CN113181143A

CN113181143A - 2-oxo-1-pyrrolidine derivative oral dissolving film and preparation method and application thereof

Info

Publication number: CN113181143A
Application number: CN202110503215.5A
Authority: CN
Inventors: 王帅; 孙庆松; 周文正; 李庆豪; 廖美林; 孙燕; 宋丹丹
Original assignee: Shanghai Huishi Management Consulting Co ltd; Zhejiang Gewenda Biomedical Technology Co ltd
Current assignee: Shanghai Huishi Management Consulting Co ltd; Zhejiang Gewenda Biomedical Technology Co ltd
Priority date: 2021-05-08
Filing date: 2021-05-08
Publication date: 2021-07-30
Anticipated expiration: 2041-05-08
Also published as: CN113181143B

Abstract

The invention discloses a 2-oxo-1-pyrrolidine derivative oral dissolving film and a preparation method and application thereof, and relates to the field of pharmaceutical preparations. The oral dissolving film agent comprises a 2-oxo-1-pyrrolidine derivative, a film forming agent and a plasticizer, and the medicine film agent can be quickly dissolved and absorbed in the oral cavity, so that the first-pass effect of the liver is avoided, and the oral dissolving film agent is safe to take; for patients with dysphagia, the medicinal membrane can be directly taken without extra warm water, and is convenient to take; in addition, the oral film agent of the invention also has no risk of blocking the oral cavity or suffocating of the conventional oral preparation, and improves the medication safety of special patients such as children, old people, mental diseases and some bedridden patients.

Description

2-oxo-1-pyrrolidine derivative oral dissolving film and preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a 2-oxo-1-pyrrolidine derivative oral dissolving film and a preparation method and application thereof.

Background

Epilepsy is a chronic brain disease which is characterized by recurrent epileptic seizures, patients have irregular seizures, can have unconscious seizures suddenly, can have clinical symptoms such as convulsion, spasm, syncope, two eyes straightening and staring, and has the characteristics of paroxysmal, transient, repetitive and stereotypy. Electroencephalogram is the most important auxiliary examination method for diagnosing epilepsy, and patients with epilepsy of about 1/3 can obtain long-term relief after treatment; in addition, 1/3 patients treated with single drug or multiple drugs can control their seizures, and the rest 1/3 patients have delayed disease and developed intractable epilepsy, and need surgery if necessary.

The 2-oxo-1-pyrrolidine derivative is a new generation of antiepileptic drug, namely, Buvalacetam ((S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butyramide) from Belgium-TimeBing (UCB), can be selectively combined with synaptobrevin 2A, and has the affinity with action sites of levetiracetam

15-30 times of that of the protein, high affinityThe effective dosage is reduced by about 10 times compared with levetiracetam, and the brivaracetam is easy to dissolve in water, has high permeability and is almost completely and rapidly absorbed after oral administration. Compared with the second-generation antiepileptic drug levetiracetam, the brivaracetam has higher drug effect and safety. The existing original tablet still has many problems, such as the taking problem of dysphagia patients, first pass effect, poor dissolution rate and the like.

Chinese patent application 201410407641.9 discloses an extended release formulation comprising a 2-oxo-1-pyrrolidine derivative, the granulate comprising an inert core, said inert core being coated with a first layer comprising an active ingredient and at least one excipient, said first layer being coated with a controlled release layer, and said active ingredient being a 2-oxo-1-pyrrolidine derivative.

However, most patients with epileptic seizures show sudden loss of consciousness and generalized tic seizures, or sudden disturbance of consciousness and loss of muscular tension, or bilateral rhythmic myoclonic tic twitching mainly of muscles of the head and upper limbs, or status epilepticus (showing persistent seizures or recurrent seizures with non-recovery of consciousness in intermittence), and if the brivaracetam is prepared into ordinary tablets or sustained-release tablets needing to be swallowed, the compliance of patients taking the tablets is poor, and even the trachea can be blocked, so that the tablets have potential danger.

In view of the above, the inventor of the present invention has conducted extensive and intensive studies, and through a large number of screening and tests, provides a brivaracetam orally-dissolving film agent, which can be rapidly dissolved and absorbed in the oral cavity, avoids the first-pass effect of the liver, and is safe to take; the medicine is suitable for epileptic, and can be directly taken by patients with dysphagia (such as the elderly and children), without need of warm water, and is convenient for administration, especially for children of 4 years old and older. At present, no research related to oral film preparation of the brivaracetam exists.

