1000 bottles of sterile filling powder by 100mg of lyophilized powder per bottle.
Taking the sterile filling powder prepared in the example 1, and measuring the moisture, insoluble particles, the maximum unknown single impurity, the total impurity and the content of the sterile filling powder; placing the sterile filling powder prepared in the example 1 at 60 ℃ for 10 days, and measuring the moisture, the maximum unknown single impurity, the total impurity and the content of the sample again; the quality of the product was evaluated by changing the amount of increase, the content and the moisture content of the impurities, and the results are shown in Table 2 below.
TABLE 2 quality evaluation of sterile filled powders
Evaluation results: example 1 the sterile filled powder had good properties, moisture, insoluble particulates, maximum unknown single impurity, total impurities, content parameters. The aseptic filling powder prepared in the example 1 is placed at 60 ℃ for 10 days for factor investigation, and has good parameters and stable quality.
Example 2
Mannitol, sulfobutyl-betacyclodextrin is used as an excipient, the buvaracetam is prepared into freeze-dried powder, the drug loading rate (ratio) is about 20 percent (w/w percent), and then the freeze-dried powder is directly subjected to aseptic filling (ampoule bottle), melt sealing and packaging.
The preparation method comprises the following steps:
weighing 15 g of sulfobutyl-betacyclodextrin, dissolving in 1000ml of water, adding 65 g of mannitol and 20 g of brivaracetam, stirring uniformly, and filtering by a 0.22 mu m microporous filter; opening a freeze dryer, pouring a sample solution into a beaker, placing the beaker on a baffle of the freeze dryer, pre-freezing the sample solution at-45 ℃, drying the sample solution for 2 hours at-15 ℃ for the first time, drying the sample solution for 20 hours at 25 ℃ for the second time, and obtaining freeze-dried powder; pulverizing lyophilized powder, directly filling into ampoule bottles, sealing ampoule bottles with 100mg lyophilized powder per ampoule bottle, and preparing into about 1000 bottle ampoule bottle sterile filling powder.
Taking the sterile filling powder prepared in the example 2, and measuring the moisture, insoluble particles, the maximum unknown single impurity, the total impurity and the content of the sterile filling powder; placing the sterile filling powder prepared in the example 2 at 60 ℃ for 10 days, and measuring the moisture, the maximum unknown single impurity, the total impurity and the content of the sample again; the quality of the product was evaluated by changing the amount of increase, the content and the moisture content of the impurities, and the results are shown in Table 3 below.
TABLE 3 quality evaluation of sterile filled powders
Evaluation results: example 2 the sterile filled powder had good properties, moisture, insoluble particulates, maximum unknown single impurity, total impurities, content parameters. The aseptic filling powder prepared in the example 2 is placed at 60 ℃ for 10 days for factor investigation, and has good parameters and stable quality.
Example 3
Using sulfobutyl-betacyclodextrin as an excipient, buvaracetam was prepared as Cheng Donggan doses with a drug loading (in terms of ratio) of about 60% (w/w%), example 3 prescribed in table 4 below:
table 4 example 3 prescription
The preparation method comprises the following steps:
40 g of sulfobutyl-betacyclodextrin is weighed and dissolved in 900ml of water, 60 g of buvaracetam is added, and the mixture is stirred uniformly; the pH was adjusted to 4-6 with 0.01mol/L hydrochloric acid, and a small amount of purified water was added to the whole volume (1000 ml), and the mixture was filtered through a 0.22 μm microporous filter; filling the liquid medicine into 7ml colorless tube-type injection bottles, opening a freeze dryer, placing a sample on a partition board of the freeze dryer, pre-freezing, primary drying, secondary drying, plugging, taking out the plugged tube-type injection bottles, and capping by using a hand-held capping machine to obtain a freeze-dried finished product prepared in the embodiment 3.
