KR100641638B1 - The new oral capsule for a quick/slow complex released drug which contains the Psudoephdrine and the Setirizine. - Google Patents

Abstract

The present invention is to maintain the drug action time constant for a combination preparation of two or more drugs with different application time, pseudoephedrine immediate pellets and sustained-release pellets, cetirizine immediate pellets are respectively filled and filled into capsules The present invention relates to a novel oral slow-release / sustained-release capsule formulation for allergic rhinitis for allergic rhinitis that prevents cross-incorporation between drugs and more precisely controls the release to sustain the drug for a long time.

Pseudoephedrine, cetirizine, genus / sustained combination

Description

The new oral capsule for a quick / slow complex released drug which contains the Psudoephdrine and the Setirizine.}             

Figure 1. Elution results of the pseudoephedrine / cetirizine mixed capsule composition (Table 5.)

The present invention provides a capsule containing two drugs having different half-lives in the body, particularly salts containing pseudoephedrine or pseudoephedrine (hereinafter referred to as pseudoephedrine) and salts containing cetirizine or cetirizine (hereinafter referred to as cetirizine). A novel oral intravenous / sustained release capsule containing pseudoephedrine and cetirizine for more precise release control without mutual incorporation among other drugs.

Cetirizine hydrochloride and pseudoephedrine, which are antihistamines to be used in the present invention, are widely used in the treatment of allergic rhinitis, asthma, runny nose, and the like.

Cetirizine is an antihistamine that is useful for antiallergic, bronchial dilatation and antispasmodics. It reaches maximum blood levels within 1 hour, half-life of 5 mg twice a day for 11 hours, and pseudoephedrine is caused by allergic rhinitis. It is prescribed with antihistamines to improve non-congestion and has a half-life of 5-7 hours. This means that the half-life of the blood is short, and the side effects are caused by an increase in blood concentration due to repeated doses, as well as the hassle of taking three to four times a day. This is because sustained release of pseudoephedrine can reduce the side effects caused by sudden rise in blood concentration by keeping blood levels constant for a long time as well as ease of taking, and it is convenient for real life by stopping or treating runny nose for a long time. It means you can.

Therefore, it can be said that the drug effect and wavelength appearing in patients with immediate release cetirizine and sustained-release pseudoephedrine using the half-life difference as the Korean medicine are very effective.

US Pat. Nos. 6,537,573 and 6,267,986 have already introduced patents for constituents using a combination of long-acting antihistamines as a second active ingredient and release modulators of pseudoephedrine and its pharmaceutically acceptable salts.

In addition, Korean Patent Laid-Open Publication No. 10-2004-005257 introduces a method for preparing a sustained-release pseudoephedrine and rapid-release drug layer in one pellet, and in Republic of Korea Patent Publication 10-2004-0007756, immediate release and sustained-release pellet and seti of pseudoephedrine It is known to fill fasteners of lysine in one capsule. In case of the method of Korean Patent Laid-Open Publication No. 10-2004-005257, it is advantageous that the manufacturing process is easy because it covers both the immediate release and the sustained release in one pellet, but the coating control layer is coated on the sustained release drug and the rapid release drug layer is coated. In this case, the slow release film is unstable, which makes it difficult to precisely control the rapid release of the release. In addition, in the method of filling the capsules of the inner, slow-release pellets and immediate-release tablets in the Republic of Korea Patent Publication No. 10-2004-0007756 in one capsule separately to prepare the pellets and tablets, in order to fill the two formulations in one empty capsule a special filler It is necessary and has a disadvantage of long manufacturing process.

The present invention provides a novel oral genus containing pseudoephedrine / cetirizine, which produces pseudoephedrine / sustained pellets and cetirizine immediate-release pellets without mutual incorporation between the two drugs in the pellets, thereby allowing more precise drug release control by mixing after process. It is aimed to produce a sustained release composite capsule. This is effective for the overall combination of two drugs with different drug durations, and is a mixed capsule formulation of pseudoephedrine hydrochloride and cetirizine hydrochloride pellets with controlled timing of drug release. have.

In addition, in the present invention, the pseudoephedrine sustained-release pellets have a more sophisticated release effect by covering the inert core with a sustained release drug layer and a sustained release control membrane. The purpose of the coating is to reduce the manufacturing process hassle.

Technical means to achieve the above object

The half-life in the body is achieved by the preparation of two different drugs: pseudoephedrine or a salt / sustained complex comprising pseudoephedrine and a slow-release sustained-release capsule formulation containing cetirizine.

 In particular, it is prepared by the preparation of the sustained-release pellets, immediate pellets, and cetirizine immediate pellets of pseudoephedrine, and each of the pellets are prepared separately to prevent the mutual incorporation of drugs and to control the release more precisely by controlling the release more than two drugs The effect of the combined preparation of the drug to maintain a long time constant, and the drug lasts for a long time to increase the synergy between the drugs.

