WO2014003371A1

WO2014003371A1 - Immediate-release and sustained-release pharmaceutical composition comprising acebrophylline

Info

Publication number: WO2014003371A1
Application number: PCT/KR2013/005505
Authority: WO
Inventors: 신용관; 김강민; 전호성; 방준석; 전세강; 이충; 고찬영; 이재걸
Original assignee: 현대약품 주식회사
Priority date: 2012-06-26
Filing date: 2013-06-21
Publication date: 2014-01-03
Also published as: KR20140001357A

Abstract

The present invention relates to an immediate-release and sustained-release pharmaceutical composition comprising acebrophylline, and to a method for preparing same. The composition of the present invention includes an immediate-release portion and a sustained-release portion that exhibit independent release characteristics, thus increasing both a rapid medicinal effect and convenience in taking medicine. Further, dissolution stability is improved in order to achieve improved treatment effects.

Description

【Specification】 ,

[Name of invention]

Pharmaceutical composition having both fast-acting and long-lasting comprising acebrophylline

[Technical Field]

The present invention relates to a pharmaceutical composition comprising acebrophylline and having a fast-acting and sustained at the same time and a method for preparing the same. The composition of the present invention may include rapid release and sustained release, which exhibit independent release characteristics, thereby simultaneously increasing fast drug efficacy and ease of taking, and improving dissolution stability, thereby improving the therapeutic effect.

[Background]- _.

^"Bro pilrin acetate (acebrophylline) cancer Brock Sol (ambroxol) ^'. It is a compound synthesized by salt Ksali fying with 7-theophylline. It is a salt consisting of acid and base, and is orally administered to ambroxol and 7-theopaline to be metabolized. Acebrophyllin selectively acts on bronchial and lung tissues to inhibit the activity of phospholipase in bronchus' alveoli, and elevates the alveolar surfactant action, resulting in an expectorant action. Also, leukotrienes

It inhibits the production of leukotrienes (LTs) and prostaglandins (PGs) and thus exhibits strong anti-inflammatory action, reducing bronchial hypersensitivity and restoring or expanding the constricted bronchus to its normal state. -Acetoxy-bromo pilrin is in Korea and is sold under the trade name sulfolanyl the (Modern drug), a first Al 2 times each lOOmg as encapsulating agents it is adapted to ^"take, to reduce the medication compliance of patients may not receive the desired therapeutic effect There is a problem. It is desirable to develop sustained-release preparations that can exhibit continuous drug efficacy in order to increase the drug swelling.However, if only the continuous drug appears without rapid drug manifestation, it is impossible to expect a rapid effect after taking the drug. In comparison with the formulation, the desired therapeutic effect cannot be expected. Therefore, the rapid onset of expression and continuous onset of expression are satisfied. Development of acebrophylline formulation is needed

[Detailed Description of the Invention]

[Technical Challenges]

Accordingly, the present inventors have studied to develop an acebrophylline formulation having both immediate release features capable of rapidly reaching effective blood levels after administration and sustained release characteristics capable of long-acting drugs. Fast drug release and continuous therapeutic effect, as well as twice daily

take 200 nig of acebrophylline once daily

The present invention has been completed by developing acebrophilized formulations which have been improved pharmaceutical formally to increase the convenience of taking.

[Technical Solution]

An object of the present invention is to provide a pharmaceutical composition having a fast-acting and sustained, including acebrophylline at the same time, taking a convenience, and a preparation method thereof.

More specifically, an object of the present invention is to provide an immediate release comprising (a) an active ingredient comprising acebrophylline and a pharmaceutically acceptable excipient, and (b) an active ingredient and sustained release base comprising acebrophylline. It is to provide a pharmaceutical composition comprising a sustained portion comprising.

It is also an object of the present invention to provide a method for preparing the pharmaceutical composition.

Advantageous Effects

The pharmaceutical composition comprising acebrophylline provided according to the present invention can have a rapid release and a sustained release, which have independent release characteristics, thereby simultaneously increasing fast drug efficacy and ease of taking, and reducing elution due to pH change. Can be taken before or after meals

Significantly improved medications with minimal bioavailability deviations:

Compliance and therapeutic effects can be expected. R2013 / 005505

【Brief Description of Drawings】 _.

Figure 1 shows the dissolution test results according to the pH of the double tablet prepared according to Example 1.

