CN110638743B

CN110638743B - Composition containing brivaracetam

Info

Publication number: CN110638743B
Application number: CN201911022254.2A
Authority: CN
Inventors: 郑红; 潘裕生; 宋林奇; 张金梁; 俞悦; 王海翔; 洪华斌
Original assignee: Lepu Pharmaceuticals Technology Co ltd
Current assignee: Lepu Pharmaceuticals Technology Co ltd
Priority date: 2019-10-25
Filing date: 2019-10-25
Publication date: 2023-03-28
Anticipated expiration: 2039-10-25
Also published as: CN110638743A

Abstract

The invention discloses a brivaracetam-containing composition, which contains (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrole-1-yl ] butanamide as an active ingredient, and also contains one or more oligosaccharides containing glucose units, wherein the active ingredient in the composition is stable for a long time.

Description

Composition containing brivaracetam

Technical Field

The invention belongs to a pharmaceutical composition, and particularly relates to a pharmaceutical composition containing (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrole-1-yl ] butanamide.

Technical Field

Brivaracetam tablets (trade name Briviact) were approved by the U.S. FDA for marketing in 2016 (10mg, 25mg,50mg,75mg, 100mg), approved for marketing in europe in the same year, approved for marketing in russia in 2017, and registered in the chinese application for 3 months in 2017. The product can be used as adjuvant therapy for partial seizure of patients with epilepsy of 16 years old or older.

Brivaracetam is a novel high affinity ligand for SV2A within presynaptic nerve terminals, and SV2A is known to play a role in epileptogenesis by modulating synaptic GABA release. Although the target of action is the same, the affinity of the brivaracetam is 15-30 times that of the levetiracetam, so that the dosage of the brivaracetam is reduced by about 10 times.

The brivaracetam raw material is white to off-white crystalline powder, is degraded under strong acid and strong alkali conditions, is stable under common oxidation conditions, but is unstable in aqueous solutions (1-11) with different pH values of hydrogen peroxide. It can be seen that the feedstock may undergo degradation during storage due to oxidation.

Therefore, it is very important to find a pharmaceutical composition which remains stable for a longer period of time, such a pharmaceutical composition having a certain reducibility, and which is capable of reducing the degradation rate of the brivaracetam starting material due to oxidation. It is also preferred that: such pharmaceutical compositions have good compressibility to facilitate processing into oral unit dosage forms, such as tablets; and they have good dissolution characteristics when processed into oral tablets which may be of different dosage strengths.

Oligosaccharides are also called oligosaccharides, and are linear or branched saccharides formed by connecting 2 to 20 identical or different monosaccharide units by glycosidic bonds. Oligosaccharides and monosaccharides are very similar in their physical and chemical properties, they are water soluble, and many oligosaccharides are sweet in taste and are oxidized by furin solution due to their reducing properties. Oligosaccharides include: maltodextrin, corn hydrolyzed oligosaccharide and dextrin.

The maltodextrin is starch hydrolysate with dextrose equivalent DE value of 5-20, and is prepared with various kinds of starch as material and through enzymic process to control hydrolysis and conversion, purification and drying. Maltodextrins are generally mixtures of various DE values. It may be white powder or concentrated liquid. Good fluidity, no peculiar smell, and almost no sweetness. Good solubility and moderate viscosity. Low hygroscopicity and no caking. Has good carrier effect, and is an excellent carrier for various sweetening agents, flavoring agents, bulking agents, etc. Has the functions of promoting product molding and well inhibiting product tissue structure. Good film forming property, not only preventing the product from deforming, but also improving the appearance of the product. The maltodextrin contains a large amount of reducing sugar, so that the maltodextrin has certain reducibility and can prevent brivaracetam raw materials from being oxidized and degraded.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a brivaracetam-containing pharmaceutical composition, which comprises one or more glucose unit-containing oligosaccharides selected from the group consisting of: dextrin, maltodextrin, and starch hydrolysis oligosaccharide. Especially maltodextrin, in an amount of 1-10% by weight of the composition, ensures slow degradation of the active agent over a long period of time.

Further optimization, wherein the ratio of maltodextrin to active ingredient is 1.

