KR102356601B1 - Controlled-release pellet compositions containing pseudoephedrine - Google Patents

Abstract

The present invention relates to a controlled-release pellet composition containing pseudoephedrine, and more particularly, to an immediate-release pellet containing pseudoephedrine or a pharmaceutically acceptable salt thereof, and pseudoephedrine or a pharmaceutically acceptable salt thereof, containing, It relates to a pellet mixture comprising sustained release pellets coated with an insoluble polymer. The pellet composition according to the present invention is characterized in that by limiting the binder used in the pseudoephedrine immediate-release pellets to a cellulose derivative, additional coating is easy and drug-release properties are strong.

Description

Controlled release pellet composition containing pseudoephedrine {CONTROLLED-RELEASE PELLET COMPOSITIONS CONTAINING PSEUDOEPHEDRINE}

The present invention relates to a controlled-release pellet composition containing pseudoephedrine, and more particularly, to an immediate-release pellet containing pseudoephedrine or a pharmaceutically acceptable salt thereof, and pseudoephedrine or a pharmaceutically acceptable salt thereof, containing, It relates to a pellet mixture comprising sustained release pellets coated with an insoluble polymer.

Pseudoephedrine (C10H15NO, MW=165.2) is an optical isomer of ephedrine, which has a similar action to ephedrine, but has a relatively small sedative effect, a half-life of about 5-7 hours, and a half-life due to an increase in the rate of elimination in acid urine. It is a shortened substance.

Examples of the pseudoephedrine salt used as pharmaceuticals include pseudoephedrine hydrochloride (C10H15NOHCl, MW=201.7) or pseudoephedrine sulfate {(C10H15NO)2H2SO4, MW=428.5}.

Such pseudoephedrine or a pharmaceutically acceptable salt thereof is known as a sympathomimetic agent, and is generally prescribed together with an antihistamine to improve nasal congestion (snot congestion) caused by allergic rhinitis.

On the other hand, nasal depressive phase and allergic rhinitis require rapid symptom relief and continuous symptom improvement. In particular, if pseudoephedrine, which has a relatively short half-life, is designed for sustained-release and an antihistamine with a long half-life is designed for immediate-release, it is effective for symptom improvement without frequent administration.

In order to achieve the above object, various types of formulations have been developed. Among them, the pharmacologically active substance can be easily separated according to the purpose, and because it is composed of a large number of fine spheres, there is no side effect of dose dumping due to the disintegration of the tablet, like a sustained-release tablet, a pellet preparation. can be developed by selecting

Korean Patent Registration No. 10-0505899 relates to a capsule composition containing loratadine and pseudoephedrine, which are non-hypnotic antihistamines, and relates to an immediate-release pellet containing loratadine and pseudoephedrine or a salt thereof, and pseudoephedrine or a salt thereof. Disclosed is a capsule composition containing sustained-release pellets, and in particular, in preparing pseudoephedrine-containing sustained-release pellets, a water-insoluble polymer and a wet-blocking agent are included to obtain a desirable dissolution aspect of the two drug components wanted to

Korean Patent Registration No. 10-0602235 relates to a controlled-release spherical granule containing cetirizine hydrochloride and pseudoephedrine hydrochloride, which are second-generation antihistamines, and contains pseudoephedrine hydrochloride in the sustained-release drug layer, pseudoephedrine hydrochloride in the immediate-release drug layer, and pseudoephedrine hydrochloride in the immediate-release drug layer. Disclosed is a composition containing cetirizine hydrochloride, and in particular, by coating an immediate-release and sustained-release drug layer in a single pellet, it was attempted to obtain a formulation with good uniformity.

Korean Patent Application Laid-Open No. 10-2008-7032260 relates to a pharmaceutical composition comprising a combination agent of piperidinoalkanol and a decongestant, in particular, by mixing two An attempt was made to obtain a desirable dissolution pattern of the drug component.