ᅳ-FIG. 2 shows the dissolution test results according to the pH of the double tablet prepared according to Example 2. ᅳ

Figure 3 shows the dissolution test results according to the pH of the double tablets prepared in Example 3.

4 is a dissolution test according to the pH of a double tablet prepared according to Example 4. The results are shown.

Figure 5 shows the dissolution test results according to the pH of the double tablets prepared according to Example 5.

Figure 6 shows the dissolution test results according to the pH of the double tablets prepared according to Example 6.

Figure 7 shows the dissolution test results according to the pH of Comparative Example 1 (quick crystal).

Figure 8 shows the dissolution test results according to the pH of Comparative Example 2 (sustained-release tablet). ^"[BEST MODE FOR CARRYING OUT THE INVENTION] ■ ^'

As one aspect for achieving the above object, the present invention

(a) an immediate release comprising an active ingredient comprising acebrophylline and a pharmaceutically acceptable excipient, and

(b) the western portion comprising the active ingredient comprising acebrophylline and a sustained release base

It relates to pharmaceutical compositions comprising a.

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

As a result of experiments by the present inventors to prepare a pharmaceutical ancestor containing acebrophylline, rapid release of the rapid-release drug can be obtained, but the drug cannot be maintained for a long time, and thus, the drug should be taken several times. That medications may not be effective

Confirmed. In addition, in the case of sustained-release preparations, the frequency of administration can be reduced, which can effectively bring stability and potential effects of medicines such as ease of taking and reducing side effects, but rapid symptoms in a short time in patients who have a fast-acting disease or severe cough. In addition to the problem that the mitigation effect can not be obtained, it was confirmed that there is a problem in the bioavailability if the dissolution rate is changed according to the change in the pH conditions.

The active ingredient is _ah. By providing a pharmaceutical ancestor that includes sebrophylline and has a rapid release and a sustained release, each of which has independent release characteristics, it is possible to simultaneously increase fast drug efficacy and ease of taking, and to reduce the dissolution rate due to pH change. In order to minimize the occurrence of bioavailability and deviation in the gastrointestinal pH changes according to the pre- or post-dose administration, it was confirmed that a significantly improved therapeutic effect can be expected to complete the present invention. The acebrophylline containing pharmaceutical composition of the present invention. As an active ingredient, acebrophylline is divided into the immediate and western parts, respectively, and the initial and sustained release amount of acebrophylline can be easily controlled by the configuration of the immediate and western parts.

In the present invention, acebrophylline is a compound synthesized by ammonium chloride to 7- theophylline (ambroxol [tr ans-4-2-am i no ^~ 3, 5-di br omobenzy 1] am i no cyclohexanol) with theophyl 1 ine-7-acet ic.

ac l [l, 3-dimethylxanthine-7-acetic acid]), refers to a salt consisting of an acid and a base.

Acebrophylline is ambroxol and 7-theophylline when given orally.

It is metabolized separately and selectively acts on lung tissue to show expectoration, and also inhibits the production of leukotriene and prostaglandin and thus anti-inflammatory effect.

Acute respiratory disease, chronic respiratory disease, acute bronchitis, chronic bronchitis. It can be used to prevent or treat bronchial asthma, sinusitis or dry rhinitis. Preferably. The present invention achieves rapid drug expression and sustained eye drug maintenance of ^{acebrophylline} , consisting of acute respiratory disease, chronic respiratory disease, acute bronchitis, chronic bronchitis, bronchial asthma, sinusitis and dry rhinitis It can be used for the prevention or treatment of abnormal diseases selected from the group.

In a preferred embodiment, the amount of acebrophylline included in the silver composition may be easily determined by those skilled in the art according to the age, sex, disease severity, and weight of the patient, but may preferably be included in an amount of 20 to 250 mg in total. More preferably 200 mg total. Including less than 20 mg of acebrophylline does not exhibit sufficient intended efficacy, and containing more than 250 mg may have side effects due to excessive pharmacological action and the mass of the composition itself increases, making administration difficult. It is undesirable because it is a problem that is not useful as a pharmaceutical composition.

In one preferred embodiment, the composition of the present invention contains acebrophylan at a weight ratio of 1: 0.5 to 1:10, more preferably from 1: 1 to 1: 8 in the immediate and western parts. Most preferably, it may be included in the weight ratio of 1: 1.2 to 1: 7.5. If it is less than the above range, the effect of including the western portion together is not properly expressed, and if it exceeds the above range, it is not preferable because a problem such as a variation in dissolution rate due to pH change may occur.

