EDARAVONE PHARMACEUTICAL COMPOSITION

Abstract

Disclosed in the present invention are an edaravone pharmaceutical composition and an application thereof as a sublingual preparation, the pharmaceutical composition containing edaravone or a salt thereof and mannitol. A sublingual administration preparation can avoid the first-pass effect of the liver, and samples feature good stability, convenience of transport and of use, among other advantages.

Claims

1. A pharmaceutical composition comprising edaravone or a salt thereof as an active ingredient, a filler, a binder and a disintegrant.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a sublingual preparation, such as a sublingual tablet.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition does not comprise 2-camphanol, preferably does not comprise active ingredients other than edaravone or a salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the filler is not lactose, starch or microcrystalline cellulose, preferably the filler comprises mannitol, more preferably the filler is mannitol.

5. The pharmaceutical composition according to claim 1, wherein the filler accounts for 25% to 90%, 30% to 80%, 35% to 75% or 40% to 70% by mass of the pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, wherein the binder is not copovidone, preferably the binder comprises hydroxypropyl methylcellulose, more preferably the binder is hydroxypropyl methylcellulose.

7. The pharmaceutical composition according to claim 1, wherein the disintegrant comprises at least one selected from the group consisting of croscarmellose sodium and crospovidone, preferably the disintegrant comprises crospovidone, more preferably the disintegrant is crospovidone.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a lubricant, for example the lubricant comprises magnesium stearate, preferably the lubricant is magnesium stearate.

9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a glidant, for example the glidant comprises silica, preferably the glidant is silica.

10. The pharmaceutical composition according to claim 1, wherein a blood concentration of the edaravone reaches 10 to 10,000 ng/mL within 0.1 to 24 hours after sublingual administration to a patient in a unit dosage form.

11. A method of treating and/or preventing cerebrovascular disease or amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 1.

12. The method according to claim 11, wherein the cerebrovascular disease is ischemic encephalopathy, such as stroke.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0028] FIG. 1 is the dissolution profile of the sublingual tablets prepared according to Examples 1 to 5.

[0029] FIG. 2 is the dissolution profile of the sublingual tablets prepared according to Examples 6 to 10.

[0030] FIG. 3 is the dissolution profile of the sublingual tablets prepared according to Examples 11 to 14.

DETAILED DESCRIPTION

[0031] The present invention discloses an edaravone pharmaceutical composition, especially in a form of sublingual preparations. Those skilled in the art can achieve this by using the content of the present invention for reference, combining the principles of pharmacy, and appropriately improving the process parameters or the formula ratio. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the scope of the present invention. The applications of the present invention have been well described through the examples, and relevant personnel can make appropriate changes, alterations or combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and apply the present invention.

[0032] The following examples are used to further illustrate the present invention, but they are not meant to limit the protection scope of the present invention in any way.

[0033] The reagents and instruments used in the examples of the present disclosure are all commercially available, and the bulk drugs and various excipients/additives, such as edaravone (Jiangsu Tiansheng Pharmaceutical Co., Ltd), lactose (FLOWLAC 100), microcrystalline cellulose (CEOLUS PH302), mannitol (Pearlitol 200SD), copovidone (PLASDONE S-630), hydroxypropyl methylcellulose (SH-E5), croscarmellose sodium (AcDi Sol), crospovidone (POLYPLASDONE XL-10), starch (tapioca starch), silica (Huzhou Zhanwang Pharmaceutical Co., Ltd.), magnesium stearate (Anhui Sunhere Pharmaceutical Excipients Co., Ltd.), are all in compliance with pharmaceutical standards.

Example 1

[0034]

TABLE-US-00001 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Lactose 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0035] Preparation method: Edaravone, lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 2

[0036]

TABLE-US-00002 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Starch 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0037] Preparation method: Edaravone, starch, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 3

[0038]

TABLE-US-00003 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Microcrystalline cellulose 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0039] Preparation method: Edaravone, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 4

[0040]

TABLE-US-00004 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0041] Preparation method: Edaravone, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 5

[0042]

TABLE-US-00005 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Lactose 41.2 Filler Copovidone 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0043] Preparation method: Edaravone, lactose, copovidone, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 6

[0044]

TABLE-US-00006 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Microcrystalline cellulose 41.2 Filler Copovidone 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0045] Preparation method: Edaravone, microcrystalline cellulose, copovidone, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 7

[0046]

TABLE-US-00007 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 41.2 Filler Copovidone 4 Binder Croscarmellose sodium 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0047] Preparation method: edaravone, mannitol, copovidone, croscarmellose sodium, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 8

[0048]

TABLE-US-00008 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Lactose 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Crospovidone 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0049] Preparation method: Edaravone, lactose, hydroxypropyl methylcellulose, crospovidone, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 9

