KR20140001357A - Immediate-release and sustained-release pharmaceutical composition comprising acebrophylline - Google Patents

Abstract

The present invention relates to an acebrophylline containing pharmaceutical composition which is both immediate-releasable and sustained-releasable, and a producing method of the same. The composition comprises a rapid-releasing part and a sustained-releasing part that has independently-releasing nature. The present invention may increase both fast medicinal effect and convenience of taking, and also can anticipate better treatment effect by improving elution stability. [Reference numerals] (AA) Dissolution rate (%); (BB) Time (h); (CC) Example 1 (pH6. 8); (DD) Example 1(pH1. 2)

Description

Pharmaceutical composition having both fast-acting and sustained at the same time containing acebrophylline {Immediate-release and sustained-release pharmaceutical composition comprising acebrophylline}

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

Acebrophylline is a compound synthesized by salting ambroxol with 7-theophylline, a salt consisting of an acid and a base, and when orally administered, ambroxol and 7- It is isolated and metabolized to theophylline. Acebrophylline selectively acts on bronchial and lung tissues to inhibit the activity of phospholipase in bronchoalveolar algae, and elevates the alveolar surface action, resulting in an expectorant action. In addition, it inhibits the production of leukotrienes (LTs) and prostaglandins (PGs) and thus exhibits strong anti-inflammatory action, thus reducing bronchial hypersensitivity and restoring or expanding the constricted bronchus to its normal state.

Acebrophylline is sold under the brand name sulfolase (modern drug) in Korea, and it is supposed to take 100mg twice a day as an encapsulating agent. There is. It is desirable to develop sustained-release drugs that can provide continuous drug efficacy in order to increase medication compliance.However, if only continuous drug appears without rapid drug effect, the patient's discomfort increases due to the rapid effect after taking the drug, and commercially available drugs In comparison with the desired therapeutic effect can not be expected. Thus, there is a need for the development of acebrophylline formulations in which both rapid and sustained expression of the drug is met.

Accordingly, the present inventors have studied to develop an acebrophylline formulation having both immediate release characteristics capable of expressing drug efficacy by rapidly reaching an effective blood concentration after administration and sustained release characteristics capable of maintaining the drug for a long time. In addition to maintaining drug expression and sustained therapeutic effects, the formulation of acebrophylline, acebrophylline, in which 100 mg of 100 mg each twice a day is taken to 200 mg once a day, improves the convenience of administration. The present invention was completed.

It is an object of the present invention to provide a pharmaceutical composition and a method for preparing the same, which have both fast-acting efficacy and sustainability and ease of taking, including acebrophylline.

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.

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 a pharmaceutical composition comprising a.

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

The present inventors have experimented to prepare a pharmaceutical composition containing acebrophylline, as a result of the rapid release of the fast-release drug, but can not be maintained for a long time, because the drug must be taken several times, resulting in low drug compliance It was confirmed that the treatment may not be due to the proper effect. In addition, in the case of sustained-release preparations, the frequency of administration can be reduced, which can effectively bring out the safety and potential effects of medicines such as ease of taking and reducing side effects, but in the short-term patients who have a severe cough or acute cough. In addition to the problem that the effect can not be obtained, it was confirmed that there is a problem in bioavailability if the dissolution rate is changed according to changes in the body conditions such as pH changes.

Therefore, by providing a pharmaceutical composition having a rapid release and a sustained release, each containing the active ingredient acebrophylline and exhibiting independent release characteristics, it is possible to simultaneously increase the fast drug efficacy and ease of taking, and the variation in dissolution rate due to pH change The present invention was completed by confirming that a markedly improved therapeutic effect can be expected because it can minimize the occurrence of variation in bioavailability with respect to pH change in the gastrointestinal tract due to pre- or postprandial administration.

The acebrophylline-containing pharmaceutical composition of the present invention includes an acebrophylline, which is an active ingredient, in the immediate and western portions, respectively, and facilitates the initial release and the sustained release of acebrophylline by the configuration of the immediate and western portions. I can regulate it.

In the present invention, acebrophylline is a compound (ambroxol [trans-4-2-amino-3,5-dibromobenzyl] amino cyclohexanol) with theophylline-7-acetic acid [1] synthesized by chlorinating ambroxol to 7-theophylline , 3-dimethylxanthine-7-acetic acid]) refers to a salt consisting of an acid and a base.

