JP6884496B1 - Injectable preparation containing levetiracetam as an active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a preparation having a small amount of insoluble fine particles generated after container filling and heat sterilization, and to provide a method for producing the above-mentioned preparation. SOLUTION: This is an injectable preparation containing levetiracetam, sodium chloride and sodium acetate, the pH is 5.53 to 5.66, and the amount of levetiracetam in the injectable preparation is 99.7 to 99.7 to the blended amount. An injectable formulation that is 100.4%. [Selection diagram] None

Description

The present invention relates to an injectable preparation containing levetiracetam as an active ingredient.

Levetiracetam ((2S) -2- (2-Oxopyrrolidine-1-yl) butyramide) is an S-enantiomer having a 2-oxo-1-pyrrolidin skeleton and one asymmetric carbon in its structure. In Japan, levetiracetam is marketed as an antiepileptic drug (Ekepla (registered trademark) intravenous drip infusion 500 mg, etc.) and is used for the treatment of partial epilepsy (including secondary generalized seizures) in epilepsy patients. .. Levetiracetam does not bind to various receptors and major ion channels, but binds to synaptic vesicle protein 2A (SV2A) at neuronal terminals, N-type Ca2 + channel inhibition, intracellular Ca2 + release inhibition, GABA and glycinergic. Suppression of allosteric inhibition of current and suppression of excessive synchronization between nerve cells have been confirmed. Since there is a correlation between the binding affinity for SV2A and the seizure-suppressing effect in various epilepsy animal models, it is considered that the binding between levetiracetam and SV2A contributes to the seizure-suppressing effect (for example,). See Non-Patent Document 1).

Regarding the method for producing levetylastam, 2-aminobutylamide is produced, which is separated as a diastereomer using optically active tartaric acid, tartaric acid is removed, and optically active ethyl (S) -4-{[1. -Aminocarbonyl] propyl} aminobutyrate hydrochloride is known, and a method of neutralizing this and converting it to lactamization to levetylacetam is known (see, for example, Patent Document 1).
Levetiracetam is also sold as a reagent by Sigma-Aldrich.
Further, in recent years, in a derivative of levetiracetam, ethyl-2-bromobutyral is condensed with a pyrrolidone skeleton and decomposed with ammonia to obtain a corresponding racemate, which is divided into optically active substances by optical resolution column chromatography. Techniques have also been developed (see, eg, Patent Document 2). Levetiracetam can also be obtained by applying this technology.

There are two dosage forms of levetiracetam currently on the market, an oral dosage form and an injectable dosage form, but since it is necessary to stop the attack quickly at the time of a seizure attack, the injectable dosage form with rapid onset of effect is a treatment for seizure. In, it is in an important position. The levetiracetam injectable form has a pH adjusted to 5.0-6.0 (see https://www.info.pmda.go.jp/go/pack/1139010F1024_1_22/), which is 2 This is because an aqueous solution of a compound having a −oxo-1-pyrrolidin skeleton exists stably within this range (see, for example, Patent Document 2).
However, in the production of this injection-type product, even if the solution before filling in the container is within the product standard value, insoluble fine particles are found when the container is filled, sterilized by heating, and then the shipment is judged. Due to the occurrence, the lot was out and there was a case where it had to be discarded. Since such insoluble fine particles may cause vascular occlusion in injectable drugs, they are strictly controlled by the Pharmaceuticals and Medical Devices Agency (PMDA), and products that cannot meet this standard are discarded. I have no choice but to do it. Therefore, there has been a demand for a means for clearing the standard and ensuring the stability of supply. The cause of the generation of insoluble fine particles is unknown, but it is presumed that it is due to a very small amount of impurities such as salts that do not appear in the standard values of the drug substance.

Kristen A Stout et.al., ACS Chem Neurosci., 2019; 10 (9): 3927-3938

Japanese Unexamined Patent Publication No. 60-252461 WO2007 / 031263 Pamphlet Special Table 2011-513360

Against this background, there has been a demand for a method of reducing the amount of product waste by preventing lot-out due to insoluble fine particles generated after container filling and heat sterilization.

In view of this situation, the present inventors have sought measures to prevent lot-out due to insoluble fine particles generated after container filling and heat sterilization, and as a result of diligent research and efforts, the liquid preparation before filling in the container. The invention was found to be able to reliably prevent lot-out by adjusting the pH of the above to 5.66 to 5.53 and the amount of levetiracetam to be 99.7 to 100.4% of the compounding amount. Has been completed. That is, the present invention is as shown below.
<1>
An injectable preparation containing levetiracetam, sodium chloride and sodium acetate.
The pH is 5.53 to 5.66 and
An injectable preparation in which the amount of levetiracetam in the injectable preparation is 99.7 to 100.4% of the blended amount.
<2>
The injectable preparation according to <1>, which is a sterilized filtration preparation.
<3>
The injectable preparation according to <1> or <2>, wherein the blending amount of levetiracetam is 10% (w / v).
<4>
(A) Step of blending levetiracetam, sodium chloride and sodium acetate, and
(B) A method for producing an injectable preparation, which comprises a step of sterilizing and filtering the solution obtained in step (a).
The amount of levetiracetam in the prefill solution obtained through the sterilization filtration in the step (b) is 99.7 to 100.4% of the blended amount of levetiracetam in the step (a), and the pH of the solution is 5. A method for producing an injectable preparation, which comprises .53 to 5.66.
<5>
(C) The production method according to <4>, further comprising a step of filling a container with the pre-filling solution obtained through the sterilization filtration of the step (b) and sterilizing by heating.