[0050]

TABLE-US-00009 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Microcrystalline cellulose 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Crospovidone 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0051] Preparation method: Edaravone, microcrystalline cellulose, hydroxypropyl methylcellulose, crospovidone, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 10

[0052]

TABLE-US-00010 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 41.2 Filler Hydroxypropyl methylcellulose 4 Binder Crospovidone 4 Disintegrant Magnesium stearate 0.8 Lubricant

[0053] Preparation method: edaravone, mannitol, hydroxypropyl methylcellulose, crospovidone and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 11

[0054]

TABLE-US-00011 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 40.4 Filler Hydroxypropyl methylcellulose 4 Binder Crospovidone 4 Disintegrant Silica 0.8 Glidant Magnesium stearate 0.8 Lubricant

[0055] Preparation method: Edaravone, mannitol, hydroxypropyl methylcellulose, crospovidone, silica, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 12

[0056]

TABLE-US-00012 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 15 Filler Hydroxypropyl methylcellulose 2 Binder Crospovidone 5 Disintegrant Silica 0.5 Glidant Magnesium stearate 0.5 Lubricant

[0057] Preparation method: Edaravone, mannitol, hydroxypropyl methylcellulose, crospovidone, silica, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 13

[0058]

TABLE-US-00013 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 30.2 Filler Hydroxypropyl methylcellulose 1.4 Binder Crospovidone 7 Disintegrant Silica 0.7 Glidant Magnesium stearate 0.7 Lubricant

[0059] Preparation method: Edaravone, mannitol, hydroxypropyl methylcellulose, crospovidone, silica, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 14

[0060]

TABLE-US-00014 Dosage per tabelet Material Name (mg) Role Edaravone 30 Active ingredient Mannitol 186 Filler Hydroxypropyl methylcellulose 10 Binder Crospovidone 20 Disintegrant Silica 2 Glidant Magnesium stearate 2 Lubricant

[0061] Preparation method: Edaravone, mannitol, hydroxypropyl methylcellulose, crospovidone, silica, and magnesium stearate were mixed uniformly according to the formula ratio, and the mixture was compressed into tablets.

Example 15

[0062] Stability test results: An appropriate amount of samples from Examples 1-14 were packaged in a simulated market packaging, and placed at a temperature of 40° C. or 60° C. for 10 days or 30 days for sampling. The characteristics, edaravone content, and related substances were determined and the results were shown in the following table:

TABLE-US-00015 Placing Content Related Examples Conditions Characteristics (%) Substances (%) Example 1 0 day White to off- 99.83 0.09 white tablets 40° C., Light yellow 99.64 0.13 10 days tablets 60° C., Light yellow 99.57 0.31 10 days tablets 40° C., Light yellow 98.48 0.76 30 days tablets 60° C., Light yellow 98.85 0.98 30 days tablets Example 2 0 day White to off- 99.62 0.07 white tablets 40° C., Light yellow 99.75 0.21 10 days tablets 60° C., Light yellow 99.82 0.36 10 days tablets 40° C., Light yellow 98.64 0.84 30 days tablets 60° C., Light yellow 98.34 0.94 30 days tablets Example 3 0 day White to off- 100.02 0.02 white tablets 40° C., Light yellow 100.04 0.16 10 days tablets 60° C., Light yellow 99.38 0.38 10 days tablets 40° C., Light yellow 98.56 0.72 30 days tablets 60° C., Light yellow 98.98 1.06 30 days tablets Example 4 0 day White to off- 99.26 0.01 white tablets 40° C., White to off- 99.75 0.05 10 days white tablets 60° C., White to off- 99.21 0.10 10 days white tablets 40° C., White to off- 99.25 0.43 30 days white tablets 60° C., White to off- 98.45 0.77 30 days white tablets Example 5 0 day White to off- 99.88 0.06 white tablets 40° C., Light yellow 99.27 0.23 10 days tablets 60° C., Light yellow 99.36 0.51 10 days tablets 40° C., Light yellow 98.25 1.01 30 days tablets 60° C., Light yellow 97.34 1.12 30 days tablets Example 6 0 day White to off- 98.24 0.10 white tablets 40° C., Light yellow 98.65 0.21 10 days tablets 60° C., Light yellow 97.15 0.54 10 days tablets 40° C., Light yellow 98.12 1.02 30 days tablets 60° C., Light yellow 97.86 1.12 30 days tablets Example 7 0 day White to off- 98.65 0.02 white tablets 40° C., White to off- 100.42 0.08 10 days white tablets 60° C., White to off- 99.56 0.10 10 days white tablets 40° C., White to off- 98.89 0.43 30 days white tablets 60° C., White to off- 98.56 0.57 30 days white tablets Example 8 0 day White to off- 100.14 0.05 white tablets 40° C., Light yellow 100.23 0.13 10 days tablets 60° C., Light yellow 100.10 0.45 10 days tablets 40° C., Light yellow 98.26 0.78 30 days tablets 60° C., Light yellow 98.84 0.95 30 days tablets Example 9 0 day White to off- 99.58 0.08 white tablets 40° C., Light yellow 99.56 0.26 10 days tablets 60° C., Light yellow 99.84 0.46 10 days tablets 40° C., Light yellow 98.56 0.98 30 days tablets 60° C., Light yellow 98.87 1.12 30 days tablets Example 10 0 day White to off- 99.52 0.01 white tablets 40° C., White to off- 99.45 0.04 10 days white tablets 60° C., White to off- 99.36 0.12 10 days white tablets 40° C., White to off- 98.78 0.42 30 days white tablets 60° C., White to off- 98.85 0.63 30 days white tablets Example 11 0 day White to off- 99.18 0.02 white tablets 40° C., White to off- 99.45 0.08 10 days white tablets 60° C., White to off- 99.25 0.16 10 days white tablets 40° C., White to off- 98.47 0.35 30 days white tablets 60° C., White to off- 98.36 0.75 30 days white tablets Example 12 0 day White to off- 99.58 0 white tablets 40° C., White to off- 99.76 0.09 10 days white tablets 60° C., White to off- 99.85 0.21 10 days white tablets 40° C., White to off- 98.37 0.31 30 days white tablets 60° C., White to off- 98.21 0.76 30 days white tablets Example 13 0 day White to off- 100.49 0 white tablets 40° C., White to off- 99.94 0.07 10 days white tablets 60° C., White to off- 98.26 0.18 10 days white tablets 40° C., White to off- 98.90 0.27 30 days white tablets 60° C., White to off- 98.40 0.81 30 days white tablets Example 14 0 day White to off- 99.86 0.02 white tablets 40° C., White to off- 99.78 0.06 10 days white tablets 60° C., White to off- 99.85 0.15 10 days white tablets 40° C., White to off- 98.57 0.24 30 days white tablets 60° C., White to off- 98.46 0.91 30 days white tablets

[0063] According to the above table, the test results of Examples 1-14 showed that after being placed at a higher temperature for 30 days, the content of the active substance edaravone in all Examples 1-14 remained above 97%, which was satisfactory; the content of the active substance edaravone in most of the examples was kept above 98% except for a few examples (Examples 5 and 6). However, the inventors unexpectedly found that when lactose, starch or microcrystalline cellulose was selected as the filler in Examples 1-3, 5-6, and 8-9, color changes occurred on the appearance of the tablets when the tablets were placed at a higher temperature. On the contrary, in Examples 4, 7, and 10-14, when mannitol was used as the filler, the tablets maintained a high content of active ingredients and produced a very small amount of related substances during being placed at a higher temperature. Moreover, the properties were unchanged, all remaining white to off-white tablets, and the stability performance was particularly excellent.

Example 16

[0064] Test method for determination of dissolution: According to the determination method of the dissolution and release (Chinese Pharmacopoeia 2015, volume IV, 0931, second method), 900 ml of water was functioned as a dissolution medium, and the rotating speed was 50 rpm. Operations were performed according to said method. Samples were taken at different time points, filtered via a 0.8 μm filter membrane, and the subsequent filtrates were taken as the test solution; 20 mmol/L ammonium acetate/acetonitrile (80:20) was added to an appropriate amount of reference substance edaravone, and the edaravone was dissolved and diluted to approximately 0.02 mg/ml for later use. The UV absorbance of the test solution was measured under the condition of 254 nm, and the dissolution rate of the samples was calculated. The results were shown in FIGS. 1, 2, and 3. The dissolution rate of examples 5, 6, and 7 which contains the adhesive copovidone was slower; the formulations of other examples had better dissolution results.

Example 17

Study on Bridging PK of Edaravone Sublingual Tablets and Injections:

Materials and Methods

[0065] Experimental animals: Beagle dogs, male, weighing 8-10 kg; available from Beijing Marshall Biotechnology Co., Ltd.; certificate No. 11400600012054; license No. SOCK (Beijing) 2016-0001.

[0066] Food and water supply: Animals were fasted for 12 hours before the test, and provided food 4 hours after administration. Animals received water ad libitum throughout the experiment. Abnormal reactions in animals were observed and recorded during drug administration and sample collection.

