KR20160012921A

KR20160012921A - Oral fast dissolving formulation containing blonanserin

Info

Publication number: KR20160012921A
Application number: KR1020150101752A
Authority: KR
Inventors: 전명관; 오재민
Original assignee: 한국콜마주식회사
Priority date: 2014-07-24
Filing date: 2015-07-17
Publication date: 2016-02-03

Abstract

The present invention relates to an oral fast-dissolving formulation which not only increases dissolvability of blonanserin to water, but also rapidly dissolves blonanserin in mouth. The oral fast-dissolving formulation comprises blonanserin and salts thereof having average particle size of 1-10 μm, an acidic pH adjustor, and a pharmaceutically acceptable additive.

Description

&Lt; / RTI > Oral fast dissolving formulation containing blonanserin < RTI ID = 0.0 >

The present invention relates to oral disintegrating agents comprising blonanserin.

Schizophrenia, a form of mental illness, is a disorder that may cause disability, social functioning, as well as symptoms such as delusions, hallucinations, broken language, and emotional desensitization. Because schizophrenia requires long-term treatment in most cases, antipsychotic drugs require not only therapeutic effects but also excellent tolerability.

One of the antipsychotic drugs, bloanacerin [2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10- hexahydrocycloocta [ b] pyridine] is a selective serotonin-dopamine antagonist acting on dopamine receptors D2 and D3 receptors and the 5-HT2A receptor, a serotonin receptor, and has been shown to be effective in treating schizophrenic positive symptoms such as hallucinations, delusions and emotional atrophy, apathia, < RTI ID = 0.0 > and the like. < / RTI > Bronan serine has a strong affinity for the dopamine D2 and D3 receptors and the serotonin 5-HT2A receptor. In particular, for D2 receptors, the affinity between haloperidol and risperidone is 20 to 94 times higher than that of haloperidol or risperidone And it is expected that the incidence of side effects is expected to be low overall because it is rarely bound to receptors other than these receptors.

Currently, oral tablets containing blownan serine are marketed under the trade name Lonasen, and oral tablets should be taken twice daily with drinking water to maintain continuous therapeutic concentrations of blownarsein. Such medication is problematic in that it is not easy to drink if drinking or drinking of drinking water is not possible due to the circumstances of the patient. In addition, there is a problem that the anticipated drug treatment effect can not be obtained because the medicinal compliance of patients having weak swallowing ability, aged children and non-cooperative mental diseases is lowered.

Korean Patent Laid-open Publication No. 10-2013-0137595 and US Patent Publication No. 2013/0143897 disclose oral sustained-release pharmaceutical compositions containing blownarsein, and the number of doses of the drug in the patient is increased from twice to once per day There has been an attempt to improve patient compliance by abbreviating once a day, but there is a problem that patients who have weak sphincter capacity can not be free from the pain of swallowing tablets because the number of medication decreases.

In addition, because of its low solubility in water, it is required to design a formulation to increase the solubility of the drug in water in order to reach the target effective blood concentration.

Korean Patent Laid-Open Publication No. 10-2013-937595 (Feb. U.S. Patent Publication No. 2013/0143897 (June 03, 2013)

Blonanserin: New serotonin-dopamine antagonist, Korean Journal of Psychopharmacology, Vol. 22, page 5 ~ 14, 2011

Under these circumstances, the present inventors have studied not only to improve the solubility of blownarcine in water, but also to develop new formulations for improving compliance and ease of administration and correct dosage. As a result, the inventors of the present invention have developed an oral disintegrating agent which is rapidly absorbed from the oral cavity and rapidly absorbed, stable in a wide pH range, stably absorbed in the digestive tract and improved in compliance with medicines and convenience Thereby completing the invention.

Accordingly, an object of the present invention is to provide an oral disintegrating agent containing blownarsein.

For example, it is an object of the present invention to provide an orally degradable preparation comprising blownan serine or a salt thereof having an average particle size of 1 to 10 mu m, an acidic pH controlling agent, and a pharmaceutically acceptable additive.

In one embodiment, the present invention relates to an oral buccal degradable preparation comprising Bronan serine or a salt thereof having an average particle size of 1 to 10 [mu] m, an acidic pH adjusting agent, and a pharmaceutically acceptable additive.

In one embodiment, the acidic pH adjusting agent of the blownarcine may be an organic acid or an inorganic acid.

In other embodiments, the acidic pH adjusting agent may comprise citric acid, tartaric acid, or fumaric acid.

In other embodiments, the acidic pH adjusting agent may be included in an amount of 1 to 5% by weight based on the total weight of the formulation.