In the specification of the present application, the "blending amount" of levetiracetam is the weight of levetiracetam at the time of blending the raw materials of the preparation. The "quantitative value" is the weight of levetiracetam in the solution before filling the container (solution before filling), and the peak area of levetiracetam and the peak area of the standard substance of levetiracetam measured by liquid chromatography. It means the weight calculated from the ratio of. In addition, this quantitative value is the same as the value for the pharmaceutical product after filling in a container.

According to the present invention, in the levetiracetam injection preparation, lot-out due to insoluble fine particles generated after container filling and heat sterilization can be prevented in advance, and the amount of product waste can be reliably reduced. Therefore, the economic efficiency in the production of the levetiracetam injectable preparation can be remarkably improved.

The present invention relates to the provision of a preparation having a small amount of insoluble fine particles generated after container filling and heat sterilization, and the provision of a method for producing the preparation.
The injectable preparation according to the present invention contains levetiracetam, sodium chloride and sodium acetate. The injectable preparation according to the present invention can be produced by blending levetiracetam, sodium chloride and sodium acetate, adjusting the pH with acetic acid, and sterilizing and filtering. Further, a sterilized and filtered solution for injection of levetiracetam may be filled in a container, sealed, and then heat sterilized. The pH range adjusted by the addition of acetic acid is 5.3 to 5.7. This is a safe range for levetiracetam to achieve a stable pH range of 5 to 6 in the final product. As acetic acid, glacial acetic acid may be used.

The content of sodium chloride contained in the injectable preparation according to the present invention is preferably 0.85 to 0.95% (w / v), more preferably 0.90% (w / v) (± 0). 0.01%). The content of sodium acetate contained in the injectable preparation according to the present invention is preferably 0.16 to 0.17% (w / v), more preferably 0.164% (w / v) ( ± 0.002%).

The solution for injection is produced by the following steps.

<Preparation process of levetiracetam injectable solution>
Step (a): Blending step Purified water for injection is added to the levetiracetam drug substance, sodium chloride and sodium acetate as raw materials, and the mixture is stirred and dissolved. The final product concentrations of levetiracetam drug substance, sodium chloride and sodium acetate were 10% (w / v), 0.85 to 0.95% (w / v), and 0.16 to 0.17%, respectively. Adjust so that it becomes (w / v). A small amount of acetic acid may be added at the time of formulation for pH pre-adjustment. As the levetiracetam drug substance to be blended, those having standard values shown in Table 1 are preferably used. After dissolution, the pH is measured and acetic acid is added while adjusting the pH to be in the range of 5.3 to 5.7 (final product concentration). After the addition of acetic acid, more purified water is added so that the final weight becomes a predetermined amount. The final concentration means the concentration in the injectable preparation according to the present invention.
Step (a) can be performed under conventional conditions.

Step (b): Sterilization filtration step The solution obtained in the step (a) is sterilized and filtered. Sterilization filtration can be performed once or more than once, but more than once is preferred. When performing two sterilization filtrations, for example, from the filtrate of the primary sterilization filtration to the container for the next secondary sterilization filtration is aseptically controlled, and after the primary sterilization filtration, the container is filled and sealed. Steps can be performed in a sterile condition. Sterilization filtration is performed by pressure filtration using a Teflon filter having a pore size of 0.2 μm to 0.4 μm, preferably 0.2 μm.
<Measurement of solution before filling>
Before filling the container with the filtrate (solution before filling) obtained through the sterilization filtration, the pH is measured and the amount of levetylacetam is measured by liquid chromatography to control the process.
The amount of levetiracetam (quantitative value) measured by liquid chromatography is calculated from the ratio of the peak area of the solution to the peak area of 500 mg of the standard levetiracetam solution dissolved in 5 ml of purified water. The measurement conditions for liquid chromatography are shown below.

Quantification method of levetiracetam: Liquid chromatography detector: Ultraviolet absorptiometer (measurement wavelength: 205 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm of silica gel for liquid chromatography.
Column temperature: Room temperature Mobile phase: Acetonitrile / diluted 2 mol / L sulfuric acid solution (1 → 100) mixed solution (24: 1)
Flow rate: 1 mL / min Area measurement range: Range of about 3 times the holding time of levetiracetam Conversion to mass is calculated from the peak area ratio with the standard product.