Taking the freeze-dried finished product prepared in the example 3, and measuring the moisture, insoluble particles, the maximum unknown single impurity, the total impurity and the content of the freeze-dried finished product; standing the freeze-dried product prepared in the example 3 at 60 ℃ for 10 days, and measuring the moisture, the maximum unknown single impurity, the total impurity and the content of the sample again; the quality of the product was evaluated by the increase in the amount of impurities, the content of impurities and the change in moisture, as shown in Table 5 below.
Table 5 evaluation of lyophilized powder quality
Evaluation results: example 3 the lyophilized powder had good parameters of properties, moisture, insoluble particles, maximum unknown single impurity, total impurity, content. The freeze-dried powder prepared in the example 3 is placed at 60 ℃ for 10 days for factor investigation, and has good parameters and stable quality.
Example 4
Using glucose as an excipient, buvaracetam was prepared in Cheng Donggan doses with a drug loading (in w/w%) of about 10%, example 4 prescribed in table 6 below:
table 6 example 4 prescription
The preparation method of the freeze-dried powder comprises the following steps:
weighing 10 g of brivaracetam, dissolving in 1000ml of water, adding 90 g of glucose, stirring uniformly, and filtering by a 0.22 mu m microporous filter; filling the liquid medicine into 7ml colorless tube-type injection bottles, opening a freeze dryer, placing a sample on a partition board of the freeze dryer, pre-freezing, primary drying, secondary drying, plugging, taking out the plugged tube-type injection bottles, and capping by using a hand-held capping machine to obtain a freeze-dried finished product prepared in the embodiment 4.
Taking the freeze-dried finished product prepared in the example 4, and measuring the moisture, insoluble particles, the maximum unknown single impurity, the total impurity and the content of the freeze-dried finished product; standing the freeze-dried product prepared in the example 4 at 60 ℃ for 10 days, and measuring the moisture, the maximum unknown single impurity, the total impurity and the content of the sample again; the quality of the product was evaluated by the increase in the amount of impurities, the content of impurities and the change in moisture, as shown in Table 7 below.
Table 7 evaluation of lyophilized powder quality
Evaluation results: the lyophilized powder of example 4 had good parameters of properties, moisture, insoluble particles, maximum unknown single impurity, total impurity, content. The freeze-dried powder prepared in the example 4 is placed at 60 ℃ for 10 days for factor investigation, and has good parameters and stable quality.
Example 5
Example 5 brivaracetam was prepared as a lyophilized formulation using hydroxypropyl betacyclodextrin, trehalose as excipients, with a drug loading (in terms of% w/w) of about 25%, example 5 being prescribed in table 8 below:
table 8 example 5 prescription
The preparation method comprises the following steps:
weighing 30 g of hydroxypropyl betacyclodextrin, dissolving in 1000ml of water, adding 25 g of brivaracetam and 45 g of trehalose, stirring uniformly, and filtering by a 0.22 mu m microporous filter; filling the liquid medicine into 7ml colorless tube-type injection bottles, opening a freeze dryer, placing a sample on a partition board of the freeze dryer, pre-freezing, primary drying, secondary drying, plugging, taking out the plugged tube-type injection bottles, and capping by using a hand-held capping machine to obtain a freeze-dried finished product prepared in the embodiment 5.
Taking the freeze-dried finished product prepared in the example 5, and measuring the moisture, insoluble particles, the maximum unknown single impurity, the total impurity and the content of the freeze-dried finished product; standing the freeze-dried product prepared in the example 5 at 60 ℃ for 10 days, and measuring the moisture, the maximum unknown single impurity, the total impurity and the content of the sample again; the quality of the product was evaluated by the increase in the amount of impurities, the content of impurities and the change in moisture, as shown in Table 9 below.
Table 9 evaluation of lyophilized powder quality
Evaluation results: the lyophilized powder of example 5 had good parameters of properties, moisture, insoluble particles, maximum unknown single impurity, total impurity, content. The freeze-dried powder prepared in the example 5 is placed at 60 ℃ for 10 days for factor investigation, and has good parameters and stable quality.
Investigation of sample compatibility stability
The clinical compatibility research is an indispensable part of medicine research and development, can play a role in guaranteeing the quality of the medicines after compatibility, and the medicines are clinically compatible with common physiological saline, glucose and sodium lactate ringer, so that the actual environment of the compatible medicine liquid needs to be considered at the same time, and the clinical use process is simulated.