In the present invention, Ca) immediate release means a preparation that dissolves rapidly in the body. After administration and rapidly elutes acebrophylline.

The immediate release part is configured for rapid drug expression of acebrophylline, and includes an active ingredient including acebrophylline and a pharmaceutically acceptable excipient. The sokbang unit may be prepared by compression into a tablet form, the initial rapid drug release allows the active ingredient to the acetoxy quickly get a bromo pilrin the effective therapeutic _{concentration.} _,

Pharmaceutically acceptable excipients included in the immediate release may be used general excipients that can improve the appearance, compression, etc. of the drug without inhibiting the bio-physical activity and properties of the drug. As such, substances that rapidly elute the drug, facilitate granulation, and promote binding when compressed into tablets may be used as fast-acting excipients.

As such excipients, disintegrants commonly used in the pharmaceutical field are recommended. In addition, diluents, binders, lubricants, preservatives, stabilizers, anti-tackifiers, glidants or coloring agents may be used. For example, corn starch, potatoes Starch or modified starch, such as starch or pregelatinized starch, hydroxypropyl cellulose carboxymethyl cellulose, microcrystalline cellulose,.

Crosslinked cells such as croscarmellose sodium, clays, lactose manny, talc, povidone, crospovidone, magnesium stearate, silicon dioxide, sodium starch glycolate, bentonite, montmorillonite, veegum, clay, etc. and the like, and effervescent agents such as sodium ^_citrate. However, it is not limited thereto. Such excipients are preferably contained in an amount of 0.1 to 70% by weight based on the increase in unit dosage form. If less than the above content may be insufficient to indicate the rapid efficacy of the drug, if more than the content

It is unfavorable because it is uneconomical and the overall weight of the unit dosage form is large and can lead to discomfort.

In the composition of the present invention, (b) the sustained portion means a formulation in which acebrophylline is slowly dissolved by slowly dissolving in the body after administration.

Unlike the immediate release, the western portion contains a substance that regulates the dissolution of acebrophylline so that the acebrophylline is slowly eluted. The western part

It is a composition for maintaining the sustained efficacy of acebrophylline _. Active ingredients including acebrophylline and sustained release bases.

The sustained release base is used to release the drug over a long period of time. Mean material. As a sustained-release base material, it is not limited to this, for example.

Polymethacrylate, eudragit, polyalkylene oxide, alginate, sodium alginate, polyvinyl alcohol, polyvinylacetate, polyvinylacetate phthalate, glycerol monostearate, polyvinylpyridone, polyethylin glycol,

Polydextrin. Pectin povidone, carbomer. Polyethylene glycol, polyox, polypropylene oxide, glyceryl behenate, solid fat, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,

Ethyl cellulose, cellulose acetate, carrageenan, salose ether;

Cellulose ester. Xanthan. Chitosan. Guar gum, gum arabic, locust bean gum, acacia gum, gellan gum, xanthan gum or waxes such as carnauba wax, beeswax, microcrystalline wax, hydroxyethylcelose and propylene glycol esters of alginic acid.

Esters, hydrogenated oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, Monoglycerides, diglycerides, triglycerides and combinations thereof

One or more selected from the group consisting of can be used. _In addition, but not limited thereto, the sustained release base is preferably contained in an amount of 10 to 90 weight ¾ based on the total weight of the unit dosage form. The sustained-release base is a pharmaceutical composition of the present invention to release the active ingredient at a constant rate for 12 to 24 hours to deliver the drug only once daily administration, if the content is less than the above effects represents groups is undesirable can result in inconvenience in taking a non-economical and the total weight of the unit dosage form becomes large if ^a shortage and excess of the content. ^'

The western part is preferable _. Enteric polymers soluble at pH above 4.5

_. It may further comprise.

As the enteric polymer, enteric cellulose derivatives, enteric

Acrylic acid copolymer, enteric maleic acid co-polymer, enteric polyvinyl derivative, hydroxypropyl methyl cellulose acetate succinate,

Hydroxypropylmethylcellloosephthalate ，

^• hydroxymethylethyl cell, cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate,

^{Cellulose Benzoate Phthalate} , ^Cellulose Propionate Phthalate, Methyl ^{Cellulose Phthalate,} carboxymethylethyl ^Cellulose ,

Ethyl hydroxyethyl cellulose ophthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer,

Methyl methacrylate copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methacrylic acid-octyl acrylate copolymer, vinyl acetate - maleic anhydride copolymer, a styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ^ether-mal lane anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer,

Acrylonitrile-methyl maleic anhydride copolymer,

Vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, Acrylonitrile-maleic anhydride in the copolymer, and their common compounds - methyl methacrylate maleic anhydride copolymer, ^i-butyl acrylate-styrene

One or more selected from the group consisting of may be used, but is not limited thereto.