Acebrophylline is metabolized into ambroxol and 7-theophylline when administered orally, selectively acts on lung tissue, shows expectoration, and also inhibits the production of leukotriene and prostaglandin, resulting in an acute respiratory tract. It can be used for the prevention or treatment of diseases, chronic respiratory diseases, acute bronchitis, chronic bronchitis, bronchial asthma, sinusitis or dry rhinitis.

Thus, preferably, the present invention achieves rapid drug expression and sustained drug maintenance of acebrophylline, 1 selected from the group 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 more than one disease.

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

In a preferred embodiment, the composition of the present invention is acebrophylline in the immediate and western parts in a weight ratio of 1: 0.5 to 1: 10, more preferably 1: 1 to 1: 8, most preferably 1: 1: It may be included in a weight ratio of 1.2 to 1: 7.5. If it does not fall within the above range, the effect of including the western portion together is not properly expressed, and if it exceeds the above range, problems such as a large variation in dissolution rate due to pH change may occur, which is not preferable.

In the present invention, (a) 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 immediate release can be prepared by pressing in tablet form, and the initial drug is released quickly to allow the active ingredient acebrophylline to reach the effective therapeutic concentration.

Pharmaceutically acceptable excipients included in the immediate release may use a general excipient that can improve the manufacture, appearance, compression, etc. of the drug without inhibiting the biological activity and properties of the drug. In addition, if desired, a substance that rapidly elutes the drug, facilitates granulation, and enhances binding force when compressed into tablets may be used as a fast-acting excipient.

Such excipients are preferably disintegrants commonly used in the pharmaceutical field. In addition, diluents, binders, lubricants, preservatives, stabilizers, anti-tackifiers, glidants or colorants may be used. For example, starch or modified starch, such as corn starch, potato starch, or pregelatinized starch, cross-linked celluloses such as hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, croscarmellose sodium, lactose, mannitol, Talc, povidone, crospovidone, magnesium stearate, silicon dioxide, sodium starch glycolate, bentonite, montmorillonite, clay such as veegum, effervescent agents such as sodium bicarbonate and citric acid, and the like, but are not limited thereto. no.

Such excipients are preferably contained in 0.1 to 70% by weight based on the total weight of the unit dosage form. If it is less than the above content may be insufficient to show the rapid efficacy of the drug, if it exceeds the above amount is uneconomical and the overall weight of the unit dosage form is large, which is not preferable because it may cause inconvenience in taking.

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

Unlike the immediate release, the western portion contains a substance that regulates the dissolution of acebrophylline so that the acebrophylline is slowly eluted. The sustained portion is a composition for the sustained medicinal efficacy of acebrophylline, and comprises an active ingredient including acebrophylline and a sustained release base.

The sustained release base means a substance used to release a drug over a long time. The sustained-release base includes, but is not limited to, polymethacrylate, eudragit, polyalkylene oxide, alginate, sodium alginate, polyvinyl alcohols, polyvinylacetate, polyvinylacetate phthalate, glycerol Monostearate, polyvinylpyrrolidone, polyethylenglycol, polydextrin, pectin, povidone, carbomer, polyethylene glycol, polyox, polypropylene oxide, glyceryl behenate, solid fat, methyl cellulose, hydroxypropyl cellulose Carnauba as hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, carrageenan, cellulose ether, cellulose ester, xanthan, chitosan, guar gum, gum arabic, locust bean gum, acacia gum, gellan gum, xanthan gum or waxes Wax, Beeswax, Microcrystalline Wax, Hydroxyethyl Cellulose, Alginic Acid Pro Is alkylene glycol esters, esters, hydrogenated oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides, and at least one member selected from the group consisting of a mixture thereof can be used.

In addition, but not limited to, the sustained-release base is preferably contained in 10 to 90% by weight 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 hours to 24 hours to deliver the drug effect only once daily administration, if the content is less than the above effects It is not preferable because it is insufficient to represent, and exceeds the content, it is uneconomical and the total weight of the unit dosage form becomes large, which may cause inconvenience in taking.

The sustained portion may further include an enteric polymer that melts at a pH of 4.5 or higher.

The enteric polymer may be an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose Acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid Copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic acid-methacrylate Methyl acid copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methacrylic acid-octyl acrylate copolymer, vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl Ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinylbutylether-maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, vinylbutylether-maleic anhydride copolymer, acrylonitrile-crylic acid Methyl maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer, and mixtures thereof. May be, but is not limited to .