 In the case of pseudoephedrine sustained-release pellets, povidone and talc were used as excipients with 0.1 to 15% by weight of the main raw material, pseudoephedrine and drug release regulator PEG 6000, as the first sustained-release matrix system. Talc, glycerol distearate, castor oil, and vegetable oil were used as excipients (suitable) with 0.1 to 20% by weight of the secondary drug release modifier ethyl cellulose and 0.2 to 20% by weight of castor wax.

     The pseudoephedrine sustained-release pellets include polyethylene glycol 6000, ethylene cellulose, castor wax, etc. as drug release regulators. In particular, the hydrophilic polymer polyethylene glycol is not only easy to use in any molding machine when used with drugs and excipients, but also drugs. The release rate of is not generally affected by processing variables such as the particle size of the drug or the compressive force during tablet processing, and it is not only pH dependent but also non-toxic and inexpensive. It was used as a pellet matrix for controlling the release rate of the drug.

In the case of pseudoephedrine and cetirizine immediate-release pellets, povidone, talc, glycerol distearate, castor oil, and vegetable oil excipients (property) are all used together at the same time with each drug, pseudoephedrine and cetirizine.

In addition, each pellet may be used a pharmaceutically acceptable pigment, which may facilitate the identification of each pellet. As the salt containing pseudoephedrine, pseudoephedrine sulfate, pseudoephedrine hydrochloride and the like are used.

Hereinafter, described in more detail through examples as follows.

Example 1 Preparation of Pseudoephedrine Sustained-release Pellets

As described in Example 1 of Table 1 below, powder (powder) mixed with 1: 1 of minute sugar, lactose and starch was used as an inert core, and the main ingredients, pseudoephedrine and sustained release control matrix, were used. PEG 6000, binder povidone and talc were mixed, water / chloroform was added, stirred, sprayed and dried in a spherical granulator. The drug cores prepared in this way are mixed with a mixture of talc, glycerol distearate, castor oil and vegetable oils with ethyl cellulose and caster wax, which are secondary sustained release matrices, and other excipients. Was completed.

Example 2 Preparation of Pseudohydrophedrine Quick Release Pellets

Pseudoephedrine and the composition of Example 2 in Table 1 below were mixed in an inert core, sprayed and dried in a spherical granulator to complete Pseudoephedrine immediate pellets.

Example 3 Preparation of Cetirizine Hydrochloride Rapid Pellets

Cetirizine hydrochloride and the composition of Table 3 below were mixed with an inert core, sprayed and dried in a spherical granulator to complete the cetirizine immediate pellet.

 Raw material name  Example 1.  Example 2.  Example 3. Hydrochloric acid pseudoephedrine 80 mg 40 mg - Cetirizine hydrochloride - - 5 mg Minute sugar + lactose + starch 71.68 mg 35.84 mg 4.48 mg PEG 6000 9.47 mg - - Ethyl Cellulose 18.04 mg - - Povidone k-30 3.94 mg 1.57 mg 0.196 mg Caster wax 2.04 mg - - Talc 4.26 mg 3.15 mg 0.397 mg Glycerol Distearate 1.65 mg 0.825 mg 0.103 mg Castor Oil 9.62 mg 4.81 mg 0.601 mg Vegetable Oil 1.49 mg 0.745 mg 0.093 mg Water / Chloro form 150/100 mg 75/50 mg 9.38 / 6.25 mg  Total (300mg medium)  202.19 mg  86.94 mg  10.87 mg

[Table 1] is based on the quantification of pseudoephedrine hydrochloride and cetirizine hydrochloride, which is 120 mg of pseudoephedrine hydrochloride and 5 mg of cetirizine hydrochloride, meaning a total weight of 300 mg capsules.

(Example 4.) Sustained hydrochloride sustained-release pellet dissolution test.

The pellet of Example 1 was subjected to HPLC elution experiment as follows with pseudoephedrine hydrochloride sustained release pellets.

 Analysis: HPLC 254 nm

 Condition: pH 1.2, pH 4.0, pH 6.8 buffer, 100 rpm

 -Standard: Korea Pharmacopoeia General Test Method 2 (Paddle)

 Measurement time: 30, 60, 120, 180, 240, 300, 360, 420, 480 (min)

Time (min) pH 1.2 pH 4.0 pH 6.8 30 14.52% 12.07% 11.76% 60 22.63% 21.38% 20.55% 120 34.26% 33.74% 29.59% 180 49.99% 45.53% 41.67% 240 67.84% 66.05% 62.37% 300 73.22% 70.54% 69.51% 360 85.61% 83.27% 78.42% 420 92.09% 89.34% 86.92% 480 96.46% 94.59% 92.37%

In the above experimental results, it can be seen that the full dissolution rate of pseudoephedrine starts from about 4 hours. The drug effect time of the rapid release of pseudoephedrine hydrochloride is about to be reached at the end. For controlled release. The half-life of pseudoephedrine is 5 hours. In the present invention, the drug release of the sustained-release drug is started just before the drug effect of the fast-acting drug is started, so that the higher drug effect can be achieved. This is because when all are eluted, the half-life of the drug naturally goes up to 12 hours or more.