Also, but not limited to, the enteric polymer is based on the total weight of the unit dosage form _. It is preferably contained in 1 to 90% by weight. Wherein the enteric polymer, and to the pharmaceutical compositions of this invention can be spite of the change of status of employees and constant dissolution of the active ingredient, and the active ingredient at a constant rate for the pharmaceutical ^composition, 12 to 24 hours of the invention It is possible to deliver the medicinal effect by only one administration on a daily basis by releasing it. If the content is less than the above, it is insufficient to achieve the same effect. If the content is exceeded, it is uneconomical and the total weight of the unit dosage form is increased. It is not preferable because it may cause inconvenience

In addition, the western part may further include a pharmaceutically acceptable excipient, and can use a general excipient that can improve the manufacture, appearance, compression, etc. of the drug within a range that does not inhibit the biological activity and properties of the drug. have. The specific content can be determined by standard pharmaceutical practices, as well as the solubility and chemical nature of the active ingredient, the route of administration chosen. Such pharmaceutically acceptable excipients may include diluents, binders, lubricants, preservatives, stabilizers, anti-tackifiers, glidants or colorants commonly used in the pharmaceutical art. -More specifically, as a diluent—starch, microcrystalline cellulose, lactose, glucose, manny, alginate. Alkaline earth metal salts, clays, polyethylene glycols and dicalcium phosphates may be used, and as binders, microcrystalline cellulose, highly disperse silica, manny, sugars such as lactose, highly disperse silica, polyethylene glycol, polyvinyl cellulose Reidon. Such as polyvinyl alcohol, copovidone

Polyvinylpyridone derivatives, natural gums, synthetic gums, gelatin, and the like, and as a lubricant, hard silicic anhydride. Talcyan stearic acid. Ste ⁱ Arlene acid _magnesium, calcium stearate, zinc stearate, sodium stearyl fumarate,

Sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, Glyceryl Monostearate, Glyceryl Palmitostearate, Glyceryl Behenate. Some stearyl fumarate, polyethylene glycol and the like can be used, but is not limited thereto. In addition, various additives such as antioxidants, colorants, flavors, preservatives, taste blockers and the like can be used in a range of conventional dosages by those of ordinary skill in the art.

As another preferred embodiment, the composition of the present invention may further comprise a coating comprising a coating base (c) outside the immediate and sustained portions. The composition of the invention (C) the coating comprises: acetoxy bromo pilrin the initial emission and the continuous emission as easily ^{"configuration} for the control of. To this end, the coating part may be formed on the outside of the double tablet including the immediate release portion and the sustained release portion. It is preferable that the coating base agent contained in a coating part contains 1 or more types of water-soluble polymer and enteric polymer. Water-soluble polymers are intended to prevent moisture, such as hydroxypropylmethylcelose, polyvinyl alcohol, polypropyltenglycol, acrylic acid polymer, polymethacrylate copolymer, polyethyleneglycol polyvinylacetate and the like. It may include one or more selected from the group consisting of the compound, but is not limited thereto.

The enteric polymer is preferably an excipient that is dissolved at a pH of 4.5 or higher, for example, an enteric cellulose derivative. Enteric acrylic acid copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives,

Hydroxy propyl methylcellulose acetate succinate,

Hydroxypropylmethylcellloosephthalate ，

Hydroxymethylethyl cell cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate,

Cellulose benzoate phthalate, Cellulose propionate phthalate. Methyl cellulose phthalate, carboxymethyl ethyl cellulose,

Ethyl hydroxyethyl cell loose phthalate, methyl hydroxyethyl cell loose, styrene-acrylic acid co-polymer. Methyl acrylate-acrylic acid copolymer,

Methyl methacrylate copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, Acrylic acid-decacrylic acid-octylate acrylate copolymer, vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, Vinyl butyl ether maleic anhydride copolymer,

