KR20040037045A - Pharmaceutical composition of oral antiallergic complex drug and its process - Google Patents

Abstract

PURPOSE: Provided is a method for manufacturing a sustained release tab or a controlled release pellet which is capable of oral administration and contains Pseudoephedrine HC1, as a sustained release drug layer and Fexofenadine HCl as a rapid release. Therefore, it releases Fexofenadine HCl rapidly then Pseudoephedrine HC1 for 12 hours. CONSTITUTION: An pharmaceutical composition for oral administration is characterized by containing an inactive core, a sustained release drug layer including Pseudoephedrine HC1, a rapid release layer including Fexofenadine HCl, and a sustained release coating control membrane.

Description

Composition of oral anti-allergic combination and its preparation method {Pharmaceutical composition of oral antiallergic complex drug and its process}

The present invention relates to a method for preparing orally administered sustained-release tablets and controlled release pellets, and more particularly, to the preparation of a sustained-release sustained-release preparation containing sympathetic nerve stimulant Pseudoephedrine hydrochloride (Pseudoephedrine HC1) and an antihistamine agent (Fexofenadine HCl) It is about a method.

Pseudoephedrine (C10H15NO, MW = 165.2) is an optical isomer of ephedrine, which acts similar to ephedrine but has a relatively small sedation. As a salt, pseudoephedrine hydrochloride (C10H15N0.HCl, MW = 201.7) and pseudoephedrine sulfate ((C10H15NO) 2.H2SO4, MW = 428.5) are used as medicines. Pseudoephedrine and its salts are SYMPATHOMIMETIC AGENT, which is usually prescribed with antihistamines for the improvement of nasal congestion due to allergic rhinitis. The half-life is about 5-7 hours and the rate of disappearance in acidic urine is shortened. It is also excreted in urine together with metabolites that have undergone some hepatic metabolism, mostly without metabolism, without undergoing MAO metabolism. Non-depressants such as pseudoephedrine are generally administered orally 3-4 times a day, but it is ideal to administer controlled release twice a day or once a day, and there is an advantage in patient compliance.

Fexofenadine (C32H39NO4.HCl, MW = 538.13) is a hydrochloride salt of fexofenadine and is used by the US Food and Drug Administration (FDA) as the active ingredient of an antihistamine known as Allegra®. The half-life is 14.4 hours and is rapidly absorbed after oral administration. Only trace amounts are metabolized, 80% excreted in the stool and 11% excreted in the urinary tract.

A conventional pharmaceutical excipient is distributed between the ibuprofen layer, the piperidinoalkanol antihistamine layer, and the ibuprofen and piperidinoalkanol layers in a conventional manufacturing method to physically separate them. Multilayer tablets comprising a layer containing are described. It has been reported by Shock et al. That the attempt to prepare a bilayer tablet failed due to the chemical degradation of piperidinoalkanol in the presence of ibuprofen.

US Pat. No. 4,996,601 discloses a region separated from an agent providing a sustained-release sympathetic stimulant of a decongested amount effective for treatment and an immediate release of an antihistamine amount of piperidinoalkane effective for treatment. Multiple compressed tablet methods comprising sympathetic neurodilators, pseudoephedrine hydrochloride with piperidinoalkanol, comprising a separate 1 region prepared with different agents to provide ol and optionally an effective decongestant amount of sympathetic neurostimulant Sustained release forms are described.

Multi-compression purification method containing immediate release form of fexofenadine hydrochloride disclosed in U.S. Patent No. 4,996,061, single-use tablet in which US Pat. No. 6613357, pseudoephedrine hydrochloride osmotic form and immediate release form fexofenadine combined in a single layer tablet There is a method for preparing a tablet, and a method for preparing in a two-layer tablet form to provide an immediate release piperidinol alkanol compound and a sustained release sympathetic stimulant in US Patent No. 6,613,357.

However, the method of preparing such sustained-release preparations suffers from unacceptable unacceptable cracking and unacceptable physical hardness and content uniformity of the final compression, and the manufacturing process is complicated and difficult, and the manufacturing cost is high. There is a limit to industrial use. In addition, there were no reported cases of preparation of pseudoephedrine hydrochloride and fexofenadine hydrochloride into pellets.