In another embodiment, the blownarcine or a salt thereof may be included in an amount of 1 to 10% by weight based on the total weight of the preparation.

In another embodiment, the pharmaceutically acceptable excipient may include one or more selected from the group consisting of a disintegrant, an excipient, a lubricant, a preservative, a stabilizer, a bulking agent, a sweetener, a foaming agent and a diluent.

Hereinafter, the present invention will be described in more detail.

As used herein, an oral cavity decomposition product refers to a compression molded product which exhibits substantially sufficient disintegration and solubility in the oral cavity by saliva without taking drinking water, and which has an appropriate hardness. Substantially sufficient disintegration and solubility means that it disintegrates or dissolves in the mouth for about 60 seconds to 120 seconds, preferably about 1 to 60 seconds, more preferably about 1 to 40 seconds. Proper hardness means sufficient hardness such that the moldings do not collapse during the manufacturing process and during the distribution process. The present invention provides a mouth rinse detoxifying preparation which can be rapidly disintegrated in the mouth and stably absorbed into the gastrointestinal mucous membrane, thereby rapidly exhibiting its pharmacological effect, and preferably provides an oral rinse remover.

Bronan serine can be used herein in the form of a free base, a pharmaceutically acceptable salt thereof, a hydrate, a racemate, an enantiomer, a polymorph, a hydrate or a solvate. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. For example, there may be mentioned acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene- Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. As a preferred example, a blonucalin free base can be used.

Bronan serine is known to have a very low solubility in water of less than 0.001 mg / mL. In one embodiment of the present invention, it was found that while the solubility of blownan serine in water is low, the dissolution rate is significantly lowered, whereas the acidic condition (about pH 1.2) shows a significantly improved dissolution profile (Comparative Example 1 and Comparative Example 2 and Fig. 2 regarding the dissolution rate of 2). It was also confirmed that the dissolution profile can be improved so as to have a faster dissolution rate by controlling the size of the Bronen serine drug particle under acidic conditions (see Fig. 1 regarding the dissolution rate of Example 1 and Comparative Example 1).

In addition, in the present invention, as described above, the difference in the dissolution state of the Bronan serine depending on the pH can affect the bioavailability of the drug as well as the absorption of the drug in the gastrointestinal tract. In addition to controlling the size of the Bronan serine drug particle, It was confirmed that addition of an acidic pH controlling agent can improve the solubility and elution in water (see FIGS. 2 to 8).

Thus, the present disclosure provides a mouth-disintegrating formulation comprising a controlled pH of the acidic pH adjusting agent and a particle size of the blownan serine, thereby allowing the blownarcine to disintegrate rapidly in the mouth, exhibiting fast initial elution, And exhibits a constant solubility and is stably absorbed in the digestive tract, and the compliance and ease of medication are improved.

For example, in consideration of the effect of improving the absorption and dissolution of the blownan serine, the average particle size of the blownarcaine may be from 1 to 10 mu m, or from 5 to 10 mu m. If the amount is less than the above range, the uniformity of the content of the preparation may be lowered, or fine particles may be generated in the manufacturing process, resulting in lowering of the content and contamination of the working environment. If the content is in excess of the above range, the effect of improving the dissolution rate or dissolution rate is insignificant . The measurement of the particle size can be performed by various techniques known in the art.

The content of the anti-inflammatory agent may be 1 to 10% by weight based on the total weight of the preparation. It may also be used in the range of 0.1 mg to 24 mg, but is not limited thereto.

As used herein, an acidic pH controlling agent refers to an organic or inorganic chemical substance capable of releasing hydrogen ions, and includes an organic acid or an inorganic acid. For example, a pH adjusting agent having a pH in the range of 2 to 5 may be used. As a specific example, a solid acid can be used. As another specific example, citric acid, tartaric acid, fumaric acid, and the like can be used, but the present invention is not limited thereto.

In one embodiment, the acidic pH adjusting agent may be included in an amount of 1 to 5% by weight based on the total weight of the preparation. If the amount is less than the above range, the effect of improving the dissolution rate or dissolution rate of blownan serine may be insignificant. If it exceeds the above range, it may be difficult to take the oral disintegrating agent due to the strong new taste of the acidic pH controlling agent.

The oral cavity decomposition products of the present invention may further comprise pharmaceutically acceptable additives and may be selected from the group consisting of disintegrants, excipients, lubricants, preservatives, stabilizers, bulking agents, sweeteners, foaming agents and diluents And the like.