Taking the freeze-dried powder of the example 1, simulating clinical use and preparation processes, respectively matching with 0.9% sodium chloride, 5% glucose and sodium lactate ringer, standing for 12 hours at room temperature, respectively sampling at initial (0 hours), 4 hours, 8 hours and 12 hours, and examining the properties, visible foreign matters, maximum (unknown) single impurities, total impurities, content and the like of the matched liquid medicine; the results of the examination are shown in Table 10 below.
Table 10 example 1 lyophilized powder stability test
Through compatibility stability experiments, the freeze-dried preparation has good compatibility stability with 0.9% sodium chloride injection, sodium lactate ringer injection and 5% glucose injection (the properties, visible foreign matters, single impurities and total impurities are all within the limit range); the freeze-dried preparation can be used by intravenous injection or intravenous drip after being re-dissolved, can be clinically matched with 0.9% sodium chloride injection, sodium lactate ringer injection and 5% glucose injection, and has good application prospect.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (5)
1. A lyophilized formulation comprising a 2-oxo-1-pyrrolidine derivative and a lyophilization excipient,
the 2-oxo-1-pyrrolidine derivative is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl) butyramide or pharmaceutically acceptable salt thereof shown in a formula II,
the freeze-drying excipient consists of one or more of mannitol and sulfobutyl-betacyclodextrin;
the 2-oxo-1-pyrrolidine derivative accounts for 10-30% of the total weight of the freeze-dried preparation.
2. The lyophilized formulation according to claim 1, wherein: the 2-oxo-1-pyrrolidine derivative is (2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butyramide.
3. The lyophilized formulation according to claim 1, wherein: the water content of the freeze-dried powder is less than 5%.
4. A method of preparing a lyophilized formulation as defined in any one of claims 1-3, wherein: the method comprises the following steps:
dissolving 2-oxo-1-pyrrolidine derivative and excipient in water, filtering with a filter membrane, filling into penicillin bottles, pre-freezing, primary drying, secondary drying, tamponading and capping, and packaging to obtain a freeze-dried preparation product;
or dissolving the 2-oxo-1-pyrrolidine derivative and the excipient in water, filtering by a filter membrane, pre-freezing, drying for the first time, drying for the second time to obtain freeze-dried powder, crushing, directly filling the freeze-dried powder into ampoule bottles, further sealing the ampoule bottles in a melting way, and packaging to obtain a freeze-dried preparation product.
5. Use of a lyophilized formulation according to any one of claims 1-4 for the preparation of a medicament for the prevention and/or treatment of epilepsy-related disorders.
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| CN104800176A (en) * | 2015-04-23 | 2015-07-29 | 广东赛烽医药科技有限公司 | Brivaracetam orally-disintegrating tablets and preparation method thereof |
| CN106692083A (en) * | 2015-11-13 | 2017-05-24 | 天津市汉康医药生物技术有限公司 | Brivaracetam pharmaceutical composition and preparation method of brivaracetam pharmaceutical composition |
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| WO2010002869A1 (en) * | 2008-07-01 | 2010-01-07 | Concert Pharmaceuticals, Inc. | 2-oxo-1-pyrrolidine derivatives |
| IL252848B1 (en) * | 2015-02-06 | 2024-03-01 | Marinus Pharmaceuticals Inc | Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders |
| CN113181143B (en) * | 2021-05-08 | 2022-09-06 | 浙江歌文达生物医药科技有限公司 | 2-oxo-1-pyrrolidine derivative oral dissolving film and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104800176A (en) * | 2015-04-23 | 2015-07-29 | 广东赛烽医药科技有限公司 | Brivaracetam orally-disintegrating tablets and preparation method thereof |
| CN106692083A (en) * | 2015-11-13 | 2017-05-24 | 天津市汉康医药生物技术有限公司 | Brivaracetam pharmaceutical composition and preparation method of brivaracetam pharmaceutical composition |
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