Therefore, the present invention is a simple manufacturing process to release the pseudo-ephedrine hydrochloride in an ideal linear form to expect a sustained release, and fexofenadine hydrochloride in the outer layer of the immediate release layer is trying to reduce the disintegration time as well as to increase the dissolution rate The present invention has been completed and is filed as a patent.

The sustained sustained-release tablet or pellet of the present invention includes suedephedrine hydrochloride in the core tablet or inert core, which is a main component that is expected to be sustained release, and fexofenadine, which is a component that is expected to be fast-acting, is removed or separately in an immediate release layer together with a carrier that provides immediate release. Rapid release pellets were prepared and included in slow release pellets and a formulation.

That is, in the present formulation, a method of preparing sudoephedrine hydrochloride as a sustained-release drug layer and fexofenadine hydrochloride as an immediate-release drug layer in the upper portion or separately, is more easy to prepare than the case where the sustained-release tablet and the rapid-release tablet are separately prepared and pressed, It has the advantage of reducing manufacturing costs and provides efficient sustained release and bioavailability.

The present invention relates to a method for producing sustained sustained-release tablets and orally administrable release pellets, and more particularly, to a controlled release type comprising principal edophilic stimulant pseudoephedrine hydrochloride and antihistamine fexofenadine hydrochloride. A sustained release coating control film is coated with the main component pseudoephedrine hydrochloride, which is expected to be sustained release, and the main component fexofenadine, which is expected to be expedited, is prepared together with a carrier which provides immediate release, or suspended hydrophilic suede is coated with an inert core. The present invention relates to a method for preparing a coating control film and then or to preparing fexofenadine hydrochloride together with a carrier for providing immediate release and a pharmaceutical composition thereof.

The preparation is characterized by rapid release of fexofenadine hydrochloride followed by continuous release of pseudoephedrine hydrochloride for at least 12 hours.

In this formulation, water-insoluble polymer was avoided on the outer surface of the drug layer for the sustained release of pseudoephedrine hydrochloride, and it was prepared by including a hydrophilic carrier in the drug layer of fexofenadine hydrochloride, which is expected to release quickly, to shorten the disintegration time and very small particles during disintegration. Dissolution rate could be increased by dispersing to.

Hereinafter, examples and experimental examples of the present invention will be described in more detail, but the present invention is not limited thereto.

Example 1 Preparation of Nuclear Tablet

1) 1200 g Pseudoephedrine HC1 (Pseudoephedrine HC1), lactose 1970g, 10 g Aerosil 200, 20 g magnesium stearate was added to the mixer and mixed for about 10 minutes.

2) The mixture of 1) was compression molded to 320 mg per tablet with a circular punch having a diameter of 10 mm to prepare a core tablet.

Example 2 Slow Release Film Coating

1) 100 mL of ethanol was stirred and 14 g of ethyl cellulose was added and dispersed.

2) 150 mL of methylene chloride was added to the dispersion of 1), followed by stirring to dissolve. Then, 1.4 g of dimethyl phthalate and 0.6 g of talc were added thereto, followed by stirring for about 30 minutes.

3) With 1000 tablets of the core tablet of Example 1, the coating machine was coated under the following conditions.

Fan speed: 12 rpm.

Inlet temperature: 45-50 degrees

Outle temperature: 35-40 degrees

Flow rate: 15 mL / min

Spray air pressure: 2kg / cm2

Example 3 Slow Release Film Coating

1) While stirring 200mL of ethanol, 28g of ethyl cellulose was added and dispersed.

2) 300 ml of methylene chloride was added to the dispersion of 1), followed by stirring to dissolve. Then, 2.8 g of diethphthalate and 1.2 g of talc were added thereto, followed by stirring for about 30 minutes.

3). Nuclear tablets of Example 1 were taken and subjected to the same conditions as in Example 2 below.

Example 4 Slow Release Film Coating

1) 300 mL of ethanol was stirred and 42 g of ethyl cellulose was added and dispersed.

2) 450 mL of methylene chloride was added to the dispersion of 1) to dissolve it, and then 4.2 g of dimethyl phthalate and 1.8 g of talc were added thereto, followed by stirring for about 30 minutes.