In addition, the enteric polymer is not limited thereto but is preferably contained in 1 to 90% by weight based on the total weight of the unit dosage form. The enteric polymer allows the pharmaceutical composition of the present invention to constantly elute the active ingredient despite the change of the condition of the subject, and the pharmaceutical composition of the present invention may also be used at a constant rate for 12 to 24 hours. It is possible to deliver the medicinal effect by only one administration on a daily basis by release. If it is less than the above content, it is insufficient to achieve the same effect. It is not preferable because it may cause.

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 the range that does not impair the biological activity and properties of the drug. have. The specific content can be determined by standard pharmaceutical practices, as well as solubility and chemical properties of the active ingredient, the route of administration chosen. Such pharmaceutically acceptable excipients may include diluents, binders, glidants, preservatives, stabilizers, anti-tackifiers, glidants or colorants commonly used in the pharmaceutical art.

More specifically, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate can be used as the diluent, and microcrystalline cellulose, highly disperse silica, mannitol, lactose as binders. Sugars such as, highly dispersible silica, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinylpyrrolidone derivatives such as copovidone, natural gums, synthetic gums, and gelatin, and the like can also be used. As a lubricant, light silicic anhydride, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate, glyceryl palmitostearate, Glyceryl Behenate, Sodium Stearyl Fumarate, Polyethylene Glycol The call or 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 the usual range of dosages by the choice of one 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. (C) the coating of the composition of the present invention is configured to easily control the initial release and sustained release amount of acebrophylline, for this purpose, the coating may be formed on the outside of the double tablet including the immediate release and sustained release.

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. The water-soluble polymer is for preventing moisture, for example, hydroxypropyl methyl cellulose, polyvinyl alcohol, polypropylene glycol, acrylic acid polymer, polymethacrylate copolymer, polyethylene glycol, polyvinylacetate and a mixture thereof One or more selected from, but is not limited thereto.

The enteric polymer is preferably an excipient that is dissolved at a pH of 4.5 or more, and examples thereof include an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, hydroxypropylmethylcellulose acetate succinate, and hydroxypropyl. Methyl cellulose phthalate, hydroxymethyl ethyl 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 cellulose Phthalate, methyl hydroxyethyl cellulose, styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, acrylic acid Tyl-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, styrene-maleic acid Anhydride copolymers, styrene-maleic acid monoester copolymers, vinylmethyl ether-maleic anhydride copolymers, ethylene-maleic anhydride copolymers, vinyl butyl ether-maleic anhydride copolymers, acrylonitrile-methyl maleic anhydride copolymers, vinyl Butyl ether-maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, butyl styrene-maleic anhydride copolymer And one kind selected from the group consisting of a mixture thereof. Include a phase, but is not limited to this.

By the coating unit, the composition of the present invention can suppress the rapid dissolution of the drug at pH 1.2, it is possible to reduce the difference with the dissolution at pH 6.8 until about 2 hours dissolution time. Therefore, it is possible to reduce the difference in drug dissolution according to the difference in pH, 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 a water-soluble polymer and an 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 range, the elution at pH 1.2 may be too suppressed to prevent elution, or the elution at pH 1.2 may not be suppressed.

In the pharmaceutical composition of the present invention, the dissolution rate of acebrophylline after 2 hours when the dissolution test at 37 ± 0.5 ℃, 50rpm to 75rpm in 900ml eluent of pH 6.8 using the paddle method according to the Korean Pharmacopoeia % To 60%, more preferably 25% to 40%, and after 12 hours, the dissolution rate of acebrophylline may be 70% to 95%, more preferably 70% to 85%. Accordingly, when the pharmaceutical composition is administered in vivo, for example, it may exhibit desirable efficacy even under a reduced number of doses once daily. Thus, 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 may preferably be formulated in a dosage form suitable for oral administration, and preferably a solid oral preparation in consideration of the productivity of the producer and the convenience and portability of the patient. It may be provided in the form.

In a preferred embodiment, the solid oral preparation may be, for example, a multi-layer tablet, a nucleated tablet, a single tablet, a coated tablet or a capsule such as double tablets and triple tablets, but is not limited thereto. The particular form and dosage of administration of the formulations of the present invention may be selected by the attending physician, depending on the characteristics of the patient, in particular age, weight, lifestyle, level of symptoms, and if desired, preferably, in order to improve dose compliance. Brophylline can be prepared to take 200 mg once daily.

