CN110638743A

CN110638743A - Composition containing brivaracetam

Info

Publication number: CN110638743A
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: Pharmaceutical Technology Co Ltd
Current assignee: Pharmaceutical Technology Co Ltd
Priority date: 2019-10-25
Filing date: 2019-10-25
Publication date: 2020-01-03
Anticipated expiration: 2039-10-25
Also published as: CN110638743B

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 at 3 months 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 in 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, and 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 long 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.

The oligosaccharide is also called oligosaccharide, and is a straight chain or branched chain-containing saccharide compound formed by connecting 2-20 same or different monosaccharide units through 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 a white powder or a 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 formation and inhibiting product tissue structure. Good film forming performance, can prevent the product from deforming and improve 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, starch hydrolyzed 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 optimized, wherein the ratio of maltodextrin to active ingredient is 1:2-1:6 by weight.

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 the oligosaccharide component under the same storage condition, and the main reason is that the oligosaccharide component can reduce the degradation rate of the brivaracetam raw material caused by oxidation. 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 intended to illustrate the invention, and any of the embodiments in the examples are not intended to be limiting.

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, the weight gain after coating being 1-6% w/w, preferably 2-3%.

Formulation 3 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. Comparison of formulation 4 resulted in 0.42% of impurity D.

Example 3

The reagent, the anhydrous lactose, the corn starch oligosaccharide, the carboxymethyl starch sodium and the added magnesium stearate are respectively sieved by a 40-mesh sieve, mixed for 20 minutes, then dry granulation is carried out by adopting a rolling method, a 20-mesh sieve is adopted for granulation, the added magnesium stearate is sieved by a 40-mesh sieve, added into the dry granules, and 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, the weight gain after coating being 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

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, 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

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 amount used in prescription 9 is appropriate.

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 prolonged period of time, and the content of impurities is significantly less than that of a similar formulation without the 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 active ingredient, characterized in that it comprises one or more oligosaccharides containing glucose units.

2. Pharmaceutical composition according to claim 1, characterized in that said oligosaccharide comprising glucose units is selected from: dextrin, maltodextrin, starch hydrolyzed oligosaccharide.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the oligosaccharide containing glucose units is maltodextrin.

4. The pharmaceutical composition according to claim 1 or 2, wherein the ratio of maltodextrin to active ingredient is 1:2 to 1:6 by weight.

5. The pharmaceutical composition of claim 1 or 2, further comprising one or more fillers, disintegrants, or lubricants.

6. Pharmaceutical composition according to claim 1, characterized in that it comprises (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as active ingredient, one or more fillers, one or more disintegrants, one or more lubricants and maltodextrin.

7. The pharmaceutical composition according to claim 6, wherein the active ingredient is present in an amount of 15 to 25% by weight of the composition, wherein the maltodextrin is present in an amount of 1 to 10% by weight of the composition, wherein the filler is present in an amount of 20 to 80% by weight of the composition, wherein the disintegrant is present in an amount of 1 to 10% by weight of the composition, wherein the lubricant is present in an amount of 0.5 to 3% by weight of the composition, and the sum of the amounts of the components of the pharmaceutical composition is 100% by weight.

8. Pharmaceutical composition according to claim 6, characterized in that it contains (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as active ingredient, maltodextrin, lactose monohydrate, crospovidone and magnesium stearate.

9. Pharmaceutical composition according to claim 6, characterized in that it contains (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as active ingredient, maltodextrin, mannitol, croscarmellose sodium and talc.

10. Pharmaceutical composition according to claim 6, characterized in that it contains (2S) -2- [ (4R) -2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl ] butanamide as active ingredient, maltodextrin, microcrystalline cellulose, croscarmellose sodium and talc.