Further preferably, the pharmaceutical composition of the present invention is formulated into an oral dosage form, such as a tablet. Thus, another aspect of the invention relates to a pharmaceutical composition comprising one or more oligosaccharides comprising glucose units, one or more fillers, disintegrants and lubricants.

Suitable fillers include: lactose, microcrystalline cellulose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, sorbitol, calcium sulfate, sucrose, and the like.

Suitable disintegrants include: crospovidone, croscarmellose sodium, carboxymethyl starch sodium, low substituted hydroxypropyl cellulose and the like.

Suitable lubricants include: magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium stearyl fumarate, and the like.

Further preferred is a pharmaceutical composition according to the invention, wherein the content of active ingredient is 15-25% by weight of the composition, wherein the content of maltodextrin is 1-10% by weight of the composition, wherein the content of filler is 20-80% by weight of the composition, wherein the content of disintegrant is 1-10% by weight of the composition, wherein the content of lubricant is 0.5-3% by weight of the composition, and the sum of the contents of the components of the pharmaceutical composition is 100% by weight.

The composition of the invention may then be coated with a tablet, for example by spray coating with a water-based film coating formulation, which may contain, for example, polyvinyl alcohol, triacetin, titanium dioxide and iron oxide. Coating ingredient mixtures are commercially available, for example, as described in the examples below. In the coating agent, for example, the content of the tablet composition is 0.5 to 10% by weight, particularly 1 to 6%, and preferably 2 to 3%.

Another aspect of the invention includes a method of preparing a stable pharmaceutical composition, specifically comprising mixing an active ingredient with an oligosaccharide comprising dextran units.

Tests prove that the pharmaceutical composition can keep the stability of the active component for a long time, and the impurity content is obviously lower than that of a similar preparation without an oligosaccharide component under the same storage condition, and the main reason is that the degradation rate of the brivaracetam raw material caused by oxidation can be reduced by the oligosaccharide component. The pharmaceutical compositions of the present invention have good compressibility to facilitate processing into oral unit dosage forms. In addition, it has good dissolution properties when processed into oral tablets which may be of varying dosage strengths.

Detailed Description

The present invention will be further described with reference to the following examples.

The following pharmaceutical compositions, in which the agents of the invention are of formula I, are given as examples to illustrate the invention, and any embodiments in the examples are not to be construed as limiting the invention.

Example 1

Mixing the reagent, lactose monohydrate, maltodextrin and crospovidone for 5 minutes, sieving by a 40-mesh sieve, mixing for 20 minutes, sieving magnesium stearate by the 40-mesh sieve, adding into the mixture, and continuously mixing for 5 minutes. The resulting homogeneous mixture is compressed into tablets.

Formula 1 was stored at 80 deg.C for 1 week, and after 1 week, it was found that only 0.07% of impurity D (the structural formula of impurity D is shown in formula II) was formed, formula II. Comparing formulation 2, 0.25% of impurity D was formed under the same storage conditions.

Example 2

Sieving the reagent, the anhydrous lactose, the dextrin and the croscarmellose sodium respectively, mixing for 20 minutes, sieving the magnesium stearate with a 40-mesh sieve, adding the sieved magnesium stearate into the mixture, and continuously mixing for 5 minutes. The resulting homogeneous mixture is compressed into tablets. The compressed tablets are coated by spraying a mixture of polyvinyl alcohol, polyethylene glycol, titanium dioxide and water in a coating pan with a weight gain of 1-6% w/w, preferably 2-3% after coating.

Formulation 3 was stored at 80 degrees ambient humidity for 1 week, after 1 week, only 0.09% of impurity D was found to be formed. Comparison of formula 4 resulted in 0.42% impurity D.

Example 3

The reagent, the anhydrous lactose, the corn starch oligosaccharide, the carboxymethyl starch sodium and the internally added magnesium stearate are respectively sieved by a 40-mesh sieve, mixed for 20 minutes, then dry granulated by adopting a rolling method, granulated by adopting a 20-mesh sieve, added with the magnesium stearate after being sieved by the 40-mesh sieve, added into the dry granules and continuously mixed for 5 minutes. The resulting homogeneous mixture is compressed into tablets. The compressed tablets are coated by spraying a mixture of polyvinyl alcohol, polyethylene glycol, titanium dioxide, yellow iron oxide and water in a coating pan with a weight gain after coating of 1-6% w/w, preferably 2-3%.