Each formulation form possible in the present invention can be obtained by methods commonly known to those skilled in the art. For example, the compositions of the sustained-release and immediate-release parts are combined with each other in a separate form to obtain a preparation in the form of a double tablet or a triple tablet in a conventional manner, or the compositions of these sustained-release and immediate-release parts are granulated, respectively. After forming in the form, these granules may be used to obtain a preparation in the form of a single tablet or capsule. Moreover, the nucleated tablet of the form in which the composition of a immediate release | round | yen surrounds the composition of a western part can also be obtained by a conventional method.

As a specific example, each step of producing the immediate release portion and the sustained release portion may be performed by a method such as dry granules, wet granules, melt granules, fluidized bed granules, direct compression, molding, and compression molding. Preferably it may be carried out by the method of dry granules, wet granules, melt granules. For example, when prepared by a direct tableting method, the western and immediate parts containing acebrophylline may be mixed orally with a pharmaceutically acceptable excipient, followed by tableting and coating in double tablets, respectively. In addition, in the case of manufacturing by compression granulation method, the western part and the immediate part including acebrophylline are mixed with a pharmaceutically acceptable excipient, respectively, and then granulated with compressed granules, sieved and compressed into tablets by double tablets. It can manufacture.

The acebrophylline-containing preparation according to the present invention is not only administered orally to give an immediate therapeutic effect, but also maintains a constant concentration of the active ingredient in plasma for a considerable time, and reduces the variation of the dissolution rule due to pH change. As a result, the number of doses can be reduced to once a day, and as a result, drug adaptability to patients can be increased, thereby increasing dose compliance.

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 the variation in dissolution rate due to pH change. It is possible to minimize the occurrence of deviations in the bioavailability according to the pre- or post-dose administration, can be expected to significantly improved medication compliance and therapeutic effects.

Figure 1 shows the dissolution test results according to the pH of the double tablet prepared according to Example 1.
Figure 2 shows the dissolution test results according to the pH of the double tablet prepared according to Example 2.
Figure 3 shows the dissolution test results according to the pH of the double tablet prepared in Example 3.
Figure 4 shows the dissolution test results according to the pH of the double tablet prepared in Example 4.
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).

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

< Example  1 to Example  6> Acebrophylline  Double tablet manufacturing to include

The western parts were mixed with the compositions of Tables 1 and 2, respectively, and compressed using a roller compactor to form dry granules. The inner part was mixed with the composition of Table 1 and Table 2 to the first mixture, compressed using a roller compactor to form dry granules, and then mixed with the secondary mixture to form granules. The prepared granules of the sustained and rapid 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.

ingredient Example 1 Example 2 Example 3 content
(weight%) content
(weight%) content
(weight%) Western Region (SR) Acebrophylline 41.67 41.67 39.71 Lactose 4.76 4.76 9.85 Carnauba Nap
(Carnauba wax) 27.38 27.38 26.47 Eudragit 25.00 25.00 21.50 Magnesium stearate 1.19 1.19 2.47 Total content 100 100 100 Immediate release (IR) Primary
mix Acebrophylline 13.89 13.89 25.00 Lactose 16.67 16.67 13.65 Microcrystalline cellulose 16.67 16.67 12.31 Sodium starch glycolate 1.67 1.67 2.00 Silicon dioxide - - 1.00 Magnesium stearate - - 1.00 Secondary
mix Mannitol 44.44 44.44 38.88 Sodium starch glycolate 5.56 5.56 4.00 Silicon dioxide - - 1.00 Magnesium stearate 1.11 1.11 1.15 Total content 100 100 100 Coater Polyvinyl alcohol - 70 70 Polymethacrylate - 30 30 Total content - 100 100

ingredient Example 4 Example 5 Example 6 content
(weight%) content
(weight%) content
(weight%) Western Region (SR) Acebrophylline 30.88 33.82 30.88 Lactose 18.68 15.74 18.68 Carnauba Nap
(Carnauba wax) 26.47 26.47 26.47 Eudragit 21.50 21.50 21.50 Magnesium stearate 2.47 2.47 2.47 Total content 100 100 100 Immediate release (IR) Primary
mix Acebrophylline 36.54 32.69 36.54 Lactose 13.65 13.65 13.65 Microcrystalline cellulose 12.31 12.31 12.31 Sodium starch glycolate 2.00 2.00 2.00 Silicon dioxide - 1.00 - Magnesium stearate - - - Secondary
mix Mannitol 30.35 33.19 30.35 Sodium starch glycolate 4.00 4.00 4.00 Silicon dioxide - - - Magnesium stearate 1.15 1.15 1.15 Total content 100 100 100 Coater Polyvinyl alcohol - 70 70 Polymethacrylate - 30 30 Total content - 100 100