In addition, 『Pharmaceutical pelletization technology (1989, Isaac Ghebre-Sellassie, Marcel Dekker)』 discloses the types of binders commonly used in the manufacture of pellets, and 『Oral controlled release formulation design and drug delivery ( 2010, Hong Wen, Wiley)] discloses formulation compatibility test methods and test items for the purpose of selecting pharmaceutically acceptable excipients. Handbook of pharmaceutical excipients 6th edition (2009, Raymond Rowe, Pharmaceutical press)” discloses the types of pharmaceutically acceptable excipients and the appropriate amount for each purpose.

On the other hand, ebastine (ebastine, C32H39NO2, MW=469.62) is a second-generation antihistamine with a small sedative effect and insignificant antimuscarinic effect. When administered orally, it is rapidly absorbed in the gastrointestinal tract and reaches its maximum plasma concentration within 2-4 hours, has a half-life of about 13 hours, and is mainly excreted in the urine.

Republic of Korea Patent No. 10-0737710 relates to a composition for treating allergic rhinitis and other allergic diseases, and a pharmaceutical composition comprising an effective amount of a leukotriene antagonist, an effective amount of an antihistamine such as evastin, and a decongestant such as pseudoephedrine is disclosing

However, there is no prior known about the release control pellet composition containing pseudoephedrine and ebastin.

Republic of Korea Patent Registration No. 10-0505899 Republic of Korea Patent Registration No. 10-0602235 Republic of Korea Patent Publication No. 10-2008-7032260 Republic of Korea Patent Registration No. 10-0737710

Pharmaceutical pelletization technology (1989, Isaac Ghebre-Sellassie, Marcel Dekker) Oral controlled release formulation design and drug delivery (2010, Hong Wen, Wiley) Handbook of pharmaceutical excipients 6th edition (2009, Raymond Rowe, Pharmaceutical press)

In order to produce pellets exhibiting immediate release and sustained release properties at the same time, in Korean Patent Registration No. 10-0505899, pseudoephedrine is sprayed with a binder on an inert carrier to prepare immediate release pellets, and then a specific water-insoluble polymer and a specific Wetting-preventing agent was applied to complete sustained-release pellets, and additionally, loratadine was applied to immediate-release pellets to complete capsules.

However, when using the pellets as described above, in order to achieve a uniform drug release rate of the unit pellets, it is preferable to prepare an immediate-release pellet as close to a spherical shape as possible before applying an additional sustained-release polymer or a sparingly soluble antihistamine.

Because otherwise, the sustained-release film coating is non-uniform, and when exposed to an aqueous medium, an initial burst of the drug may occur undesirably. This is because, in the case of coating, there is a problem in that the manufacturing time and cost increase.

A more problematic point in the case of using pellets is that the mixtures of the unit pellets prepared in this way are filled in one capsule to complete the formulation. In this way, the different drug release tendencies of individual capsules containing the pellet mixture, that is, the drug release deviation of the unit capsules, act as a cause.

However, in the prior art, it is not possible to provide an immediate-release pellet as close to a spherical shape as possible.

In addition, the production of pellets has many process variables unlike tablets, so even in the same embodiment, pellets with completely different surface properties and release patterns can sometimes be made, even in the same embodiment, depending on the composition of drugs and excipients, unless skilled workers This may vary. Therefore, it is very important to produce a consistent product to form a uniform coating film even in large fluctuations in working conditions.

In fact, as a result of the present inventors' preparation of immediate-release pellets of pseudoephedrine with reference to the prior art described above, the surface properties of the pellets were completely different depending on the type of binder and process conditions. The pattern of western release was also markedly different.

One embodiment of the present invention aims to solve the problems of the prior art described above in the controlled-release pellet composition containing pseudoephedrine.

Another embodiment of the present invention is to improve the problems with the prior art of the above-described controlled-release pellet composition while additionally containing ebastin together with pseudoephedrine as a problem to be solved.

The present inventors surprisingly found that when a cellulose derivative is selected as a binder in the preparation of the pseudoephedrine immediate-release layer, it is not significantly affected by process conditions and the amount of binder compared to other binders, and forms an immediate-release core having uniform surface properties. Based on this, the present invention was completed.