The excipient for assisting disintegration or disintegration may be selected from one or more species commonly used in the production of tablets, and examples thereof include mannitol (e.g., spray-dried mannitol), sorbitol, proctose, lactose, deck The present invention relates to a method for producing a microcrystalline cellulose comprising the steps of mixing and granulating a microcrystalline cellulose, starch and derivatives thereof, colloid, carboxymethylcellulose, F-lactose, xylitol, glucose, saccharin, fructose, maltose, maltodextrin, erythritol, arabitol, crospovidone, croscarmellose sodium, MELT; Fuji chemical), Ludiflash (BASF), and the like. Spray-dried mannitol is prepared by spray drying a crystalline mannitol aqueous solution or is commercially available (for example PEARLITOL SD 200 ™, Roquette, France; PARTECK M200, Merck, Germany). There are two types of fmels, fmelt type M and type C, which are commercially available as a mixture of D-mannitol, xylitol, microcrystalline cellulose, crospovidone and magnesium aluminometal silicate, calcium phosphate.

The disintegrant or disintegration-assisting excipient may be contained in an amount of 10 to 95% by weight based on the total weight of the tablet. If the content is less than the above range, the function as a decongestant detergent may not be satisfied, and if the content is exceeded, problems such as an increase in residual sensation in the mouth or discomfort may occur.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate, silicon dioxide, colloidal silicon dioxide, polyethylene glycol, talc, glyceryl behenate and glyceryl distearate. But is not limited to.

The oral disintegrating agent of the present invention may further include a flavoring agent or a sweetening agent to further improve the functionality. Examples of the flavor include strawberry incense essence, lemon incense essence, banana incense essence, strawberry incense cotton, lemon incense cotton, grape incense cotton, banana incense cotton or orange incense cotton. As the sweetening agent, a natural sweetening agent or artificial sweetening agent can be used. Examples of the sweetening agent include sugar, glucose, honey, xylitol, aspartame, sorbitol, sucralose, acesulfame, saccharin or anhydrous citric acid.

The oral cavity decomposition product of the present invention can be produced by a conventional production method, and can be produced by a direct tableting method, a dry granulation method, a wet granulation method or the like.

For example, the active ingredient may be prepared in the form of a tablet after mixing with a blonaserin, a pH adjusting agent, and other pharmaceutical additives (disintegrants, excipients, lubricants, sweeteners, flavoring agents, etc.). In addition, granules are prepared by mixing blownan serine with a pH adjusting agent as an active ingredient and then mechanically compression-molded, and then added with other pharmaceutical additives such as disintegrants, excipients, lubricants, sweeteners and flavors, Tablets can be prepared. In the case of the wet granulation method, granules are prepared by spray-drying the blownan serine, oral solubilizing agent and excipient as an active ingredient, or granules are prepared by using a fluidized bed granulator or a high-speed granulator, , A lubricant, a sweetener, a flavoring agent, and the like may be added and mixed to prepare a tablet.

The present invention improves the solubility of Bronan serine in water by inducing stable oral absorption and rapid drug efficacy by providing an oral disintegrating agent containing Bronan serine, and also, when there is no drinking water to be taken together, It is possible to increase the compliance of patients who are weak and have weak soft power.

1 shows the dissolution test results of blownan serine in the first solution (pH 1.2) of the dissolution test liquid described in the Korean Pharmacopoeia (10th Edition) General Test Method for the oral disintegration-resistant tablets prepared according to Example 1 and Comparative Example 1 Fig.
2 is a graph showing the dissolution test result of water of the oral fast disintegration tablet prepared according to Comparative Example 2. Fig.
Fig. 3 is a graph showing the dissolution test results of the oral disintegrating tablet prepared in Example 2 in water. Fig.
4 is a graph showing the dissolution test results of water of the oral fast disintegration tablet prepared according to Example 3. Fig.
FIG. 5 is a graph showing the dissolution test results of the oral disintegrating tablet prepared in Example 4 in water. FIG.
FIG. 6 is a graph showing the dissolution test results of the oral disintegrating tablet prepared in Example 5 in water. FIG.
7 is a graph showing the dissolution test results of water of the oral fast disintegration tablet prepared according to Example 6. Fig.
8 is a graph showing the dissolution test results of water of the oral fast disintegration tablet prepared according to Example 7. Fig.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

Example One. Bloonanserin Mouth Crucible Manufacture of tablets

Bronan serine (average particle size of 5 μm), spray dried mannitol, crospovidone, sucralose and orange incense cotton were mixed in the contents and ratios as shown in Table 1. After magnesium stearate was finally mixed in the resulting mixture, tablets were prepared with a tablet weight of 120 mg using a conventional tableting method.