< Comparative Example  1> Acebrophylline  Containing Immediate  Produce

Sulforase capsules (Hyundai Pharm, Korea) were used.

< Comparative Example  2> Acebrophylline  Preparation of sustained-release tablets containing

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

ingredient Comparative Example 2 Content (% by weight) Western Region (SR) Acebrophylline 41.67 Lactose 4.76 Carnauba Nap
(Carnauba wax) 27.38 Eudragit 25.00 Magnesium stearate 1.19 Total content 100 Immediate release (IR) Primary
mix Acebrophylline - Lactose - Microcrystalline cellulose - Sodium starch glycolate - Silicon dioxide - Magnesium stearate - Secondary
mix Mannitol - Sodium starch glycolate - Silicon dioxide - Magnesium stearate - Total content - Coater Polyvinyl alcohol - Polymethacrylate - Total content -

< Experimental Example > pH  1.2 and pH6 . At 8  Dissolution experiment

For the formulations of Examples 1 to 6, and Comparative Examples 1 and 2, respectively, using a paddle method, the pharmacopeia No. 2 method, at 37 ± 0.5 ° C. and 50 rpm in 900 ml of eluent at pH 1.2 or pH6.8 Dissolution test was performed. The eluate was taken at each sampling time, filtered through a 0.2 μm filter to obtain a sample solution, and the new eluate was equally corrected after the eluate was taken. The dissolution rate of the active ingredient was analyzed from the sample solution obtained every hour. Dissolution rate 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 of the experiment, in the case of the formulation (Comparative tablet) of Comparative Example 1, 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, indicating that the drug was almost eluted within 1 to 2 hours. . Meanwhile, in the case of the formulation of Comparative Example 2 (sustained-release tablet), the drug was slowly released until 24 hours, but the difference in dissolution 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. In addition, 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 fast-acting and sustained-release sustained-release tablet.

As such, the pharmaceutical composition of the present invention can have both rapid release and sustained release, which exhibit independent release characteristics, thereby simultaneously increasing fast drug efficacy and ease of taking, and dissolution stability against pH change can be significantly improved, thereby improving treatment. It can be seen that the effect can be expected.

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 1
(pH6.8) 13.4 16.4 20.5 27.7 39.1 56.4 77.6 82.8 87.2 97.5 Example 1
(pH1.2) 18.3 24.2 35.6 45.6 60.1 74.4 81.6 86.5 91.2 96.5

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 2
(pH6.8) 13.6 15.7 19.4 26.1 37.3 56.4 76.0 86.2 88.3 98.9 Example 2
(pH1.2) 11.2 16.8 23.7 36.3 51.6 68.4 77.6 84.0 88.9 98.4

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 3
(pH6.8) 21.8 25.7 31.3 37.7 48.2 66.4 78.5 86.0 89.0 95.0 Example 3
(pH1.2) 16.0 23.5 35.1 50.7 69.5 84.5 88.6 95.2 97.0 99.2

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 4
(pH6.8) 37.1 41.0 49.7 55.5 69.5 82.8 90.1 95.6 98.4 101.0 Example 4
(pH1.2) 37.0 43.2 66.0 75.6 74.3 95.8 98.0 99.8 100.0 101.1

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 5
(pH6.8) 34.5 38.9 42.5 52.6 59.4 76.2 85.1 92.3 94.3 96.1 Example 5
(pH1.2) 26.2 34.1 45.6 61.4 79.8 91.6 95.4 97.2 98.5 98.6

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Example 6
(pH6.8) 37.1 41.0 46.6 54.1 65.0 83.2 92.5 95.9 97.2 98.3 Example 6
(pH1.2) 32.2 41.6 52.2 63.6 81.1 92.3 97.3 97.3 97.4 97.6

