Briracetam oral soluble film pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a briracetam oral soluble film pharmaceutical composition and a preparation method thereof. The oral soluble film pharmaceutical composition comprises the following components: briracetam, a film-forming material, a plasticizer, ion exchange resin, a pigment and a flavoring agent. The Briracetam oral soluble film pharmaceutical composition is good in appearance, moderate in flexibility, good in taste, short in dissolution time limit, rapid in effect taking and convenient to carry, and the medication compliance and safety of patients with dysphagia are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a brivaracetam orodispersible film-forming pharmaceutical composition and a preparation method thereof. Background Art

[0002] Brivaracetam, also known as buvacetam, is a derivative of levetiracetam. Brivaracetam can bind to central synaptic vesicle protein 2A (SV2A) with strong selectivity and reversibility, exerting anti-epileptic effects by affecting synaptic function; as well as inhibiting voltage-dependent sodium ion channels, reducing the duration and frequency of epileptic discharges, thereby reducing epileptic seizures. Compared with previous generation drugs, brivaracetam has milder side effects and is well tolerated in all key trials. Most adverse reactions are mild to moderate. Commonly reported adverse reactions are drowsiness, dizziness, fatigue, etc. The incidence of mental and cognitive side effects is relatively low, with better safety and tolerability, effectively improving the quality of life of patients.

[0003] Brivaracetam was first developed and marketed by UCB Pharma SA. Its marketed dosage forms mainly include tablets, injections, and oral solutions, all under the trade name Briviact. It has not yet been launched in China.

[0004] Since epilepsy patients need to take medication for a long time to prevent seizures, the convenience of carrying and taking the medicine needs to be considered. Conventional tablets need to be taken with water, and the water or oral liquid used for taking them has the characteristics of large volume and weight, which is not convenient to carry.

[0005] Patent CN112957348A discloses a brivaracetam oral film, which is prepared by a casting process, but does not mention a larger specification of 10-100 mg of brivaracetam and a daily dosage of up to 200 mg for adults. Under this specification, the concentration of the raw material in the film is high.

[0006] Therefore, the present application aims to provide a brivaracetam orodispersible film-forming agent with a simple preparation process, good taste of the finished product, good mechanical properties, and guaranteed safety and effectiveness in clinical use. Summary of the invention

[0007] In order to simplify the preparation process and improve the taste of the preparation, the technical solution adopted by the present invention is:

[0008] A brivaracetam orodissolving film pharmaceutical composition, characterized in that it comprises the following components: 20.0-50.0wt% of brivaracetam, 20.0-40.0wt% of film-forming material, 10.0-20.0wt% of plasticizer, 10.0-35.0wt% of ion exchange resin, 0.1-3.0wt% of flavoring agent, and 0.1-2.0wt% of pigment.

[0009] Furthermore, the film-forming material is selected from one or a combination of hypromellose E5 and hypromellose E15, and the mass ratio of hypromellose E5 to hypromellose E15 is 1:1-2:1.

[0010] Furthermore, the plasticizer is polyethylene glycol.

[0011] Furthermore, the ion exchange resin is selected from one of polyclinic or polyclinic potassium or a combination thereof, and the mass ratio of brivaracetam to the ion exchange resin is 2:1-1:1.

[0012] Furthermore, the flavoring agent is selected from one or more of saccharin sodium, acesulfame potassium, sucralose, and neotame, with neotame being more preferred.

[0013] Furthermore, the pigment is selected from one or a combination of sunset yellow, carmine, yellow iron oxide, carotene, and titanium dioxide.

[0014] Furthermore, the preparation method of the brivaracetam orodispersible film pharmaceutical composition comprises the following steps:

[0015] (1) weighing the components according to the ratio, adding brivaracetam and ion exchange resin into purified water, stirring for 180 min-300 min, and obtaining solution A;

[0016] (2) adding film-forming material 1 and pigment to solution A, stirring for 30-80 min, emulsifying for 5-20 min, and obtaining solution B;

[0017] (3) adding the prescribed amount of film-forming material 2 and plasticizer to the solution B obtained in step (2), stirring until dissolved, to obtain solution C;

[0018] (4) adding a prescribed amount of flavoring agent to the solution C obtained in step (3), stirring until dissolved, to obtain a solution D, wherein the viscosity of the solution D is 7000-12000 mPa·s;

[0019] (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film;

[0020] (6) Cut and package the rolled film, and control the film weight difference within ±5% to obtain the finished product.

[0021] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0022] 1. The prescription uses ion exchange resin to adsorb brivaracetam, which is more effective in reducing the bitterness and duration of brivaracetam after it dissolves in the mouth compared to the inclusion masking of cyclodextrin.