Formulation 5 was stored at 80 degrees in a wet condition for 1 week, after 1 week, only 0.10% of impurity D was found to be formed. Comparing formulation 6, 0.46% of impurity D was formed.

Example 4

The reagent, the microcrystalline cellulose, the corn starch oligosaccharide, the maltodextrin and the added talcum powder are mixed for 5 minutes, sieved by a 40-mesh sieve and mixed for 20 minutes, then dry granulation is carried out by adopting a rolling method, a 20-mesh sieve is used for carrying out granulation, the added talcum powder is sieved by the 40-mesh sieve and added into the dry granules, and then the mixture is continuously mixed for 5 minutes. The resulting homogeneous mixture is compressed into tablets. Coating the compressed tablets by spraying a mixture of polyvinyl alcohol, polyethylene glycol, titanium dioxide, yellow iron oxide and water in a coating pan, the weight gain after coating being 1-6% w/w, preferably 2-3%.

Formulation 7 was stored at 80 degrees at ambient humidity for 1 week, after 1 week, only 0.09% of impurity D was found to be formed. Comparing formulation 8, 0.51% of impurity D was formed.

Example 5

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Mixing the reagent, microcrystalline cellulose, corn starch oligosaccharide, maltodextrin and added talcum powder for 5 minutes, sieving with a 40-mesh sieve, mixing for 20 minutes, performing dry granulation by adopting a rolling method, grading by adopting a 20-mesh sieve, adding the added talcum powder into the dry granules after sieving with the 40-mesh sieve, and continuously mixing for 5 minutes. The resulting homogeneous mixture is compressed into tablets. The compressed tablets are coated by spraying a mixture of polyvinyl alcohol, polyethylene glycol, titanium dioxide, yellow iron oxide and water in a coating pan with a weight gain after coating of 1-6% w/w, preferably 2-3%.

Formulation 9 was stored at 80 degrees humidify for 1 week, after 1 week, only 0.10% of impurity D was found to be formed. Formula 10, forming 0.43% of impurity D, formula 11, forming 0.19% of impurity D. Therefore, the dosage in the prescription 9 is proper.

As can be seen from the above tests, the pharmaceutical composition of the present invention can maintain the stability of the active ingredient over a long period of time, and the content of impurities is significantly less than that of a similar preparation containing no oligosaccharide ingredient when stored under the same conditions.

The generation of impurity D may be related to the oxidizing environment and moisture. The oligosaccharide has certain reducibility due to the aldehyde group, and has certain reduction effect on the generation of the impurity D. However, the oligosaccharide belongs to an auxiliary material which is easy to absorb moisture, the dosage in the prescription is too large, and the composition absorbs moisture in the storage process, so that the impurity D is increased. Therefore, the oligosaccharide dosage in the formula is appropriate.

Claims

1. A pharmaceutical composition comprising (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as an active ingredient, said pharmaceutical composition having a formulation of: 50.00g of maltodextrin, 100.00g of active ingredients, 380.00g of lactose monohydrate, 30.00g of crospovidone and 5.00g of magnesium stearate.

2. A pharmaceutical composition comprising (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as an active ingredient, said pharmaceutical composition being formulated as: 40.00g of dextrin, 100.00g of active ingredients, 365.00g of anhydrous lactose, 25.00g of croscarmellose sodium and 5.00g of magnesium stearate.

3. A pharmaceutical composition comprising (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as an active ingredient, said pharmaceutical composition being formulated as: 30.00g of corn starch oligosaccharide, 100.00g of active ingredients, 300.00g of anhydrous lactose, 25.00g of carboxymethyl starch sodium and 5.00g of magnesium stearate.

4. A pharmaceutical composition comprising (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as an active ingredient, said pharmaceutical composition being formulated as: 15.00g of corn starch oligosaccharide, 15.00g of maltodextrin, 100.00g of active ingredients, 300.00g of microcrystalline cellulose, 5.00g of talcum powder and 25.00g of crospovidone.

5. A pharmaceutical composition comprising (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as an active ingredient, said pharmaceutical composition having a formulation of: 40.00g of maltodextrin, 100.00g of active ingredients, 380.00g of lactose monohydrate, 30.00g of crospovidone and 5.00g of magnesium stearate.