Acrylonitrile-methyl maleic acid maleic anhydride copolymer,

Plastic part is an ether-maleic anhydride _copolymer. Acrylonitrile-methyl maleic acid maleic anhydride copolymer, vinyl butyl ether "maleic anhydride copolymer, acrylonitrile ¾-methyl maleic acid anhydride copolymer,

Butyl acrylate-styrene-maleic anhydride ^' copolymer and mixtures thereof: may be one or more selected from the group, but is not limited thereto. ^'

By the coating unit, the composition of the present invention can suppress the rapid dissolution of the drug at pH 1.2, and can reduce the difference from the dissolution at pH 6.8 until the eluting time of about 2 hours. Therefore, it is possible to reduce the difference in drug dissolution according to the pH and the difference, it is possible to suppress the rapid dissolution of the drug in the gastric environment during drug administration to maintain long-term continuous expression. _. In the present invention, when the coating base includes both the water-soluble polymer and the enteric polymer, it is preferable to include the water-soluble polymer and the enteric polymer in a weight ratio of 0: 1: 1 to 1: 0.1. If the ratio is out of the above range, the elution at pH 1.2 is too suppressed to dissolve or the elution at .pH 1.2. It may not be suppressed. ^'

When the hayeoteul pharmaceutical ^'composition paddle (paddle) Method 37 ± 0.5 ^° C, in the leaching solution 900ml of pH 6.8 by using according to the for the ^KP' eluting with 50rpm to 75rpm examination of the invention, the acetoxy bromo pilrin after 2 hours The dissolution rate is 20% to 60%, more preferably 25% to 40%, and after 12 hours, the dissolution rate of acebrophylline may be 70% to 95%, and more preferably 70% to 85%. Accordingly, when the pharmaceutical composition is administered in vivo, for example, the drug may exhibit desirable efficacy even under reduced doses once daily. Therefore, the pharmaceutical composition can be used to improve the convenience of the patient.

The pharmaceutical composition of the present invention is not limited thereto but preferably It may be formulated in a dosage form suitable for oral administration,

Preferably, it may be provided in the form of a solid oral preparation in consideration of the productivity of the producer and the convenience and portability of the patient. _.

For example, the solid oral preparation may be, for example, a multilayer tablet, a nucleated tablet, a single tablet, a coated tablet or a capsule, such as a double tablet or a triple tablet. But now it is not limited. The specific form of administration of the formulations of the invention and _. The dosage may be selected by the attending physician depending on the patient's characteristics, in particular age, weight, lifestyle and level of symptoms. Preferably, 2 oσ πσ once daily with acebrophyllan to improve compliance It can be prepared to take. ;

Each formulation form possible in the present invention can be obtained by methods commonly known to those skilled in the art. For example, each composition of the said western part and immediate release part. Combined in separate forms to obtain a preparation in the form of double tablets or trichophyte tablets in a conventional manner, or to form the compositions of these sustained and rapid release in the form of granules, respectively, using these granules In tablet or capsule form

^■ You can also get a preparation. In addition, according to a conventional method,

The nucleated tablet of the form which surrounds the composition of a western part can also be obtained.

As a specific example, each step of producing the immediate and sustained parts, dry granules, wet granules, molten granules. Fluidized bed granules, direct compression. It may be carried out by a method such as molding and compression molding. Preferably it may be carried out by dry granulation, wet granulation, melt granulation method. For example, when prepared by a direct tableting method, the western and immediate parts including acebrophylline may be mixed orally formulated with a pharmaceutically acceptable excipient, followed by tableting and coating in double tablets. In addition, when prepared by the compressed granulation method, the western part and the immediate part including acebrophylline are respectively mixed with ^' pharmaceutically acceptable excipients

The granules may be prepared by compressing granules, sieved, and then compressed into tablets and coated.

The acebrophylline containing formulations according to the present invention are administered orally to give an immediate therapeutic effect, as well as maintaining a constant concentration of the active ingredient in the plasma for a considerable time. deviation of elution due to ρΗ change It is very useful because it can reduce the number of doses to once a day, as well as increase the drug adaptability to patients as a result. [Form for implementation of invention]

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, the present invention is not limited by the following examples. <Example 1 to Example 6> The western-definition of the double-definition tank containing acebrophylline was mixed with the compositions of Tables 1 and 2, respectively, and compressed using a ler compactor to form dry granules. The inner part is mixed with the composition of Table 1 and Table 2 until the first mixing, and it is compressed by using a compactor.