[0023] 2. The preparation process uses a combination of the flavoring agent neotame and ion exchange resin to ensure that there is still enough sweetness to enhance the taste when brivaracetam is present, thereby ensuring the compliance of pediatric patients with the medication.

[0024] 3. The film-forming material in the prescription is preferably a combination of hypromellose E5 and hypromellose E15, and the mass ratio of the two is preferably 1:1-2:1, which ensures that the brivaracetam oral fast-dissolving film has a high drug loading process stability.

[0025] 4. In the formula, the film-forming materials hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15 are compounded with the plasticizer polyethylene glycol to obtain a film with good flexibility, good dispersibility and gloss.

[0026] 5. The colorant is preferably a combination of yellow iron oxide and titanium dioxide, which has both shading and coloring effects, ensuring the stability of brivaracetam while beautifying the appearance. It does not contain pigments that often have azo residues, effectively avoiding the problem of low reducing ability and sensitivity of children to azo substances when taking the medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Data graph showing the effect of flavor correctives on the taste of oral fast-dissolving films (electronic tongue data);

[0028] Figure 2 This is a data chart showing the effect of taste masking on the taste of oral fast-dissolving films (electronic tongue data). DETAILED DESCRIPTION

[0029] The present invention is further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description progresses, but it should be understood that the embodiments are only exemplary and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications or replacements all fall within the protection scope of the present invention.

[0030] Example

[0031] The saturated solubility of brivaracetam in water is about 46.8 mg / ml, and it can be completely dissolved when the film is prepared into a pharmaceutical solution.

[0032] The prescription compositions of Examples 1-8 are as follows:

[0033] composition Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Unit of measurement (g) (g) (g) (g) (g) (g) (g) (g) Brivaracetam 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Hydroxypropyl methylcellulose E5 5.50 6.75 7.00 7.00 7.00 7.00 7.00 7.00 Hydroxypropyl methylcellulose E15 5.50 4.50 4.00 4.00 4.00 4.00 4.00 4.00 Polyethylene glycol 400 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Titanium Dioxide 0.30 0.30 0.30 0.30 0.30 0.30 0.30 0.30 Yellow Iron Oxide 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyclinic potassium 7.50 7.50 7.50 5.00 7.50 10.00 10.00 10.00 Neotame 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.80

[0034] Comparative Example

[0035] The prescription compositions of Comparative Examples 1-7 are as follows:

[0036]

[0037]

[0038] The preparation method is as follows:

[0039] (1) weighing the components according to the ratio, adding brivaracetam and ion exchange resin into purified water, stirring for 180 min-300 min, and obtaining solution A;

[0040] (2) adding film-forming material 1 and pigment to solution A, stirring for 30-80 min, emulsifying for 5-20 min, and obtaining solution B;

[0041] (3) adding the prescribed amount of film-forming material 2 and plasticizer to the solution B obtained in step (2), stirring until dissolved, to obtain solution C;

[0042] (4) adding a prescribed amount of flavoring agent to the solution C obtained in step (3), stirring until dissolved, to obtain a solution D;

[0043] (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film;

[0044] (6) Cut and package the rolled film, and control the film weight difference within ±5% to obtain the finished product.

[0045] Experimental Results

[0046] 1. Liquid Viscosity Detection

[0047] test Example 1 Example 2 Example 3 Comparative Example 6 Comparative Example 7 HPMC E5 / E15 ratio 1:1 1.5:1 1.75:1 0.57:1 3:1 Minimum detection viscosity 11652mPa·s 9254mPa·s 7694mPa·s 15662mPa·s 5405mPa·s Maximum viscosity 12325mPa·s 10752mPa·s 9928mPa·s 14967mPa·s 6221mPa·s

[0048] After the preparation of the drug solution in Example 1, the viscosity was about 12000 mPa·s. Examples 2 and 3 gradually reduced the prescription ratio of the highly viscous hypromellose E15, and increased the ratio of hypromellose E5 year-on-year. The viscosity of the intermediate product drug solution of different proportions of film-forming agents in Examples 1-3 can be controlled at 7000-12000 mPa·s, and the viscosity range is suitable for the needs of mass production equipment, and can ensure that the film has a high drug loading process stability.

[0049] Comparative Example 6 significantly increased the high viscosity of Hydroxypropyl Methylcellulose E15, and conducted a test with a film-forming material ratio lower than 1:1. The results showed that the viscosity of the liquid could reach 15000mPa·s. At this viscosity, the liquid had a very high dispersion risk when entering the coating equipment. Comparative Example 7 conducted a test with a film-forming material ratio of 3:1. The results showed that the liquid viscosity was about 6000mPa·s, and the adhesion to the substrate was insufficient during the coating process, and the uniformity risk was high. Therefore, the film-forming agent ratio is preferably in the range of 1:1 to 2:1.