Disclosure of Invention

The invention aims to provide a 2-oxo-1-pyrrolidine derivative oral dissolving film, a preparation method and application thereof, and a medicament for treating epilepsy, which have the advantages of better dissolution rate, quicker response, wide applicability, simple process, stable content, high safety and good application prospect.

In order to achieve the purpose, the technical scheme of the invention is as follows:

in the present invention, in the case of the present invention,

the term "about" is a logarithmic quantity modifier and is meant to include within + or-5% of the modified quantity.

The oral dissolving film agent can be rapidly dispersed in the oral cavity and absorbed by the oral mucosa or sublingual tissue to enter blood circulation;

the flavoring agent and the coloring agent are medically acceptable auxiliary materials, the dosage of the flavoring agent and the coloring agent accords with relevant regulations, the purpose of the flavoring agent is to improve or shield the unpleasant odor and taste of the medicine, and the purpose of the coloring agent is to distinguish different specifications of the oral film dissolving agent.

The ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide is the brivaracetam.

First, the present invention provides an orally dissolving film agent comprising a 2-oxo-1-pyrrolidine derivative, a film-forming agent and a plasticizer.

Preferably, the 2-oxo-1-pyrrolidine derivative is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide represented by formula I or a pharmaceutically acceptable salt thereof,

further preferred is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide represented by formula I.

Preferably, the 2-oxo-1-pyrrolidine derivative is present in an amount of 2 to 80%, more preferably 5 to 60% by weight of the total weight of the oromelt film formulation.

Preferably, the film forming agent accounts for more than 10% of the total weight of the oral dissolving film agent.

Preferably, the plasticizer accounts for more than 10% of the total weight of the mouth dissolving film agent.

Preferably, the film forming agent includes, but is not limited to, at least one of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol (PVA), povidone, ethylene-vinyl acetate copolymer (EVA), polyvinylpyrrolidone, copovidone, sodium alginate, polyacrylic acid, and gelatin, and more preferably at least one of hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone, and povidone.

Preferably, the plasticizer includes, but is not limited to, at least one of glycerin, polyethylene glycol, ethylene glycol, propylene glycol, butylene glycol, sorbitol, polysorbate.

Preferably, the oral film dissolving agent further comprises a flavoring agent, and further preferably, the flavoring agent comprises at least one of sucrose, fruit essence, glucose, saccharin sodium, aspartame, sucralose, maltose, sodium cyclamate and stevioside.

Preferably, the oral dissolving film agent further comprises a coloring agent, and further preferably, the coloring agent comprises at least one of amaranth, carmine, erythrosine, lemon yellow, sunset yellow, indigo blue and brilliant blue.

The invention further provides an application of the oral dissolving film agent in preparation of a medicine for treating epilepsy.

Secondly, the invention also provides a preparation method of the oral dissolving film agent, which comprises the following steps: dissolving a prescribed amount of film forming agent in a solvent to obtain a mixed solution, adding a prescribed amount of plasticizer into the mixed solution, dissolving, then sequentially adding a prescribed amount of 2-oxo-1-pyrrolidine derivative, a flavoring agent and a coloring agent solution, dissolving, removing bubbles in the solution, then uniformly coating on a substrate, and heating and drying to form a film.

Preferably, the solvent is water, and the temperature is 50 to 100 ℃, and more preferably 90 ℃. Water with the temperature of more than 90 ℃ is beneficial to the dispersion and swelling of hydroxypropyl methyl cellulose and hydroxypropyl cellulose; the lower the water temperature, the longer the hydroxypropylmethylcellulose, hydroxypropylcellulose, needs to be dispersed and swollen.

Preferably, when the film-forming agent comprises sodium carboxymethylcellulose and contains two or more components, the sodium carboxymethylcellulose should be added after the addition of the 2-oxo-1-pyrrolidine derivative.

Finally, the invention provides a medicament for treating epilepsy, which is characterized in that the dosage form of the medicament is an oral dissolving film agent, and the active ingredient is a 2-oxo-1-pyrrolidine derivative.