(unit:%) 0.25h 0.5h 1h 1.5h 2h 3h Comparative Example 1
(pH6.8) 58.5 73.4 83.5 87.3 90.2 92.7 Comparative Example 1
(pH1.2) 80 93.5 101 101.6 101.5 101.9

(unit:%) 0.25h 0.5h 1h 2h 4h 8h 12h 16h 18h 21h Comparative Example 2
(pH6.8) 5.0 8.0 10.0 16.5 26.1 44.2 58.0 70.0 76.0 83.0 Comparative Example 2
(pH1.2) 6.3 9.9 15.0 27.6 47.5 73.0 83.0 88.0 92.0 97.0

Claims (15)

(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
&Lt; / RTI &gt;
The pharmaceutical composition of claim 1 comprising acebrophylline in an amount of 20 to 250 mg in total.
The pharmaceutical composition of claim 1, wherein the immediate and sustained parts of acebrophylline are included in a weight ratio of 1: 0.5 to 1:10.
The method of claim 1, wherein the sustained-release base is polymethacrylate, eudragit, polyalkylene oxide, alginate, sodium alginate, polyvinyl alcohols, polyvinylacetate, polyvinylacetate phthalate, glycerol monostearate, Polyvinylpyrrolidone, polyethylenglycol, 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, cellulose ether, cellulose ester, xanthan, chitosan, guar gum, gum arabic, locust bean gum, acacia gum, gellan gum, xanthan gum or waxes as carnauba wax, beeswax, Microcrystalline Wax, Hydroxyethyl Cellulose, Alginate Propylene Glycol Ester , Esters, hydrogenated oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides, and at least one member selected from the group consisting of a pharmaceutical composition or a mixture thereof.
The pharmaceutical composition of claim 1, wherein the sustained portion further comprises an enteric polymer that melts at a pH of 4.5 or higher.
The enteric polymer according to claim 5, wherein the enteric polymer is an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethyl 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 phthalate, methyl hydroxyethyl cellulose, Styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, methacrylic 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 , Vinyl methyl ether maleic anhydride copolymer, ethylene maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylonitrile 1 type selected from the group consisting of methyl maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, butyl styrene-maleic anhydride copolymer and mixtures thereof Pharmaceutical composition of the above.
The pharmaceutical composition of claim 1, further comprising a coating comprising (c) a coating base.
8. The pharmaceutical composition of claim 7, wherein the coating base comprises a water soluble polymer.
The method of claim 8, wherein the water-soluble polymer is selected from the group consisting of hydroxypropyl methyl cellulose, polyvinyl alcohol, polypropylene glycol, acrylic acid polymer, polymethacrylate copolymer, polyethylene glycol, polyvinylacetate and mixtures thereof A pharmaceutical composition that is at least one species.
8. The pharmaceutical composition of claim 7, wherein the coating base comprises an enteric polymer soluble at pH 4.5 or above.
The enteric polymer according to claim 10, wherein the enteric polymer is an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl Ethyl 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 cellulose phthalate, methyl hydroxyethyl cellulose , Styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, meta Methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methacrylic acid-octyl acrylate copolymer, vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester Copolymer, vinyl methyl ether maleic anhydride copolymer, ethylene maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylonitrile- methyl maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, acrylic Ronitrile-methyl maleic anhydride copolymer, vinylbutylether-maleic anhydride copolymer, acrylonitrile-methyl maleic anhydride copolymer, butyl-styrene-maleic anhydride copolymer and mixtures thereof At least one pharmaceutical composition.
According to claim 1, wherein the pharmaceutical composition is acebrophylline after 2 hours when the dissolution test at 37 ± 0.5 ℃, 50rpm to 75rpm in 900ml eluent of pH 6.8 using the paddle method according to the Korean Pharmacopoeia A dissolution rate of 20% to 60%, and a dissolution rate of acebrophylline after 12 hours of 70% to 95%.
The pharmaceutical composition of claim 1, which is provided in the form of a solid oral formulation.
The pharmaceutical composition according to claim 13, wherein the solid oral preparation is a multilayer tablet, a nucleated tablet, a single tablet or a coated tablet.
The pharmaceutical composition according to claim 1, which is used for the prevention or treatment of at least one disease selected from the group consisting of acute respiratory disease, chronic respiratory disease, acute bronchitis, chronic bronchitis, bronchial asthma, sinusitis and dry rhinitis.

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