That is, the present invention solves the above problems through the following means:

(1) (A) a core, which is a drug-free spherical inert material, and

(B) A pellet composition comprising a drug layer coated with pseudoephedrine or a pharmaceutically acceptable salt thereof on the surface of (A) and a cellulose derivative as a binder.

(2) The pellet composition according to the above (1), characterized in that the surface of the drug layer (B) is further coated with ebastin or a pharmaceutically acceptable salt thereof.

(3) The pellet composition according to the above (1), characterized in that the sustained-release layer is further coated on the surface of the drug layer (B).

(4) The pellet composition according to (3), wherein the weight of the sustained-release layer is 24 wt% or less based on the total weight of the core (A) and the drug layer (B).

(5) The pellet composition according to (3), wherein the dissolution rate of pseudoephedrine or a pharmaceutically acceptable salt thereof is 46 mg/hr or less over the entire section.

(6) The pellet composition according to (1) to (5), wherein the cellulose derivative is at least one selected from the group consisting of methyl cellulose, hypromellose and hydroxypropyl cellulose.

(7) A pellet mixture obtained by mixing the pellet composition according to (1) or (2) and the pellet composition according to (3) above.

(8) A pharmaceutically acceptable capsule preparation comprising the pellet mixture according to (7) above.

According to one embodiment of the present invention, it is possible to manufacture pellets as close to a spherical shape as possible so that the coating of the sustained-release layer can be made uniformly. In addition, it is possible to manufacture pellets with strong drug release properties without being sensitive to the production process. In addition, drug release can be efficiently controlled even with a smaller amount of sustained-release film coating. Through this, it is possible to provide a controlled release pellet composition containing pseudoephedrine effective for a long time without the risk of initial drug mass release.

According to another embodiment of the present invention, while improving the surface properties of the pseudoephedrine immediate-release layer, the sustained-release coating using a water-insoluble polymer and the surface properties of the ebastin immediate-release coating are also improved to compare the dissolution pattern of the finally completed pellets It is possible to provide a controlled-release pellet composition containing pseudoephedrine having robustness of drug-release properties when done.

1 is a photograph of the pseudoephedrine immediate-release pellets prepared in Examples 1 to 9 using a digital microscope, respectively.
2 is a photograph of the pellets prepared in Example 1 using a field emission scanning electron microscope (Field Emission Scanning Electron Microsope).
3 is a photograph of the pseudoephedrine immediate-release pellets prepared in Comparative Examples 1 to 11 using a digital microscope, respectively.
4 is a photograph of the pellets prepared in Comparative Example 1 using a field emission scanning electron microscope.
5 is a dissolution test result of the pseudoephedrine sustained-release pellets prepared in Examples 10 and 11 and Comparative Examples 13 and 14.

As used herein, the term "pharmaceutically acceptable salt" refers to a hydrochloride salt, a sulfate salt, or an equivalent non-toxic salt of a drug.

The term "pellet" refers to drug-containing particles having a diameter in the range of about 100 to 1500 microns.

The term "core" refers to a conventionally known drug-free spherical inert material capable of additionally applying an immediate-release layer or a sustained-release layer, and is not particularly limited. For example, sugar spheres or microcrystalline cellulose spheres may be used.

The term "immediate release" refers to the property of a pharmaceutical composition in which the total dose of an active ingredient becomes bioavailable without significant delay.

"Modified release" refers to the property of a pharmaceutical composition in which an active ingredient becomes bioavailable over a period of time after administration.

The term "water-insoluble polymer" refers to a sustained-release base that does not dissolve in any one of the buffer solutions of pH about 1.0 to about 8.0, and is not particularly limited. For example, ethyl cellulose or methacrylic acid copolymerization (trade name: Eudragit) and the like.

The "therapeutically effective amount" of ebastin and pseudoephedrine refers to an amount necessary to obtain a desired therapeutic response upon oral administration, and can be easily determined by a person skilled in the art. For example, the effective dose of ebastin and pseudoephedrine hydrochloride may be 20 mg/day and 240 mg/day, respectively, and in the case of a unit dosage form administered twice a day, the contents of ebastine and pseudoephedrine hydrochloride are 10 mg and 120 mg, respectively. may be mg.