Preferably, the 2-oxo-1-pyrrolidine derivative is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide shown in formula I and pharmaceutically acceptable salts thereof, preferably ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide shown in formula I,

compared with the prior art, the invention has the beneficial effects that:

(1) the film agent of the invention can be directly taken, the administration does not need drinking water, the taking is convenient, and the film agent is especially suitable for dysphagia patients, such as the old and children over 4 years old.

(2) The dissolution rate of the oral dissolution film agent of the invention is superior to that of the original ground tablet in the phosphate buffer solution with the pH value of 6.0; under the condition of a hydrochloric acid solution with the pH value of 1.2, the dissolution rate of the compound is superior to that of the original ground tablet; in aqueous solution, the dissolution rate of the self-made film agent is also superior to that of the originally ground tablet, the self-made film agent can achieve rapid release (the dissolution amount can reach 80 percent of the marked amount in 5 minutes) under different pH conditions, the medicine film agent can be rapidly dispersed in the oral cavity and can be rapidly absorbed by the oral mucosa or sublingual tissues to enter blood circulation, the effect of taking effect faster is achieved, the first pass effect of the conventional oral preparation is avoided, and the administration is safer.

(3) The brivaracetam oral dissolving film agent prepared by the invention has simple process and is convenient for commercial production.

(4) In a 6-month medicament acceleration experiment (40 ℃ and 75% RH), the prepared oral soluble film agent of the invention has no obvious change in property and content; the related substances have impurity growth within the limit, and the quality is stable and controllable.

(5) The oral film of the brivaracetam has no risk of blocking the oral cavity or suffocating by the conventional oral preparation, and improves the medication safety of special patients such as children, old people, mental diseases and some bedridden patients.

Drawings

FIG. 1 is a graph comparing dissolution curves of a self-made film agent and a primary ground tablet in a phosphate buffer solution with a pH of 6.0;

FIG. 2 is a comparison graph of dissolution curves of a self-made film agent and a primary grinding tablet in water;

FIG. 3 is a graph showing the comparison of dissolution curves of a self-made film agent and a primary tablet in hydrochloric acid solution with pH of 1.2.

Detailed Description

The following non-limiting examples are presented to enable those of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. The following is merely an exemplary illustration of the scope of the invention as claimed, and various changes and modifications of the invention of the present application may be made by those skilled in the art based on the disclosure, which also fall within the scope of the invention as claimed.

The present invention will be further described below by way of specific examples. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

In the examples herein, the disintegration time was measured by holding the orally dissolving film with a paper clip, checking it against 0921 (method under the item of disintegration time limit inspection tablet) on the four-part general rule of the chinese pharmacopoeia 2015 edition, recording the time for the orally dissolving film to completely dissolve and pass through a screen, and recording the mean value of the disintegration time of 6 tablets of orally dissolving film.

In the tension measurement, the prepared finished orosoxazine film is placed on a tensile strength tester, and after a sample is broken at a certain speed, the tensile strength is read, and the tensile strength of 6 sheets of orosoxazine film is recorded.

In the test of dissolution amount (degree), if not specifically stated, according to the second method (paddle method) of dissolution and release determination method in chinese pharmacopoeia (2015 edition, four general rules 0931), the volume of dissolution medium is 900ml of aqueous solution, the dissolution medium needs to be degassed, the temperature is 37 ℃ ± 0.5 ℃, the rotation speed is 45 revolutions per minute, 6 samples are taken and put into a dissolution cup for dissolution test, and the average value of the dissolution amount of 6 pieces of oral dissolution membrane is calculated.

Examples 1 to 3

Examples 1-3 using hydroxypropylmethylcellulose and/or sodium carboxymethylcellulose as film-forming agent, different plasticizers were investigated and brivaracetam was prepared as a film-forming agent at a drug loading (ratio) of about 5% to 25% (w/w%) for oromucosal administration, examples 1-3 being formulated as follows:

table 1.

Examples 1-3 preparation methods: dispersing hydroxypropyl methylcellulose with the prescription amount into hot water with the temperature of 90 ℃, stirring to dissolve the hydroxypropyl methylcellulose, cooling to room temperature, sequentially adding plasticizer with the prescription amount into the solution, stirring to dissolve, sequentially adding brivaracetam, sodium carboxymethylcellulose (if any) and a flavoring agent, stirring to dissolve, ultrasonically removing bubbles in the solution, uniformly coating the medicine on a base material, heating, drying to form a film, cutting into a proper shape and size, and packaging.

