CN116763746A - Bulleprazole orally disintegrating tablet and preparation method thereof - Google Patents

Abstract

The invention discloses an orally disintegrating tablet containing bripiprazole, which consists of mannitol with good taste, microcrystalline cellulose with certain disintegration effect, an adhesive, a disintegrating agent, a flavoring agent and a lubricant. The bripiprazole orally disintegrating tablet disclosed by the invention is not required to be used by patients or only required to be used by a small amount of water, is not required to be chewed, is placed in the oral cavity, is rapidly dissolved or disintegrated in saliva, and is effective after entering the digestive system for absorption along with the autonomous and involuntary swallowing actions of the users, so that the bripiprazole orally disintegrating tablet is suitable for the treatment of acute and maintenance of major depression of adults and the treatment of acute treatment of generalized anxiety of adults. The invention also provides a preparation method, which is simple in process and low in cost, and belongs to the technical field of medical pharmacy.

Description

Bulleprazole orally disintegrating tablet and preparation method thereof

Technical Field

The invention relates to an anti-major depression orally disintegrating tablet and a preparation method thereof, wherein the active ingredient is bripiprazole, the preparation process is simple and controllable, and the preparation still has the same and stable dissolution characteristics of the active ingredient under different content conditions, has quick response and good compliance after oral administration, and belongs to the technical field of medicines.

Background

Brexpiprazole was approved by the U.S. Food and Drug Administration (FDA) for marketing at 10, 7, 2015. This compound was originally discovered by tsukamurels pharmaceuticals and developed by a combination of tsukamurella and northland and has been registered in the united states market in early october under the trade name Rexulti. Brexpiprazole, acting as a 5-HT/DA activity modulator, antagonizes the 5-HT2A receptor and the norepinephrine a receptor, and has partial agonist action at the 5-HT1A receptor and the D2 receptor. Is suitable for treating adult patients with schizophrenia, and can be used in combination with antidepressant for adjuvant treatment of adult major depressive disorder.

Bripiprazole (Brexpiprazole) is poorly compatible and slow to take orally in normal tablets for mental patients, especially in the elderly and children. It is highly desirable to develop a formulation that does not require water for administration, is easy to swallow, can be administered anywhere and anytime, and has a rapid onset of action. In recent years, oral immediate-release solid preparations are hot spots for research, the medicines can be rapidly disintegrated or dispersed into fine particles under the condition of no water (or only a small amount of water exists), the disintegration time is generally 1-3min, the medicines enter the digestive tract along with the swallowing action, the dispersing area in the gastrointestinal tract is large and more uniform, the medicines can rapidly take effect, and the local irritation of the medicines to the gastrointestinal tract and the adverse reaction reduction are avoided. The absorption and metabolism process in the body is consistent with that of the common tablet. It can be seen that the oral immediate release solid formulation has advantages over other dosage forms.

Bresxiprazole is a class II drug with low water solubility and high permeability compounds according to the BCS system. U.S. patent No.7,888,362,8,349,840,8,618,109 describes brenginiprazole products, and uses for the treatment of Major Depressive Disorder (MDD) and schizophrenia.

U.S. patent No.10,30,7419 and its family equivalents U.S. publication No. 20140234417,2010158227,201015824,2010165215 and US20190240215 disclose brenggipramzole tablet compositions and methods of making tablets. The tablet composition disclosed in the U.S. application comprises excipients comprising diluents (lactose, corn starch and microcrystalline cellulose), binders (hydroxypropyl cellulose), disintegrants (low substituted hydroxypropyl cellulose, carboxymethyl starch), and lubricants (magnesium stearate), and a granulation (dry and wet) process for preparing bressazole tablets, and the tablet composition has excellent disintegration, storage stability and higher light stability. Use of I) hydroxypropyl cellulose as the preferred binder and II) use of a coating containing a coating to obtain hydroxypropyl cellulose of the described nature.

Indian patent application No.201611038602 discloses solid oral pharmaceutical compositions comprising Brexpiprazole substantially free of disintegrants and/or binders.

Indian patent application No.201721002429 discloses a pharmaceutical composition comprising Brexpiprazole, a binder and a stabilizer, wherein the binder is selected from the group consisting of a genone or a borodone and a stabilizer selected from the group consisting of EDTA salts and ascorbic acid or derivatives thereof.