[Immediate release pellets]

Immediate-release pellets according to an embodiment of the present invention include a composition in which a therapeutically effective amount of pseudoephedrine or a pharmaceutically acceptable salt thereof is coated on the core and the surface together with a binder.

This can be prepared, for example, by dissolving pseudoephedrine or a pharmaceutically acceptable salt thereof and a binder in purified water, dispersing it with an adsorbent, filtration to prepare a coating solution, and then spraying it on the core.

Immediate-release pellets according to another embodiment of the present invention are the pseudoephedrine or pharmaceutically acceptable salts thereof coated with ebastin or pharmaceutically acceptable salts thereof on the surface of the pseudoephedrine pellets prepared as described above. includes

This can be prepared by, for example, dissolving ebastin or a pharmaceutically acceptable salt thereof and a binder in purified water to prepare a coating solution, and then spraying it on the immediate-release pellets prepared above.

Meanwhile, in the present invention, a cellulose derivative may be used as a binder for the expression of a desired effect, preferably methyl cellulose, hydroxypropyl cellulose or hypromellose may be used, and more preferably hypromellose is used. can be used

In addition, the immediate-release pellets may further contain one or more pharmaceutically acceptable additives such as, for example, excipients, disintegrants or lubricants. In particular, for the purpose of improving the dissolution of ebastin or a pharmaceutically acceptable salt thereof, various additives known in the art may be additionally contained.

Immediate-release pellets according to the present invention have a strong surface properties.

[Sustained Release Pellets]

The sustained-release pellet according to the present invention contains a core, pseudoephedrine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable binder, and a sustained-release layer.

This can be prepared, for example, by adding a water-insoluble polymer and a plasticizer to purified water and stirring to prepare a coating solution, and then spraying it on the immediate-release pellets according to the present invention.

The sustained-release pellet according to the present invention has a small drug release deviation, and the initial mass release of the drug does not occur. Specifically, in the sustained-release pellets according to the present invention, the upper limit of the section dissolution rate (mg/hr) is 80 or less, preferably 46 or less, and more preferably 23 or less.

In addition, since the sustained-release pellets according to the present invention use immediate-release pellets having a solid surface property, the drug release deviation is small without excessive coating of the sustained-release layer, and the effect that the initial mass release of the drug does not occur can be achieved.

Specifically, the sustained-release layer in the sustained-release pellet according to the present invention is 24 wt% or less, further 18 wt% or less, further 12 wt% or less, relative to the weight of the immediate-release layer, it is possible to achieve the above desirable effect.

[Capsule]

The capsule composition according to the present invention can be formulated by appropriately filling the above-described immediate-release pellets and sustained-release pellets in a capsule.

When the capsule composition according to the present invention is administered orally, the dissolution pattern of the drug is preferably controlled compared to that of the conventional tablet composition.

Therefore, the capsule composition according to the present invention exhibits a rapid and sustained effect upon administration regardless of various factors related to the gastrointestinal environment.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Examples 1 to 4 - Preparation of immediate-release pellets

As shown in Table 1 below, immediate-release pellets of pseudoephedrine salts using a cellulose derivative as a binder were prepared, respectively. Specifically, pseudoephedrine hydrochloride and a binder (hypromellose in Examples 1 and 2, methyl cellulose in Example 3, and hydroxypropyl cellulose were used in Example 4) were sequentially dissolved in 120 mg of purified water, and colloidal After dispersing the silicon dioxide, it was filtered through a 100 mesh sieve to prepare a coating solution. Thereafter, the prepared coating solution was sprayed on the sugar sphere, which is the core, using a fluidized bed coater (GPCG-1, Glatt) to prepare a pseudoephedrine immediate release layer. Air volume (Fan Hz) 25, supply air temperature 60 degrees, product temperature 43 degrees, spray air pressure (bar) 1.5, and the average amount of binder injection (g/min) 20 were prepared.