The brivaracetam oral solution films prepared in the embodiments 1 to 3 have complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the prepared oral dissolution film can be rapidly dispersed within 1 minute. The prepared oral solution film is subjected to the measurement of parameters such as thickness, tension, disintegration time, dissolution and the like, and the following table is shown:

table 2.

Examples 4 to 6

Examples 4-6 using hydroxypropylmethyl cellulose and hydroxypropyl cellulose, brivaracetam was prepared as a film-forming agent with a drug loading of about 14% -60% (w/w%) for oromucosal administration, according to the following recipe:

table 3.

Examples 4-6 methods of preparation: dispersing hydroxypropyl methylcellulose and hydroxypropyl cellulose in a prescription amount into hot water at 90 ℃, stirring to dissolve, cooling to room temperature, sequentially adding plasticizers (polyethylene glycol 400, sorbitol and propylene glycol) in the prescription amount into the solution, stirring to dissolve, sequentially adding brivaracetam and a flavoring agent, and stirring to dissolve; removing bubbles in the solution by ultrasonic treatment, uniformly coating the medicine on the substrate, heating, drying to form film, cutting into suitable shape and size, and packaging.

The brivaracetam oral solution film prepared according to the examples 4-6 has complete and smooth appearance, uniform color and no bubbles; the addition of the hydroxypropyl cellulose greatly improves the drug loading, but greatly prolongs the disintegration time of the orally dissolving film, and the prepared orally dissolving film is subjected to parameter measurement such as thickness, tension, disintegration time, dissolution and the like, as shown in the following table:

table 4.

Examples 7 to 9

Examples 7-9 using copovidone/povidone, brivaracetam was prepared as a film-forming agent with a drug loading of about 7% -50% (w/w%) for oromucosal administration, formulated as follows:

table 5.

Examples 7-9 preparation methods: dispersing the film-forming agent into purified water, stirring to dissolve, adding plasticizer, stirring to dissolve, adding main drugs including brivaracetam, correctant, and pigment (the pigment is added to make solution, and the solvent is removed at last), stirring to dissolve; removing bubbles by ultrasonic treatment, uniformly coating the medicinal material on the substrate, heating, drying to form film, cutting into suitable shape and size, and packaging.

The brivaracetam oral solution films prepared according to the examples 7-9 have complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the obtained film is quickly dissolved in water, thereby being beneficial to the quick release of the medicine. The prepared oral solution film is subjected to the measurement of parameters such as thickness, tension, disintegration time, dissolution and the like, and the following table is shown:

table 6.

Stability test

Taking an example, setting the temperature and humidity at 40 ℃/RH 75% according to the ICH stability principle, carrying out an accelerated stability test for 6 months, and inspecting items including characters, contents and related substances. The samples were placed in a stability box and sampled at months 0, 1, 2, 3, 6 at the beginning of the test. The test sample accelerated stability test results are shown in the following table.

Table 7.

As a result: the characters and the contents have no obvious change in various examinations; the single impurity and the total impurity of related substances in 6 months are increased within the limit, and the prepared oral dissolving film has good quality stability.

Examples 10 to 12

A film formulation was prepared using hydroxypropylmethylcellulose/copovidone/povidone, the formulation was implemented as follows:

table 8.

Examples 10-12 preparation methods: dispersing hydroxypropyl methylcellulose with the prescription amount into hot water at 90 ℃, stirring to dissolve, cooling to room temperature, adding polyethylene glycol 400 (or sorbitol), brivaracetam and a flavoring agent with the prescription amount into the solution, and stirring to dissolve; removing bubbles in the solution by ultrasonic treatment, uniformly coating the medicine on the substrate, heating, drying to form film, cutting into suitable shape and size, and packaging.

The brivaracetam oral solution films prepared according to the examples 10-12 have complete and smooth appearance, uniform color and no bubbles; the content dissolution meets the requirements, and the obtained film is quickly dissolved in water, thereby being beneficial to the quick release of the medicine. The prepared oral solution film is subjected to the measurement of parameters such as thickness, tension, disintegration time, dissolution and the like, and the following table is shown:

table 9.

As can be seen, the orodispersible films prepared in examples 10-12 have good parameters.