[0050] 2. Mechanical properties testing

[0051] In comparative example 1, glycerol was used as the plasticizer, and demolding was difficult during the coating process; in comparative example 2, propylene glycol was used as the plasticizer, and demolding was difficult, and the film was soft in physical properties and had no obvious elasticity when bent. However, after the plasticizer was changed to polyethylene glycol 400 in example 3, the demolding process was smooth, and the film had excellent elasticity and plasticity. Polyethylene glycol is preferably used as the plasticizer.

[0052] Mechanical properties of the films of Examples 4-6 and Comparative Example 3:

[0053]

[0054] The film-forming effects of Examples 4-6 were good, while the film-forming effect of Comparative Example 3 was at risk of solid-liquid separation. Therefore, the taste-masking material was selected as polyclerin potassium. The mechanical properties of the film decreased with the increase of the proportion of polyclerin potassium. The ratio of brivaracetam to polyclerin potassium was preferably 2:1-1:1.

[0055] 3. Taste Testing

[0056] 3.1 Effect of flavor enhancers

[0057] Brivaracetam API has a very strong bitter taste. Figure 1 : The data results of the flavor correctives affecting the taste of oral fast-dissolving films show that the composite sweetener systems of sucralose / saccharin sodium and sucralose / acesulfame potassium / aspartame were used in Comparative Examples 4 and 5, respectively, and had no effect on bitterness compared to the examples, and the sweetness and sweet aftertaste were much lower than the neotame in Example 7. In Examples 7-8, the sweetener was changed to neotame, which is 10 times sweeter than sucralose, and the sweetness was very obvious, but the neotame prescription ratios in Examples 7 and 8 were different, and the change in the neotame ratio had a lower effect on sweetness.

[0058] 3.2 Effect of taste masking method

[0059] According to the attached Figure 2 : The data results of the taste masking method affecting the taste of the oral instant dissolving film show that Examples 4-6 all use potassium polyclinic to adsorb brivaracetam, and the bitterness and bitter aftertaste are significantly reduced. The higher the proportion of potassium polyclinic, the more obvious the reduction in bitterness. However, Comparative Example 3 uses sulfobutyl beta-cyclodextrin to encapsulate brivaracetam, which still exhibits a strong bitter taste in the oral cavity. Therefore, the taste masking method of the present application uses ion exchange resin to adsorb brivaracetam, which more effectively reduces the degree and duration of bitterness of brivaracetam after dissolution in the oral cavity.

[0060] The present invention illustrates the brivaracetam orodissolving film pharmaceutical composition and the preparation method thereof through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A brivaracetam orodispersible film pharmaceutical composition, characterized in that: Includes the following components: Brivaracetam 20.0-50.0wt%, film-forming material 20.0-40.0wt%, plasticizer 10.0-20.0wt%, ion exchange resin 10.0-35.0wt%, flavoring agent 0.1-3.0wt%, pigment 0.1-2.0wt%.

2. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The film-forming material is selected from one of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15 or a combination thereof.

3. The brivaracetam orodispersible film pharmaceutical composition according to claim 2, characterized in that: The mass ratio of the film-forming materials hydroxypropyl methylcellulose E5 to hydroxypropyl methylcellulose E15 is 1:1-2:

1.

4. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The plasticizer is polyethylene glycol.

5. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The ion exchange resin is selected from one of polyclerin and polyclerin potassium or a combination thereof.

6. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The mass ratio of brivaracetam to ion exchange resin is 2:1-1:

1.

7. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The flavoring agent is selected from one or more of saccharin sodium, acesulfame potassium, sucralose, and neotame.

8. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The flavoring agent is neotame.

9. The brivaracetam orodispersible film pharmaceutical composition according to claim 1, characterized in that: The pigment is selected from one of sunset yellow, carmine, yellow iron oxide, carotene, titanium dioxide or a combination thereof.

10. The brivaracetam orodispersible film pharmaceutical composition according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) weighing the components according to the ratio, adding brivaracetam and ion exchange resin into purified water, stirring for 180 min-300 min, and obtaining solution A; (2) adding film-forming material 1 and pigment to solution A, stirring for 30-80 min, emulsifying for 5-20 min, and obtaining solution B; (3) adding the prescribed amount of film-forming material 2 and plasticizer to the solution B obtained in step (2), stirring until dissolved, to obtain solution C; (4) adding a prescribed amount of flavoring agent to the solution C obtained in step (3), stirring until dissolved, to obtain a solution D, wherein the viscosity of the solution D is 7000-12000 mPa·s; (5) allowing the solution D obtained in step (4) to stand and defoam, coating the bubble-free adhesive on a high-temperature resistant PET tape, drying at a temperature of 50-70° C., and removing the film; (6) Cut and package the rolled film, and control the film weight difference within ±5% to obtain the finished product.

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