3) The core tablet of Example 1 was taken and subjected to the same conditions as in Example 2 below.

Example 5 Slow Release Film Coating

1) 28 g of polymethyl methacrylate was added to 500 mL of acetone, followed by stirring and dissolving.

2) 2.8 g of dibutyl sebacate and 1.2 g of talc were added to the solution of 1) and stirred for about 30 minutes.

2) The core tablet of Example 1 was taken and subjected to the same conditions as in Example 2 below.

Example 6 Rapid Release Drug Layer Coating

1) While stirring 250 ml of purified water, 2.4 g of polyvinylpyrrolidone and 60 g of fexofenadine hydrochloride were dissolved in this order, and 0.6 g of hard silicic anhydride was added and dispersed.

2) With the coating solution of 1), 1000 tablets of the sustained-release tablet of Example 3 were used as the core and coated under the following conditions.

Fan speed: 12 rpm.

Inlet temperature: 55-60 degrees

Outle temperature: 40-45 degrees

Flow rate: 10mL / min

Spray air pressure: 2kg / cm2

TABLE 1 Sustained release film prescription comparison table (1 tablet equivalent) of Example 2-Example 5

ingredient Example 2 Example 3 Example 4 Example 5 Ethyl Cellulose 14mg 28mg 42mg - Polymethyl methacrylate - - - 28mg Die Phthalate 1.4mg 2.8mg 4.2mg - Dibutyl sebacate - - - 2.8mg Talc 0.6mg 1.2mg 1.8mg 1.2mg ethanol 0.1ml 0.2ml 0.3ml - Methylene chloride 0.15ml 0.3ml 0.45ml - Acetone - - - 0.5ml Total share 16 mg 32mg 48mg 32mg

Excluding volatile solvents

Example 7 Preparation of Core Pellets

1) Into a mixed solution of 2000 ml of ethanol and 1500 ml of purified water, 45 g of polyvinylpyrrolidone and 1200 g of pseudoephedrine hydrochloride were dissolved, and 5 g of hard silicic anhydride was added and dispersed.

2) Put 550g of white granules in the fluidized bed coater and spray with a coating solution of 2) at the rate of 20ml / min at the inlet temperature of 70-75 degrees, the outlet temperature of 40-45 degrees, and the spray pressure of 2kg / cm2. It was.

Example 8 Preparation of Sustained Release Pellets

1) After stirring 450 mL of ethanol, 45 g of ethyl cellulose was added and dispersed.

2) 450 mL of methylene chloride was added to the dispersion of 1) to dissolve it, and then 4.5 g of diethphthalate and 4.5 g of talc were added thereto, followed by stirring for about 30 minutes.

3) In the fluidized bed coating machine, 540 g of the core pellets of Example 7 were removed to obtain sustained-release pellets under conditions of an inlet temperature of 45-50 degrees, an outlet temperature of 35-40 degrees, a flow rate of 20 mL / min, and a spray air pressure of 2 kg / cm 2.

Example 9 Preparation of Sustained Release Pellets

1) After stirring 800 mL of acetone, 48 g of polymethacrylate was added to dissolve it.

2) 4.8 g of dibutyl sebacate and 1.2 g of Aerosil 200 were added to the solution of 1) and stirred for about 30 minutes.

3) Pellets were prepared under the same conditions as in Example 8 with 540 g of the core pellets of Example 6.

[Example 10] Preparation of fexofenadine immediate release pellet

1) 20 g of polyvinylpyrrolidone and 600 g of fexofenadine hydrochloride were dissolved in a mixture of 1500 ml of ethanol and 1500 ml of purified water.

2) 2 g of hard silicic anhydride and 28 g of crospovidone were added to the solution of 1) and stirred for 30 minutes.

3) The suspension of 2) was coated under the same conditions as in Example 7 below using 550 g of sugar granules as a core.

Example 11 Fast-release drug layer coating of fexofenadine hydrochloride

1) 6 g of polyvinylpyrrolidone and 180 g of fexofenadine hydrochloride were dissolved in a mixture of 450 ml of ethanol and 450 ml of purified water.