designation Example 1 Example 2 Example 3 Example 4 Pseudoephedrine hydrochloride (mg) 120 120 120 120 Hypromellose (mg) 3.6 7.2 - - Methylcellulose (mg) - - 3.6 - Hydroxypropyl cellulose (mg) - - - 3.6 Colloidal silicon dioxide (mg) 0.24 0.24 0.24 0.24 Sugar sphere (mg) 80 80 80 80 Pellets total weight (solids) (mg) 203.84 207.44 203.84 203.84

Examples 5 to 9 - Preparation of immediate-release pellets under various coating conditions

It was prepared under various coating conditions using the same composition as in Example 1. Specifically, as shown in Table 2 below, a pseudoephedrine immediate-release layer was prepared by subdividing the fluidized bed coater for each condition. Through this, it was attempted to confirm whether the core using a cellulose derivative as a binder has robustness.

division Example 5 Example 6 Example 7 Example 8 Example 9 Airflow (Fan Hz) 25 25 30 40 25 Supply air temperature (℃) 45 45 30 80 45 Product temperature (℃) 35 35 28 52 35 Spray air pressure (bar) 1.2 1.5 1.5 1.5 2.2 Average amount of binder spraying (g/min) 5 30 10 20 20

The characteristics of Examples 5 to 9 are as follows.

Example 5: Conditions where temperature and binder injection amount are small

Example 6: Conditions with low temperature and large amount of binder injection

Example 7: Conditions with very low temperature

Example 8: Very high temperature conditions

Example 9: Conditions where spray air pressure is very high

Comparative Examples 1 to 6 - Preparation of immediate-release pellets

As shown in Table 3 below, using polyvinylpyrrolidone as a binder, pseudoephedrine immediate-release layers were prepared in the same manner as in Example 1, respectively. As a coating solvent, 120 mg of purified water was used in Comparative Examples 1, 4, 5, and 6, respectively, 240 mg of purified water was used in Comparative Example 2, and 80 mg of purified water and 100 mg of ethanol were used in Comparative Example 3.

designation Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Pseudoephedrine hydrochloride (mg) 120 120 120 120 120 120 Polyvinylpyrrolidone (mg) 3.6 3.6 3.6 7.2 15 22 Colloidal silicon dioxide (mg) 0.24 0.24 0.24 0.24 0.24 0.24 Sugar Spear 25-30 (mg) 80 80 80 80 80 80 Pellets total weight (solids) (mg) 203.84 203.84 203.84 207.44 215.24 222.24

Comparative Examples 7 to 11 - Preparation of immediate-release pellets under various coating conditions

It was prepared under various coating conditions using the same composition as in Comparative Example 1. Specifically, similarly to Examples 5 to 9, as shown in Table 4 below, a pseudoephedrine immediate-release layer was prepared by subdividing the fluidized bed coater for each condition.

division Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Airflow (Fan Hz) 25 25 30 40 25 Supply air temperature (℃) 45 45 30 80 45 Product temperature (℃) 35 35 28 52 35 Spray air pressure (bar) 1.2 1.5 1.5 1.5 2.2 Average amount of binder spraying (g/min) 5 30 10 20 20

Examples 10 to 12 - Preparation of sustained-release pellets

As shown in Table 5 below, each sustained-release layer was coated on the immediate-release pellets of Example 1. Ethyl cellulose aqueous dispersion, triethyl citrate, and polyethylene glycol-polyvinyl alcohol copolymer were sequentially added to purified water and stirred to prepare a sustained-release coating solution. The amount of each purified water used was 13 mg in Example 10, 19 mg in Example 11, and 25 mg in Example 12. A pseudoephedrine sustained-release layer was prepared by spraying the prepared coating solution on the immediate-release layer core using a fluidized bed coater (GPCG-1, Glatt). Airflow (Fan Hz) 25, supply air temperature 50 degrees, product temperature 36 degrees, spray air pressure (bar) 1.5, and the average amount of binder injection (g/min) 10 was prepared. Then, it was dried in a 60 degree chamber for 3 hours to form a uniform film.