Comparison of data of self-made film agent and original-ground tablet in different dissolution media

According to the second method (paddle method) of determination of dissolution rate and release rate in the Chinese pharmacopoeia (2015 edition four general rules 0931), 900ml dissolution media (prepared with hydrochloric acid solution with pH1.2, phosphate buffer solution with pH6.0 and water respectively) are degassed, the temperature is 37 ℃ +/-0.5 ℃, the rotation speed is 45 rpm, 6 samples are taken and put into a dissolution cup for dissolution test, the samples are taken for 5, 10, 15 and 30 minutes respectively, and the dissolution conditions of the self-made film agent and the original tablet in different dissolution media are respectively examined according to the determination of high performance liquid chromatography (the pharmacopoeia 2015 edition four general rules 0512), and the results are shown in the following table.

TABLE 10 comparison of dissolution curves in water for self-made film and ground tablets

TABLE 11 comparison of dissolution curves of self-made film and ground tablets in HCl solution pH1.2

TABLE 12 comparison of dissolution curves of self-made film and ground tablets in phosphate buffer solution at pH6.0

It can be seen that the dissolution rate of the self-made film agent of the invention in different dissolution media (PH1.2 hydrochloric acid, PH6.0 phosphate buffer solution, aqueous solution) can reach 80% of the marked amount within 5min, which is far higher than that of the original tablet, and the release of the prepared oral dissolution film agent drug is far better than that of the original tablet.

The oral dissolving film agent is the oral dissolving film agent, and the brivaracetam is easy to dissolve in water and has high permeability, so that the oral dissolving film agent is almost completely and quickly absorbed after oral administration, and a new solution is provided for patients with epilepsy (especially children, old people and some bedridden patients with chewing and swallowing difficulties).

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims

1. An orally disintegrating film comprising a 2-oxo-1-pyrrolidine derivative, a film-forming agent and a plasticizer.

2. An oral film dissolving agent according to claim 1, wherein the 2-oxo-1-pyrrolidine derivative is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide of formula I or a pharmaceutically acceptable salt thereof, preferably ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butanamide of formula I,

3. an orally dissolving film according to claim 1, wherein said 2-oxo-1-pyrrolidine derivative is present in an amount of 2-80%, preferably 5-60% by weight of the total weight of the orally dissolving film.

4. An orally dissolving film according to claim 1, wherein said film former comprises more than 10% by weight of the total weight of the film and said plasticizer comprises more than 10% by weight of the total weight of the film.

5. An oral film dissolving agent according to claim 1, wherein the film forming agent is at least one selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone, copovidone, sodium alginate, polyacrylic acid, and gelatin, preferably at least one selected from hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone, copovidone, and povidone; the plasticizer is at least one selected from glycerin, polyethylene glycol, ethylene glycol, propylene glycol, butanediol, sorbitol and polysorbate.

6. The oral film forming agent of claim 1, further comprising a flavoring agent, preferably, the flavoring agent is at least one selected from sucrose, fruit essence, glucose, saccharin sodium, aspartame, sucralose, maltose, sodium cyclamate, and stevioside.

7. The oral film formulation according to claim 1, further comprising a coloring agent, preferably at least one coloring agent selected from amaranth, carmine, erythrosine, lemon yellow, sunset yellow, indigo blue, and brilliant blue.

8. Use of an oral film formulation according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of epilepsy.

9. A method of preparing an orally dissolving film formulation according to any one of claims 1 to 7, comprising the steps of: dissolving a prescribed amount of film forming agent in a solvent to obtain a mixed solution, adding a prescribed amount of plasticizer into the mixed solution, dissolving, then sequentially adding a prescribed amount of 2-oxo-1-pyrrolidine derivative, a flavoring agent and a coloring agent solution, dissolving, removing bubbles in the solution, then uniformly coating on a substrate, and heating and drying to form a film.

10. A medicine for treating epilepsy is characterized in that the dosage form of the medicine is an oral dissolving film agent, the active ingredient is a 2-oxo-1-pyrrolidine derivative, preferably, the 2-oxo-1-pyrrolidine derivative is ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butyramide shown in formula I and pharmaceutically acceptable salts thereof, preferably ((2S) -2- [ (4R) -2-oxo-4-propyl-1-pyrrolidinyl ] butyramide shown in formula I,