The compositions of the prior art are useful in minimizing the problems associated with bresspiprazole compositions, but there remains a need to design pharmaceutical compositions for bressprazole tablets that are economically and commercially viable, have excellent dissolution, storage stability and high photostability.

The inventors of the present invention found that the use of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl beta cyclodextrin as excipients in pharmaceutical compositions of Brexprazole or pharmaceutically acceptable salts thereof exhibited excellent dissolution and storage stability and were similar to the marketed reference product Rexulti.

Furthermore, the inventors of the present invention found that the bulk drug particle size d90.ltoreq.15 μm compared to the market reference product REXULTI provides improved dissolution and bioavailability compared to the market reference product REXULTI.

Disclosure of Invention

The invention aims at solving the problems in the background art and provides an orally disintegrating tablet and a preparation method thereof, which are mainly used for the application of special crowds, especially patients suffering from depression, unwilling to take medicines actively or not taking medicines in a special environment, such as children, old people, dysphagia or patients in a special environment.

The technical scheme of the invention for achieving the purpose is as follows:

the invention provides a bripiprazole orally disintegrating tablet which comprises the following components in percentage by weight: 1-5% of bupivazole, 20-90% of filler, 1-5% of disintegrating agent, 0.5-5% of flavoring agent and 0.05-5% of lubricant, wherein the complexing agent is hydroxypropyl beta cyclodextrin, glucolactone and the adhesive is preferably hydroxypropyl methylcellulose. The filler is one or more of delta-mannitol, lactose, microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH103, microcrystalline cellulose PH105, and starch, and delta-mannitol and microcrystalline cellulose PH105 are particularly preferred.

The disintegrating agent is one or more of croscarmellose sodium, crospovidone CL, low-substituted hydroxypropyl cellulose and carboxymethylcellulose calcium. The preparation method comprises the following steps:

(1) Pulverizing the bripiprazole with air flow, wherein the particle size D90 is less than or equal to 10 mu m; and (5) standby.

(2) Dissolving the raw materials and complexing agent in 50% ethanol-water solution, placing filler into fluidized bed, granulating by top spraying, controlling temperature at 35-55deg.C, drying until water content is lower than 3%, and sieving with 24 mesh sieve.

(3) Adding the granulated particles, the external disintegrating agent and the flavoring agent, uniformly mixing, and then adding the lubricant and uniformly mixing.

(4) Tabletting the mixture obtained in the step (3) to obtain the product with the hardness of 20-40N.

Detailed Description

The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the invention.

The tablets pressed in the following examples and comparative examples were each pressed with the same type of tablet press and the hardness was controlled in the range of 20 to 40N, as not otherwise described.

1. Test

TABLE 1

Names of raw and auxiliary materials	Example 1	Example 2	Example 3	Example 4
					Burisperidone	1.00	2.00	3.00	4.00
Delta-mannitol	60.20	66.60	60.20	58.20
					Microcrystalline cellulose PH102 (internal)	31.30	23.90	29.30	20.30
Croscarmellose sodium (internal adding)	3.00	3.00	—	—
					Crosslinked povidone XL (internal adding)	—	—	3.0	8.0
Hydroxypropyl methylcellulose (wetting agent)	1.00	1.00	1.00	1.00
					Hydroxypropyl beta cyclodextrin (wetting agent)	1.00	1.00	1.00	1.00
Croscarmellose sodium (plus)	2.00	2.00	—	—
					Crosslinked povidone XL (with the addition)	—	—	2.00	7.00
Magnesium stearate (external)	0.50	0.50	0.50	0.50

The preparation process comprises the following steps:

(1) Pulverizing the bripiprazole with air flow, wherein the particle size D90 is less than or equal to 10 mu m; and (5) standby.

(2) Dissolving the raw materials, binder and complexing agent in 50% ethanol-water solution, placing filler into fluidized bed, granulating by top spraying, controlling temperature at 35-55deg.C, drying until water content is lower than 3%, and sieving with 24 mesh sieve.

(3) Adding the granulated particles, the external disintegrating agent and the flavoring agent, uniformly mixing, and then adding the lubricant and uniformly mixing.