designation Example 10 Example 11 Example 12 Immediate-release pellets of Example 1 (mg) 203.84 203.84 203.84 Ethyl cellulose aqueous dispersion (mg) 63.45 95.18 126.9 Triethyl Citrate (mg) 4.57 6.85 9.14 Polyethylene glycol-polyvinyl alcohol copolymer (mg) 0.86 1.28 1.71 Pellets total weight (solids) (mg) 228.3 240.53 252.76 Coating rate (%) relative to immediate release core weight 12% w/w (%w/w) 18% w/w (%w/w) 24 wt% (%w/w)

Comparative Examples 12 to 14 - Preparation of sustained-release pellets

As shown in Table 6 below, each sustained-release layer was coated on the immediate-release pellets of Comparative Example 1. Ethyl cellulose aqueous dispersion, triethyl citrate, and polyethylene glycol-polyvinyl alcohol copolymer were sequentially added to purified water and stirred to prepare a sustained-release coating solution. The amount of each purified water used was 7 mg in Comparative Example 12, 13 mg in Comparative Example 13, and 19 mg in Comparative Example 14. A pseudoephedrine sustained-release layer was prepared by spraying the prepared coating solution on the immediate-release layer core using a fluidized bed coater (GPCG-1, Glatt). Air volume (Fan Hz) 25, supply air temperature 50 degrees, product temperature 36 degrees, spray air pressure (bar) 1.5, and the average amount of binder injection (g/min) 10 were prepared. Then, it was dried in a 60 degree chamber for 3 hours to form a uniform film.

designation Comparative Example 12 Comparative Example 13 Comparative Example 14 Immediate-release pellets of Comparative Example 1 (mg) 203.84 203.84 203.84 Ethyl cellulose aqueous dispersion (mg) 37.01 63.45 95.18 Triethyl Citrate (mg) 2.66 4.57 6.85 Polyethylene glycol-polyvinyl alcohol copolymer (mg) 0.5 0.86 1.28 Pellets total weight (solids) (mg) 218.11 228.3 240.53 Coating rate (%) relative to immediate release core weight 7% by weight (%w/w) 12% w/w (%w/w) 18% w/w (%w/w)

Example 13 and Comparative Example 15 - Preparation of immediate-release pellets further containing evastin

As shown in Table 7 below, the immediate-release pellets prepared according to Example 1 and Comparative Example 1 were coated with an evastin immediate-release layer. Evastin, poloxamer, hypromellose, lactose and polyethylene glycol were sequentially added to 269 mg of purified water and stirred to prepare an evastin coating solution. Ebastin immediate-release layer was prepared by spraying the prepared coating solution on pseudoephedrine immediate-release pellets using a fluidized bed coater (GPCG-1, Glatt). Air volume (Fan Hz) 30, supply air temperature 90 degrees, product temperature 42 degrees, spray air pressure (bar) 2.0, and the average amount of binder injection (g/min) 20 were prepared.

designation Example 13 Comparative Example 15 Immediate-release pellets of Example 1 (mg) 67.94 - Immediate-release pellets of Comparative Example 1 (mg) - 67.94 Ebastin (mg) 10 10 Poloxamer (mg) One One Hypromellose (mg) 20 20 Lactose (mg) 3.5 3.5 Polyethylene glycol (mg) 1.5 1.5 Pellets total weight (solids) (mg) 103.94 103.94

Example 14 - Preparation of capsules

As shown in Table 8 below, the pseudoephedrine sustained-release pellets prepared in Example 12 and the pseudoephedrine and ebastin immediate-release pellets prepared in Example 13 were mixed and filled in a capsule to prepare a composite capsule. Only two-thirds of the equivalent amount of Example 12 was taken to fill the equivalent amount of 120 mg pseudoephedrine hydrochloride.

Pseudoephedrine sustained release pellets (modified release) designation Example 12 (take only two-thirds of that amount) Immediate-release pellets of Example 1 (mg) 135.89 Ethyl cellulose aqueous dispersion (mg) 84.60 Triethyl Citrate (mg) 6.09 Polyethylene glycol-polyvinyl alcohol copolymer (mg) 1.14 Pseudoephedrine and ebastin immediate release pellets designation Example 13 Immediate-release pellets of Example 1 (mg) 67.94 Ebastin (mg) 10 Poloxamer (mg) One Hypromellose (mg) 20 Lactose (mg) 3.5 Polyethylene glycol (mg) 1.5 Total pellet weight (mg) 272.45 No. 1 Gelatin Capsule (mg) 77 Total weight of capsules (mg) 349.45

Experimental Example 1 - Observation of surface pattern

The surface of each pellet was observed using a digital microscope and a field emission scanning electron microscope to confirm that the pseudoephedrine immediate-release layer prepared using various binders was properly prepared.