After dry granules were formed, a secondary mixture was added and mixed to form granules. The prepared granules of the sustained and immediate release were compressed into double tablets. After tableting, the coating base of Table 1 and Table 2 was used to coat 6% of the weight of the double tablet.

Table 1

Comparative Example 1 Preparation of Rapid Formula Containing Acebrophylline

Sulforase capsules (Hyundai Pharm., Korea) were used.

Comparative Example 2 Preparation of Sustained-release Tablet Containing Acebrophylline

-Sustained-release tablets were prepared by mixing with the composition shown in Table 3, using a compactor to compact dry granules, and tableting with a tableting machine.

Table 3

Experimental Example Dissolution at pH 1.2 and ρΗ6 · 8

Examples 1 to 6 and the formulations of Comparative Examples 1 and 2, respectively, using a paddle method of the pharmacopeia No. 2 method in the eluate of pH 1.2 or pH6.8 at 37 ^° C 0.5 ^° C, An elution test was performed at 50 rpm. The eluate was taken at each sampling time, filtered through a 0.¾mi filter to form a sample solution, and after the eluate was taken, the new ^' eluate was calibrated. The dissolution rate of the active ingredient was analyzed from the sample solution obtained every hour. Dissolution * Analysis was analyzed using HPLC, and the dissolution rate test results over time are shown in Tables 4 to 11 and FIGS. 1 to 8, respectively.

As a result, in the case of Comparative Example 1 (rapid release), all drugs were eluted within 1 hour at pH 1.2, and the dissolution rate was 90% or more within 2 hours at pH 6.8, and the drug was almost eluted within 1 2 hours. Meanwhile. In the case of the Comparative Example 2 formulation (sustained-release tablet), the drug was slowly released until 24 hours, but the dissolution difference according to pH was relatively large.

On the other hand, in the case of the double tablet of the present invention, the difference in dissolution rate according to pH was small compared to the case of simply consisting of sustained-release tablets, and it was confirmed that the dissolution stability was very excellent. As well as. In the case of the double tablet of the present invention, a large amount of acebrophylline was eluted within a short period of time and maintained a high dissolution rate even after 12 hours, it was confirmed that it has both the fast-acting and sustained-release sustained-release tablet.

like this. The pharmaceutical composition of the present invention can have both rapid release and sustained release, which have independent release characteristics, thereby increasing fast drug efficacy and ease of taking at the same time, and improving dissolution stability against pH: change. I can see that we can expect it.

TABLE 4

Table 5

Table 9

Table 10

Table 11

Claims

[Claim]

[Claim 1]

(a) Immediate release comprising an active ingredient comprising acebrophylline and a pharmaceutically acceptable excipient. And

Pharmaceutical composition comprising a.

【Claim 2】.

The pharmaceutical composition of claim 1 comprising acebrophylline in an amount of 20 to 250 nig in total.

[Claim 3]

The pharmaceutical composition according to claim 1, wherein the immediate and western parts of acebrophylline are included in an increase ratio of 1: 0.5 to 1:10. -

[Claim 4] /

The method of claim 1, wherein the sustained-release base is polymetha triacrylate. Eudragit, polyalkylene oxide, alginate, sodium alginate, pulley vinyl alcohol,

Polyvinylacetate, polyvinylacetate phthalate,

Glycerol monostearate, Polyvinylpyrrolidone, Polyethylen glycol,

Polydextrin, pectin, povidone, carbomer, polycetylene glycol, polyox, polypropyltenoxide, glyceryl behenate, solid fat, methylcellulose, hydroxypropyl salose, hydroxypropyl methylcellulose ，

Ethylcellulose. Cellulose acetate, carrageenan, cellulose ether.

Carnauba wax as cellulose ester, xanthan, chitosan, guar gum, gum arabic, locust bean gum, acacia gum, gellan gum, xanthan gum or waxes. Beeswax, microcrystalline wax, hydroxyethylcellulose, alginate propylene glycol ester, ester, hardened oil, natural wax, synthetic wax, hydrocarbon. Fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides, and mixtures thereof At least one pharmaceutical composition selected from the group consisting of.

[Claim 5]

The pharmaceutical composition of claim 1, wherein the sustained portion further comprises an enteric 5 polymer that melts at a pH of 4.5 or higher. .