2) 0.6 g of hard silicic anhydride and 8.4 g of crospovidone were added to the solution of 1) and stirred for 30 minutes.

3) The suspension of 2) was coated under the same conditions as in Example 7 below using 594 g of the sustained-release pellet of Example 8 as a core.

Preparation Example 1 Preparation of Capsule

1) 198 g of the sustained-release pellet of Example 8 and 120 g of the immediate-release pellet of Example 10 were mixed with 6 g of talc and 6 g of hard silicic anhydride for 10 minutes and then filled into No. 1 hard capsule to contain 330 mg per capsule.

Preparation Example 2 Preparation of Capsule

1) 263 g of the pellet of Example 11 was mixed with 4 g of talc and 3 g of hard silicic anhydride for 10 minutes, and then filled into No. 1 hard capsule containing 270 mg per capsule.

Experimental Example 1

Take one tablet of Example 6 and one capsule of Formulation Example 1, Formulation 2, and 900 mL of 0.001 mol / L hydrochloric acid at pH 3.0 as a test solution. According to the dissolution test was carried out at 50 revolutions per minute. At each sample collection time, 5 ml of the test solution was taken, filtered through a membrane filter with a pore size of 0.45 um, and analyzed under the following conditions. The results are shown in Table 4 below.

HPLC analysis conditions

Detector: UV absorbance photometer (wavelength 210nm)

Column: Whatman Partisil 10SCX (5㎛, 250 × 4.6mm)

Mobile phase: Acetonitrile: Phosphate buffer solution (pH 2.0) = 450 ml: 550 ml

Phosphate buffer solution of pH 2.0: Dissolve 1 g of water in 7 g of sodium dihydrogen phosphate monohydrate and adjust to pH 2.0 with phosphoric acid.

Flow rate: 1.0mL / min

Injection volume: 10µl

[Table 2] Dissolution Rate of Pseudohydrophedrine Hydrochloride (%)

Minutes Example 6 Formulation Example 1 Formulation Example 2 0 0 0 0 45 31.0 ± 3.21 (Note) 27.1 ± 0.12 29.1 ± 2.12 180 57.2 ± 2.47 60.7 ± 0.21 58.7 ± 1.21 300 78.5 ± 1.59 72.3 ± 1.53 75.3 ± 0..83 720 98.3 ± 1.25 94.4 ± 1.48 96.4 ± 1.08

Note ± mean deviation, n = 3

TABLE 3 Dissolution rate of fexofenadine hydrochloride (%)

Minutes Example 6 Formulation Example 1 Formulation Example 2 0 0 0 0 15 92.3 ± 2.38 (Note) 97.3 ± 1.35 96.0 ± 2.08 30 97.1 ± 1.35 98.1 ± 1.45 97.1 ± 1.52 45 98.2 ± 2.61 98.5 ± 2.01 98.5 ± 1.11 60 98.5 ± 1.69 98.5 ± 1.09 98.5 ± 1.30

Note ± mean deviation, n = 3

As described above, the present invention comprises sudoephedrine hydrochloride as a sustained-release drug layer in a single tablet or pellet and fexofenadine hydrochloride as a rapid-release drug layer to rapidly release fexofenadine hydrochloride, and then continuously releases sudoephedrine hydrochloride for 12 hours. Preparation of the formulation is possible.

Claims (6)

Oral Administration Pharmaceutical Compositions Containing Pseudophedrine Hydrochloride and Fexofenadine Hydrochloride The tablet of claim 1, wherein the pharmaceutical composition consists of a core tablet, a sustained release coating control membrane, and a rapid release drug layer. The pellet according to claim 1, wherein the pharmaceutical composition is composed of an inert core, a sustained release drug layer, a sustained release coating control film, and a rapid release drug layer. The pharmaceutical composition according to claim 2 or 3, wherein the sustained release coating control film is composed of a water insoluble polymer and a pharmaceutically acceptable additive. The pharmaceutical composition according to claim 4, wherein the water-insoluble polymer is selected from at least one of ethyl cellulose and polymethyl methacrylate. The pharmaceutical composition according to claim 2 or 3, wherein the rapid-release drug layer is fixed or separated on the sustained-release drug layer and the sustained-release coating control membrane.