As shown in FIGS. 1 and 2 , when a cellulose derivative is used as a binder of the pseudoephedrine immediate-release layer, it can be seen that a surface shape close to a spherical shape is exhibited under all conditions.

On the other hand, as shown in FIGS. 3 and 4 , when polyvinylpyrrolidone was used as a binder, most of the results showed a very irregular rough surface shape far from a spherical shape.

Experimental Example 2 - Dissolution Test

The dissolution test for the above examples was carried out in 900 mL of pH 6.8 phosphate buffer (Korean Pharmacopoeia, disintegration test method 2 solution) according to the dissolution test method 2 of the Korean Pharmacopoeia at 37.5 ° C., 50 rpm. 5 , it can be seen that the pseudoephedrine dissolution rates of Comparative Examples 12 to 14 using polyvinylpyrrolidone as a binder were much higher than those of Examples 10 to 12 using hypromellose.

This is a typical initial drug mass release phenomenon that occurs because the sustained-release coating film is not uniformly applied to the non-smooth pseudoephedrine immediate-release core. Table 9 below shows the drug release amount and section dissolution rate over time when the coating rates of the sustained-release coating film relative to the weight of the pseudoephedrine immediate-release pellets were 12% and 18%.

Example 10 Comparative Example 13 Coating rate (%) of the sustained-release coating film relative to the weight of the pseudoephedrine immediate-release pellets 12% dissolution time Cumulative drug release
(mg) section dissolution rate
(mg/hour) Cumulative drug release
(mg) section dissolution rate
(mg/hour) 1 hours 46mg 46 117mg 117 2 hours 71mg 25 123mg 6 3 hours 86mg 15 123mg 0 4 hours 95mg 9 123mg 0 6 hours 107mg 6 123mg 0 Example 11 Comparative Example 14 Coating rate (%) of the sustained-release coating film relative to the weight of the pseudoephedrine immediate-release pellets 18% dissolution time Cumulative drug release
(mg) section dissolution rate
(mg/hour) Cumulative drug release
(mg) section dissolution rate
(mg/hour) 1 hours 23mg 23 103mg 103 2 hours 51mg 28 118mg 15 3 hours 67mg 16 121mg 3 4 hours 79mg 12 121mg 0 6 hours 93mg 7 121mg 0

Claims (8)

(A) a core, which is a drug-free spherical inert material, and
(B) immediate-release pellets comprising a drug layer coated with pseudoephedrine or a pharmaceutically acceptable salt thereof on the surface of (A) and a cellulose derivative as a binder; and
(A) a core, which is a drug-free spherical inert material, and
(B) a drug layer coated with pseudoephedrine or a pharmaceutically acceptable salt thereof on the surface of (A) and a cellulose derivative as a binder;
(C) a pellet mixture comprising sustained-release pellets comprising a sustained-release layer coated on the surface of (B),
Evastin or a pharmaceutically acceptable salt thereof is additionally coated on the surface of the drug layer (B) contained in the immediate-release pellets. delete delete The pellet mixture according to claim 1, wherein the weight of the sustained-release layer is 24 wt% or less based on the total weight of the core (A) and the drug layer (B). The pellet mixture according to claim 1, wherein the dissolution rate of pseudoephedrine or a pharmaceutically acceptable salt thereof contained in the drug layer (B) included in the sustained-release pellet is 46 mg/hour or less over the entire section. The pellet mixture according to claim 1, wherein the cellulose derivative is at least one selected from the group consisting of methyl cellulose, hypromellose and hydroxypropyl cellulose. delete A pharmaceutically acceptable capsule formulation comprising the pellet mixture according to claim 1 .

Images