Example 2. Bloonanserin Mouth Crucible Manufacture of tablets

The tablets were prepared in the same amounts and ratios as shown in Table 1 except that anhydrous citric acid was further added to the tablets in the same manner as in Example 1 to prepare tablets having a tablet weight of 120 mg.

Example 3 to Example 6. Bloonanserin Mouth Crucible Manufacture of tablets

Bronan serine (average particle size of 5 mu m), fummet type seed, anhydrous citric acid, sucralose and orange incense cotton were mixed in the contents and ratios as shown in Table 1. After magnesium stearate was finally mixed in the resulting mixture, tablets were prepared with a tablet weight of 120 mg using a conventional tableting method.

Example 7. Bloonanserin Mouth Crucible Manufacture of tablets

The tablets were prepared in the contents and ratios as shown in Table 1, except that the addition of croscarmellose sodium and crospovidone was further added in comparison with the above-mentioned Example 5 to prepare tablets having a tablet weight of 120 mg .

Comparative Example One. Bloonanserin Mouth Crucible Manufacture of tablets

The same procedure as in Example 1 was repeated except that the blonan serine having an average particle size of 50 mu m was used instead of the blonan serum having an average particle size of 5 mu m in the content and ratio shown in Table 2, &Lt; / RTI >

Comparative Example 2. Bloonanserin Mouth Crucible Manufacture of tablets

The tablets were prepared in the contents and ratios as shown in Table 2, except that anhydrous citric acid was excluded, as compared with Examples 3 and 4, thereby obtaining tablets having a tablet weight of 120 mg.

Comparative Example 3. Commercial product

A commercially available blonacerin tablet "Ronasen" (Bukwang Pharmaceutical) was used.

The compositions of Examples 1 to 7 Example One 2 3 4 5 6 7 Bloonanserin
(Average particle size 5 m) 3.3 3.3 3.3 3.3 3.3 3.3 3.3 Bloonanserin
(Average particle size 50 m) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Spray dried mannitol 86.7 83.3 0.0 0.0 0.0 0.0 0.0 Mr. Efmelt type 0.0 0.0 93.3 92.5 91.7 90.8 51.7 Rudi Fresh 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Cross Camelos Na 0.0 0.0 0.0 0.0 0.0 0.0 20.0 Crospovidone 8.3 8.3 0.0 0.0 0.0 0.0 20.0 Anhydrous citric acid 0.0 3.3 1.7 2.5 3.3 4.2 3.3 Sucralose 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Orange incense cotton 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Magnesium stearate 0.4 0.4 0.4 0.4 0.4 0.4 0.4 % Sum 100.0 100.0 100.0 100.0 100.0 100.0 100.0

The compositions of Comparative Examples 1 and 2 Comparative Example One 2 Bloonanserin
(Average particle size 5 m) 0.0 3.3 Bloonanserin
(Average particle size 50 m) 3.3 0.0 Spray dried mannitol 86.7 0.0 Mr. Efmelt type 0.0 95.0 Rudi Fresh 0.0 0.0 Cross Camelos Na 0.0 0.0 Crospovidone 8.3 0.0 Anhydrous citric acid 0.0 0.0 Sucralose 0.8 0.8 Orange incense cotton 0.4 0.4 Magnesium stearate 0.4 0.4 % Sum 100.0 100.0

Experimental Example One. Oral disintegration rate Measure

The rate of oral disintegration was measured by placing the tablets in the oral cavity of a subject and gently pressing the tablets with the tongue while measuring the time taken for the tablets to completely disintegrate. The results are shown in Table 2 below. According to the US Food and Drug Administration guidelines, it is recommended that oral disintegration time be within 30 seconds. All of Examples 1 to 7 showed that these standards were met, but in the case of Comparative Example 3, which is a commercial product, it was not suitable as an oral disintegrating agent for more than 3 minutes.

Oral disintegration time (sec) Example 1 6.5 Example 2 8.5 Example 3 8 Example 4 8 Example 5 8.5 Example 6 8 Example 7 7 Comparative Example 1 8.5 Comparative Example 2 8.5 Comparative Example 3 235

Experimental Example 2. Bronnan Serine Dissolution rate measurement

In order to measure the dissolution rate of Bronan serine, three tablets of each of the oral disintegration-resistant tablets prepared in Examples 1 to 7 and Comparative Examples 1 and 2 were diluted with the first elution solution test solution described in the General Test of Pharmacopoeia (10th Edition) (pH 1.2) or 900 mL of water, and the dissolution rate of the blownan serine was measured using the Korean Pharmacopoeia (10th edition) dissolution test (second method).