6. The ^"eu according to claim 5, wherein the enteric polymer is agarose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, hydroxypropyl by enteric _selreul. Methyl Cellulose Acetate Succinate,

Agarose phthalate, a hard hydroxypropyl methyl _selreul,

Hardoxymethylethyl cell is a low phthalate. Cellulose acetate phthalate, Cellulose acetate succinate, Cellulose acetate maleate.

Cellulose benzoate phthalate, Cellulose propionate art phthalate, Methyl salose phthalate, Carboxymethyl ethyl cellulose,

Ethyl hydroxyethyl cell, cellulose phthalate, methyl hydroxyethyl cell,. Styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer,

Methyl methacrylate copolymer, butyl styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methacrylate-octyl acrylate copolymer, vinyl acetate —Maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinylbutyl ether-maleic anhydride copolymer,

ᅵ. Acrylonitrile methacrylate maleic anhydride copolymer,

Vinyl butyl ether maleic anhydride copolymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer vinyl butyl ether- maleic anhydride copolymer, acrylonitrile- methyl maleic anhydride copolymer

Butyl acrylate-sutiten-maleic anhydride copolymer and mixtures thereof

At least one pharmaceutical composition selected from the group consisting of.

[Claim 7]

. ^■ The pharmaceutical composition of claim 1, further comprising a coating comprising (c) a coating base.

[Claim 8]

According to claim 17. Wherein said coating base comprises a water soluble polymer.

[Claim 9]

The method of claim 8, wherein the water-soluble polymer

Hydroxypropyl methylcellose, polyvinyl alcohol. Polypropylene glycol, acrylic acid polymer. Polymethacrylate copolymer ᅳ Polyethylene glycol.

At least one pharmaceutical composition selected from the group consisting of polyvinylacetate and mixtures thereof.

[Claim 10]

8. The pharmaceutical composition of claim 7, wherein the coating base comprises an enteric polymer that melts at a pH above 4.5.

[Claim 11]

The enteric polymer according to claim 10, wherein the enteric polymer is an enteric cellulose derivative 1, an enteric acrylic acid-based copolymer, an enteric maleic acid-based copolymer, an enteric polybi ¹ derivative, hydroxyoxymethyl cellulose acetate succinate,

Hydroxypropylmethylcelloseophthalate.

Hydroxymethylethyl Cellulose Phosphate, Cellulose Acetate Phthalate, Cellulose Acetate Succinate, Cellulose Acetate Maleate, Cellulose Benzoate Phthalate, Cellulose Propionate Phthalate, Methyl Cellulose Phosphate, Carboxymethyl ethyl cellulose, ：

Ethyl hydroxyethyl cellulose, phthalate phthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, Methyl methacrylate copolymer, butyl styrene-acrylic acid copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-acrylate acrylate copolymer, acrylic acid-methacrylic acid—octyl acrylate copolymer, vinyl acetate -Maleic anhydride copolymer, styrene-maleic anhydride co-polymer, styrene-maleic acid monoester

5 Copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic acid \ anhydride copolymer. Vinyl butyl ether-maleic anhydride copolymer,

Acrylonitrile-methyl maleic anhydride copolymer,

Vinyl butyl ether maleic anhydride co-polymer, acrylonitrile-methyl methacrylate maleic anhydride copolymer, vinal butyl ether ᅳ maleic anhydride copolymer,

0 acrylonitrile-methyl maleic acid anhydride copolymer,

At least one pharmaceutical composition selected from the group consisting of butyl acrylate-styrene-maleic anhydride co-polymer and a combination thereof. -

.

[Claim 12]

5 The method of claim 1, wherein the pharmaceutical composition is according to the

Elution test at 37 ± 0.5 ° C, 50rpm to 75rpm in 900nil eluent at pH 6.8 using the paddle method. A pharmaceutical composition having an acebrophylline dissolution rate of 20% to 60% after 2 hours and an acebrophylline dissolution rate of 70% to 95% after 12 hours. -

[Claim 13]

The pharmaceutical composition according to claim 1, which is provided in the form of a solid oral preparation. _.

【Claim 14】 _. 약제 The pharmaceutical composition according to claim 13, wherein the solid oral preparation is a multilayer tablet, a nucleated tablet, a single tablet or a nasal tablet.

[Claim 15]

The acute respiratory disease of claim 1. Chronic respiratory disease, acute bronchitis, A pharmaceutical composition for use in the prevention or treatment of at least one disease selected from the group consisting of chronic bronchitis, bronchial asthma, sinusitis and dry rhinitis.