<Quality adjustment>
The ratio of the amount of levetiracetam to the blended amount (hereinafter referred to as "quantitative value ratio") when the pH is 5.53 to 5.66, more preferably 5.55 to 5.65, and the amount of levetiracetam as measured by liquid chromatography is used. When it is 99.7 to 100.4%, more preferably 99.7 to 100.3%, it is sent to the next container filling, sealing, and heat sterilization steps to obtain the final product.
Lots in which at least one of the pH and the quantitative value ratio is out of the above range are combined with other lots and sterilized and filtered in the same manner as in the step (b), and the pH and the quantitative value ratio are brought into the above range. Make sure it is included. That is, the pH of the lot that was sterilized and filtered after lot matching was 5.53 to 5.66, more preferably 5.55 to 5.65, and the quantitative value of levetiracetam by liquid chromatography was 99 of the blending amount. When it is confirmed that the content is .7 to 100.4%, more preferably 99.7 to 100.3%, the final product is subjected to the final filling, sealing, and heat sterilization steps.
In the present specification, heat sterilization is preferably performed at 110 ° C. to 125 ° C. at a pressure of 1 to 2 atm for 1 to 3 hours.

Hereinafter, the present invention will be described in more detail with reference to examples.

According to the formulation of the stock solution for injection of levetiracetam shown in Table 2 below, the formulation components were charged into a 300 L tank equipped with a weighing device, solubilized by stirring, and acetic acid was added while monitoring the pH under stirring to adjust the pH. It was adjusted to be between 5.3 and 5.7. Purified water was further added to this until the weight reached 209.3 kg, and the mixture was sufficiently stirred to obtain a stock solution for injection of levetiracetam. Levetiracetam conforming to the standards shown in Table 1 above was purchased from UCB Society Anonym and used. Levetiracetam can also be purchased from Sigma-Aldrich.

The stock solution for injection of levetiracetam prepared in this way is sent to a filtration device kept in a sterile state in a sterile room through a line kept in a pre-cleaned state, and sterilized and filtered using a 0.20 μm pore-sized Teflon filter. Was transferred to a 300 L tank in a sterile room. From the inside of this tank, it was sent to the filtration device again through an aseptic pipe, further filtered and sterilized, and transferred to a 300 L tank. The solution transferred to the tank was used as an injection solution. A part of the injectable solution of levetiracetam was sampled, and the pH value and the amount of levetiracetam (quantitative value) were determined. The method for quantifying levetiracetam by liquid chromatography is as described above. The remaining injection solution was dispensed into 10 ml vials in 5 ml increments, capped, sealed, and finally sterilized at 120 ° C. and 2 atm for 1 hour.

37 lots were produced in the above process. The product (vial bottle) is sampled 48 hours after production, and the insoluble fine particle test method specified by the 15th revised Japanese Pharmacopoeia (PMDA; https://www.pmda.go.jp/files/000163176.pdf). The number of insoluble fine particles of 25 μm or more and the number of insoluble fine particles of 10 μm or more measured by the first method were measured according to the first method (light shielding particle measurement method). The results are shown in Table 3.
From experience, it is known that if the number of insoluble fine particles of 25 μm or more is 150 or less and the number of insoluble fine particles of 10 μm or more is not 50 or less, the safety of the injection is likely to be impaired. However, out of 37 lots, lot No. 5, No. 6 and No. 9 deviated from this standard and was lotted out. It can be seen that the conditions for excluding these lots are pH 5.53 to 5.66, and the quantitative value of levetiracetam is 99.7 to 100.4% of the compounding amount (Table 3). Even if this condition is not satisfied, the criteria for insoluble fine particles may be satisfied, but in order to reliably prevent lot-out, it is necessary to satisfy the above conditions. By the way, lot No. 11, No. 21, No. 34, No. All 36 satisfy the above conditions. Further, if the range of the quantitative value ratio is set to 99.7 to 100.3%, lot-out can be prevented more reliably.

The present invention can be applied to an injectable preparation of levetiracetam.

Claims (4)

Sterilized filtration product for injection containing levetiracetam.
Contains sodium chloride and sodium acetate,
Sterilization filtration is performed after dissolution of all components with a filter having a pore size of 0.2 μm.
The pH of the solution after sterilization filtration is 5.53 to 5.66.
A sterilized filtration preparation for injection, wherein the amount of levetiracetam in the preparation for injection is 99.7 to 100.4% of the blended amount. The sterile filtered preparation for injection according to claim 1 , wherein the concentration of levetiracetam in the preparation for injection is 10% (w / v). (A) Step of blending levetiracetam, sodium chloride and sodium acetate, and
(B) A method for producing a sterile filtered preparation for injection, which comprises a step of sterilizing and filtering the solution obtained in step (a) with a filter having a pore size of 0.2 μm.
The amount of levetiracetam in the pre-filling solution obtained through the sterilization filtration in step (b) is 99.7 to 100.4% of the blended amount of levetiracetam in step (a), and the pH of the solution is 5. A method for producing a sterile filtered preparation for injection, which comprises .53 to 5.66. The production method according to claim 3 , further comprising a step of filling a container with a pre-filling solution obtained through sterilization filtration in step (b) and sterilizing by heating.