Bronan serine is known to have a very low solubility in water of less than 0.001 mg / mL. In one embodiment of the present invention, it was found that while the solubility of blownan serine in water is low, the dissolution rate is significantly lowered, whereas the acidic condition (about pH 1.2) shows a significantly improved dissolution profile (Comparative Example 1 and Comparative Example 2 and Fig. 2 regarding the dissolution rate of 2).

The elution rates of the tablets of Example 1 and Comparative Example 1 were compared in the first solution (pH 1.2) of the dissolution test liquid to confirm the difference in dissolution rate depending on the average particle size of the blonanserin. The tablets of Example 1 and Comparative Example 1 were similar in basic composition except that the tablets of Example 1 contained blownan serine having an average particle size of 5 μm whereas the tablets of Comparative Example 1 contained blownan serine having an average particle size of 50 μm . As a result, as shown in FIG. 1, it was confirmed that the dissolution rate of Example 1 was significantly improved as compared with Comparative Example 1.

Next, the dissolution rates of the tablets of Examples 3 to 6 and Comparative Example 2 were compared in water in order to confirm the difference in the dissolution rate of Bronan serine with the addition of the pH adjusting agent. The tablets of Examples 3 to 6 and Comparative Example 2 were similar in basic composition except that the tablets of Comparative Example 2 did not contain a pH adjuster and the tablets of Examples 3 to 6 contained 1.7 wt% (Example 3), 2.5 wt% (Example 4), 3.3 wt% (Example 5) and 4.2 wt% (Example 6). As a result, as shown in FIG. 2 and FIG. 4 to FIG. 7, Comparative Example 2 containing no pH controlling agent showed only about 10% by weight of elution at 60 minutes, whereas Examples 3 to 6 were comparable to Comparative Example 2 It was confirmed that the dissolution rate in water was greatly improved.

Next, the dissolution rates of the tablets of Example 2, Example 5 and Example 7 were compared in water in order to confirm the difference in dissolution rate due to disintegration. The tablets of Example 2, Example 5 and Example 7 had similar basic compositions and included both blownan serine with an average particle size of 5 [mu] m and anhydrous citric acid in an amount ranging from 3.3% by weight, 83.3% by weight of dried mannitol and 8.3% by weight of crospovidone, and the tablet of Example 5 contained 91.7% by weight of the fmelt type seed as the disintegrant, whereas the tablets of Example 7 contained the fmelt type seeds 51.7 20.0% by weight of croscarmellose sodium, and 20.0% by weight of crospovidone. As a result, as shown in FIG. 3, FIG. 6, and FIG. 8, it was confirmed that both Example 2, Example 5 and Example 7 exhibited excellent dissolution rate in water even when the type and content of the disintegrant were changed.

(Unit: wt%) 0 minutes 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes Example 2 0 51.9 68.7 75.3 85.2 91.6 94.5 Example 3 0 24.5 32.9 37.9 43.0 48.4 53.2 Example 4 0 51.6 64.2 67.7 74.5 79.2 79.2 Example 5 0 57.5 75.6 82.7 87.9 95.4 98.5 Example 6 0 67.5 93.2 97.9 98.1 99.4 99.9 Example 7 0 61.3 72.1 78.9 83.4 90.2 95.7 Comparative Example 2 0 1.6 3.8 5.0 7.1 8.8 10.1

Claims

Orally degradable formulations, comprising an effective amount of Bronan serine or a salt thereof having an average particle size of 1 to 10 mu m, an acidic pH controlling agent, and a pharmaceutically acceptable additive.

The orally degradable preparation according to claim 1, wherein the acidic pH adjusting agent is an organic acid or an inorganic acid.

The buccal degradable preparation according to claim 1, wherein the acidic pH controlling agent comprises citric acid, tartaric acid or fumaric acid.

The buccal degradable preparation according to claim 1, wherein the acidic pH adjusting agent is contained in an amount of 1 to 5% by weight based on the total weight of the preparation.

The orally degradable preparation according to claim 1, wherein the blownarcine or a salt thereof is contained in an amount of 1 to 10% by weight based on the total weight of the preparation.

The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable additive comprises at least one selected from the group consisting of a disintegrant, an excipient, a lubricant, a preservative, a stabilizer, a bulking agent, a sweetener, a foaming agent and a diluent. Oral degradable preparation.