[0067] Test drugs: Edaravone injection: specification: 10 mg/5 mL (Nanjing Simcere Pharmaceutical Co., Ltd.); sublingual tablets prepared according to the formula ratio of Example 5 (specification: 30 mg/tablet, tablet weight: 80 mg); sublingual tablets prepared according to the formula ratio of Example 7 (specification: 30 mg/tablet, tablet weight: 80 mg); sublingual tablets prepared according to the formula ratio of Example 13 (specification: 30 mg/tablet, tablet weight: 70 mg); sublingual tablets prepared according to the formula ratio of Example 14 (specification: 30 mg/tablet, tablet weight: 250 mg).

[0068] Methods: The dogs were weighed on the day of the experiment, and the body weight of each dog was recorded for dripping or sublingual administration and calculation of related pharmacokinetic parameters.

[0069] Group 1: Dripping Administration of Edaravone Injection (N=2)

[0070] Dosage for administration: 12 mL, a total of 24 mg edaravone was administered.

[0071] The dogs were administered by intravenous dripping and dripping was ended after 12 minutes. The initiation time of dripping was regarded as the time point of 0 min, and then the whole blood was collected at time points of 5 min, 12 min, 30 min, 45 min as well as 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h.

[0072] Group 2: Sublingual Administration of One Sublingual Tablet of Example 5 (N=3).

[0073] The Beagle dogs were administered sublingually by inserting the tablet under the tongue of the dogs at a dose of 1 tablet/dog with their mouth kept fixed for 12 minutes to prevent the tablet from falling out. Since involuntary saliva secretion and swallowing affect the efficacy of sublingual administration, their mouth needs to be fixed for 12 minutes. The time when the tablet was placed under the tongue was regarded as the time point of 0 min, and then the whole blood was collected at time points of 5 min, 12 min, 30 min, 45 min as well as 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h.

[0074] Group 3: Sublingual Administration of One Sublingual Tablet of Example 7 (N=3).

[0075] The Beagle dogs were administered sublingually by inserting the tablet under the tongue of the dogs at a dose of 1 tablet/dog with their mouth kept fixed for 12 minutes to prevent the tablet from falling out. Since involuntary saliva secretion and swallowing affect the efficacy of sublingual administration, their mouth needs to be fixed for 12 minutes. The time when the tablet was placed under the tongue was regarded as the time point of 0 min, and then the whole blood was collected at time points of 5 min, 12 min, 30 min, 45 min as well as 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h.

[0076] Group 4: Sublingual Administration of One Sublingual Tablet of Example 13 (N=3).

[0077] The Beagle dogs were administered sublingually by inserting the tablet under the tongue of the dogs at a dose of 1 tablet/dog with their mouth kept fixed for 12 minutes to prevent the tablet from falling out. Since involuntary saliva secretion and swallowing affect the efficacy of sublingual administration, their mouth needs to be fixed for 12 minutes. The time when the tablet was placed under the tongue was regarded as the time point of 0 min, and then the whole blood was collected at time points of 5 min, 12 min, 30 min, 45 min as well as 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h.

[0078] Group 5: Sublingual Administration of One Sublingual Tablet of Example 14 (N=3).

[0079] The Beagle dogs were administered sublingually by inserting the tablet under the tongue of the dogs at a dose of 1 tablet/dog with their mouth kept fixed for 12 minutes to prevent the tablet from falling out. Since involuntary saliva secretion and swallowing affect the efficacy of sublingual administration, their mouth needs to be fixed for 12 minutes. The time when the tablet was placed under the tongue was regarded as the time point of 0 min, and then the whole blood was collected at time points of 5 min, 12 min, 30 min, 45 min as well as 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h.

[0080] Experimental results: Each average pharmacokinetic parameter of edaravone in plasma after intravenous dripping of edaravone injection and sublingual administration of edaravone sublingual tablets in Beagle dogs.

TABLE-US-00016 Intravenous Exam- Exam- Exam- Exam- injection ple 5 ple 7 ple 13 ple 14 T.sub.max (h) 0.50 0.75 0.67 0.63 0.50 C.sub.max (ng/mL) 7195 5230 6029 8380 9580 AUC.sub.0-24 h 12060 8115 9218 15693 12281 (h*ng/mL) AUC.sub.0-24 h/dose 3934 2551 2880 4939 3934 (ng .Math. h .Math. kg .Math. mL.sup.−1 .Math. mg.sup.−1) MRT.sub.last (h) 2.87 3.39 3.25 3.18 3.51 F (%) / 64 73 125.5 100.0

[0081] The results of the PK bridging of the administration of sublingual tablets and injections for Beagle dogs showed that, for the edaravone sublingual preparations in Example 13 and in Example 14, edaravone was almost completely absorbed, meeting the conditions for sublingual administration. Edaravone sublingual tablets have advantages such as good pharmacokinetic properties, high bioavailability and convenient of use.