(Example 5.) Pseudohydrophedrine hydrochloride immediate release pellet dissolution test.

The pellet of Example 2 was subjected to HPLC elution experiment as follows, with pseudoephedrine hydrochloride immediate release pellets.

 Analysis: HPLC 254 nm

 Condition: pH 1.2, pH 4.0, pH 6.8 buffer, 100 rpm

 -Standard: Korea Pharmacopoeia General Test Method 2 (Paddle)

 Measurement time: 15, 30, 60, 90, 120, 240 (min)

Time (min) pH 1.2 pH 4.0 pH 6.8 15 67.35% 66.29% 65.80% 30 77.29% 75.57% 70.66% 60 85.67% 82.43% 79.48% 90 89.26% 87.26% 84.59% 120 92.38% 91.44% 90.53% 240 99.96% 98.73% 98.06%

The results of Table 2 and Table 3 are the average of the results of three or more dissolution experiments. The results of Table 3 above show that the dissolution rate rises constantly. In addition, the dissolution results can be calculated by using pseudoephedrine 120 mg of pseudoephedrine sustained-release pellets and immediate-release pellets with two results, which are shown in Table 5.

(Example 6.) Cetirizine hydrochloride immediate release pellet dissolution test.

The pellets of Example 3 were subjected to HPLC elution experiments with the following criteria as cetirizine hydrochloride immediate release pellets.

 Analysis: HPLC 230 nm

 Condition: pH 1.2, pH 4.0, pH 6.8 buffer, 100 rpm

 -Standard: Korea Pharmacopoeia General Test Method 2 (Paddle)

 Measurement time: 15, 30, 45, 60 (min)

Time (min) pH 1.2 pH 4.0 pH 6.8 15 97.69% 95.32% 94.85% 30 98.53% 97.60% 96.04% 45 99.18% 98.72% 97.96% 60 99.63% 99.01% 98.73%

Since cetirizine hydrochloride has a half-life of 11 hours, sufficient results can be expected from the above experiments.

Example 7 Elution Experiment of a Formulation Filled with Capsules of Three Pellets of the Invention

Elution experiments of pseudoephedrine / cetirizine capsule formulations containing the three pellets were performed. This was analyzed as 120 mg with pseudoephedrine hydrochloride and 5 mg with cetirizine hydrochloride, respectively.

 Analysis: HPLC 254, 230 nm

 Condition: pH 1.2 buffer, 100 rpm

 -Standard: Korea Pharmacopoeia General Test Method 2 (Paddle)

 Measurement time: 30, 60, 120, 180, 240, 300, 360, 420, 480 (min)

Time (min) As pseudoephedrine hydrochloride (120mg) As cetirizine hydrochloride (5 mg) 30 36.22% 98.26% 60 43.65% 99.17% 120 56.72% 101.33% 180 62.93% - 240 78.54% - 300 83.79% - 360 90.77% - 420 94.59% - 480 98.21% -

Hereinafter, the present invention is a combination of two drugs having different drug durations, and includes a capsule containing a sustained release control pellet composition in which a short half-life drug is adapted to the effect of a long half-life drug. Pellets. However, the drug substance is not limited to this and can be applied to all formulations that release short half-life drugs to the effect of long half-life drugs.

The present invention solved the problem of the conventional formulation by manufacturing the inner and sustained pellets of pseudoephedrine and cetirizine, respectively, eliminating mutual incorporation between drugs and precisely adjusting the degree of drug release to maximize the effect of drugs by releasing the maximum effect. I could see it. For higher bioavailability of pseudoephedrine / cetirizine, it is effective to control the degree of release of each pellet and to provide a combined slow-release capsule for allergic rhinitis with three pellets as one agent.

Claims (5)

Pseudoephedrine sustained-release pellets consisting of pseudoephedrine or salts containing pseudoephedrine, and rapid-release pellets include three types of pellets each containing a drug having the same composition and a long-life drug as the sustained-release pellets having a short half-life of the drug. In filling the capsules of the drug to prevent incorporation between the drugs and to keep the drug action time constant for a long time, The pseudoephedrine sustained-release pellets are based on pseudoephedrine as the primary sustained-release matrix system, using 0.1 to 15% by weight of PEG 6000 relative to the total weight, and the second drug release to the secondary sustained-release matrix system. Novel oral slow-release for new oral, characterized in that the use of 0.1 to 20% by weight of acetyl cellulose, 0.2 to 20% by weight of castor wax, to prevent the incorporation of drugs and to keep the drug action time constant for a long time. Complex capsules. delete delete delete delete

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