(4) Tabletting the mixture obtained in the step (3) to obtain the product with the hardness of 20-40N.

2. Quality evaluation method

Method 1: compressibility check

The tablet press with the same model is used for pressing, and the hardness is controlled within the range of 20-40N. The hardness was examined with emphasis on whether there were abnormal conditions such as chipping, softening and/or sticking.

Method 2: examination of disintegration time limit

2ml of water (37 ℃) is taken and placed in a 5ml test tube, the sample prepared in the above example is added, timing is started until all the sample is disintegrated into independent fine particles, timing is stopped, the disintegration time is recorded, the test tube is not required to be moved in the disintegration process, 6 tablets are taken each time for detection, and the average value is obtained.

Method 3: mouthfeel inspection

6 healthy volunteers were selected, and the samples prepared in the above examples were placed on the lingual surface to start timing until all of them were disintegrated in the oral cavity to stop timing, the disintegration time was recorded, and the sensation in the oral cavity from the placement in the mouth to the complete disintegration of the tablet, such as sweet/bitter, presence or absence of gritty sensation, etc., was felt.

Method 4: dissolution behavior inspection

The dissolution detection is carried out according to the dissolution detection method of the bripiprazole tablet published by the FDA under the following conditions:

test solution: 0.1MHCl Medium

Paddle rotational speed: 50rpm

Volume of test solution: 900ml

The samples prepared in the above examples were subjected to dissolution test, and the dissolution (REXULLI) of the commercially available tablets was all fast-dissolving if the cumulative dissolution rate was >85% for 15min in the dissolution evaluation index according to CDE related files.

Method 5: stability check

The samples prepared in the above examples were left for 6 months at a high temperature of 40℃and a relative humidity of 75% + -5%, and the stability of the samples was examined.

3. Evaluation result

TABLE 3 Table 3

As is apparent from the above, the bripiprazole orally disintegrating tablet prepared by the prescription and the preparation method provided by the invention has the advantages of good compressibility, rapid disintegration, good taste, no gritty feel, rapid dissolution and stable dissolution after being placed for 6 months. In addition, because the using amount of the flavoring agent is small and menthol is easy to agglomerate, partial filler is firstly blended with the flavoring agent, so that the uniformity and the taste of the mixture are improved, and the raw material medicine and the heavy silicon dioxide are premixed, so that the taste is effectively improved, and the uniform mixture is also facilitated. Therefore, the invention does not need special production conditions, has the characteristics of low production cost and convenient carrying, storage, transportation and administration, improves the medication compliance of patients, and has higher practical application value.

Claims (4)

1. An orally disintegrating tablet of bripiprazole, characterized in that the preparation consists of the following components in percentage by weight: 1-5% of bripiprazole, 20-75% of filler, 1-5% of disintegrating agent, 0.5-5% of flavoring agent, 0.05-5% of lubricant and 1-5% of complexing agent, wherein the complexing agent is hydroxypropyl beta cyclodextrin and glucolactone; the binder is preferably hydroxypropyl methylcellulose.

2. Orally disintegrating tablet of bripiprazole according to claim 1, characterized in that the filler is one or more of δ -mannitol, lactose, microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH103, microcrystalline cellulose PH105, starch, particularly preferably δ -mannitol and microcrystalline cellulose PH105.

3. The orally disintegrating tablet of bripiprazole according to claim 1, characterized in that said disintegrant is one or more of croscarmellose sodium, crospovidone CL, low substituted hydroxypropylcellulose, carboxymethylcellulose calcium.

4. The orally disintegrating tablet of bripiprazole according to claim 1, characterized in that said formulation is prepared by the following steps:

(1) Pulverizing the bripiprazole with air flow, wherein the particle size D90 is less than or equal to 10 mu m; and (5) standby.

(2) Dissolving the raw materials and complexing agent in 50% ethanol-water solution, placing filler into fluidized bed, granulating by top spraying, controlling temperature at 35-55deg.C, drying until water content is lower than 3%, and sieving with 24 mesh sieve.

(3) Adding the granulated particles, the external disintegrating agent and the flavoring agent, uniformly mixing, and then adding the lubricant and uniformly mixing.

(4) Tabletting the mixture obtained in the step (3) to obtain the product with the hardness of 20-40N.