CN1706385B - New composition for treating seasonal and perennial allergic rhinitis - Google Patents

Abstract

The present invention relates to one new kind of medicine composition containing levocetirizine (or its pharmaceutically acceptable salt) and pseudoepherine (or its pharmaceutically acceptable salt). The medicine composition is pressed into double layer including the first layer containing levocetirizine (or its pharmaceutically acceptable salt) in the amount for resisting allergy effectively and the second layer containing pseudoepherine (or its pharmaceutically acceptable salt) in the amount as effective decongestant for nose. The medicine composition is used in treating seasonal and perennial allergic rhinitis.

Description

Novel compositions for the treatment of seasonal and perennial allergic rhinitis

technical field

The invention relates to a double-layer sustained-release oral composition. One layer contains the non-sedating antihistamine levocetirizine (or a pharmaceutically acceptable salt thereof) and the other layer contains the nasal decongestant pseudoephedrine (or a pharmaceutically acceptable salt thereof). The one containing levocetirizine (or its pharmaceutically acceptable salt) is the immediate release layer, and the one containing pseudoephedrine (or its pharmaceutically acceptable salt) is the slow release layer.

Background technique

Levocetirizine (or its pharmaceutically acceptable salt) is first listed in Germany, and then listed in the United Kingdom, Belgium, France and other countries. Clinically used for the treatment of various allergic diseases caused by histamine, such as seasonal and perennial allergic rhinitis, EP058146, WO9406429, US5698558, etc. have described the antiallergic effects of levocetirizine. Levocetirizine has a longer half-life in vivo, and the effective antihistamine dose is 2.5-10 mg per day.

Pseudoephedrine (or its pharmaceutically acceptable salt) is a nasal decongestant that can shrink nasal blood vessels and reduce symptoms such as runny nose and nasal congestion. It has been used in combination with antihistamines for the treatment of allergic rhinitis for a long time. The half-life of pseudoephedrine in the body is significantly shorter than that of levocetirizine, and the daily dose is 60 mg to 360 mg.

According to statistics, about 59% of people suffer from seasonal and perennial allergic rhinitis, and 30% of them are accompanied by nasal congestion. The common symptoms are runny nose, itching, sneezing and nasal congestion. Commonly used treatment methods are nasal drops or oral administration of pseudoephedrine (or its pharmaceutically acceptable salt), or oral antiallergic drug treatment. These treatments are inconvenient for patients to take. Currently on the market, there are compound preparations composed of anti-allergic drugs such as cetirizine hydrochloride and loratadine and anti-nasal decongestant drug pseudoephedrine hydrochloride for the treatment of seasonal and perennial allergic rhinitis. At the same time as amines, it can also reduce nasal congestion and give patients the best treatment. In the present invention, levocetirizine hydrochloride (or other pharmaceutically acceptable salts) is used instead of cetirizine hydrochloride or loratadine, and pseudoephedrine (or its pharmaceutically acceptable salts) is used to form a composite preparation. Levocetirizine is the active optical body of cetirizine, its activity is twice that of cetirizine, and its anti-allergic activity is stronger than that of cetirizine and loratadine. Use levocetirizine instead of cetirizine Lizine, not only can reduce its dosage, but also improve its safety and effectiveness.

The present invention relates to sustained-release double-layer tablets of levocetirizine hydrochloride/pseudoephedrine hydrochloride, levocetirizine hydrochloride has a longer half-life, and can be kept effective for 24 hours by taking the medicine once or twice a day. Immediate-release layer: Pseudoephedrine hydrochloride has a short half-life in the human body, and needs to be taken four times a day, and the patient's compliance is low, so it is made into a sustained-release layer. Making sustained-release double-layer tablets can not only avoid the "peak-valley" phenomenon caused by frequent administration, maintain the steady-state blood drug concentration in the body, improve safety and effectiveness, but also separate the two main drugs into granules and tablets, and also The physical and chemical reactions between drugs can be avoided, and the stability of drugs can be improved. Therefore, the levocetirizine (or its pharmaceutically acceptable salt) and pseudoephedrine (or its pharmaceutically acceptable salt) sustained-release double-layer tablet that is administered once a day or twice a day is made, It has good clinical treatment value and good social benefits.

Contents of the invention

What the present invention will develop is a kind of levocetirizine or its pharmaceutically acceptable salt and pharmaceutical excipients and pseudoephedrine or its pharmaceutically acceptable salt and its preparation once a day or twice a day. Sustained-release double-layer tablets of polymer materials and auxiliary materials required for sustained-release preparations. Levocetirizine is a second-generation antihistamine, and pseudoephedrine is an antinasal decongestant. Levocetirizine/pseudoephedrine sustained-release double-layer tablet refers to the rapid-release layer containing 5 mg levocetirizine and the sustained-release layer containing 240 mg pseudoephedrine, while maintaining the rapid onset of action and long half-life of levocetirizine At the same time, to improve the pharmacokinetic properties of pseudoephedrine that must be administered multiple times a day, once or twice a day, the two have a better synergistic effect.

Levocetirizine has a longer half-life in vivo, and the effective antihistamine dose is 2.5-10 mg per day. The optimal daily dose is 5 mg, which can be administered once in 24 hours, or divided into two equal doses, once every 12 hours, with a dose of 2.5 mg each time.

Pseudoephedrine has a short half-life in the body, the daily dose for adults is 120 mg to 360 mg, and the daily dose for children is 60 to 180 mg. When immediate-release formulations are used, adult patients are usually given a dose of 60-80 mg once, three times every 24 hours. It can also be made into a sustained-release solid preparation, for example, a 120 mg preparation can be effective for 12 hours and administered twice a day; a 240 mg drug can be effective for 24 hours to match the half-life of levocetirizine long features.

The active ingredients of the pharmaceutical composition of the present invention are levocetirizine or a pharmaceutically acceptable salt thereof and pseudoephedrine or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt refers to hydrochloride, sulfate, phosphate, maleate, citrate, tartrate, palmitate, acetate, nitrate.

Pharmaceutical excipients may include: fillers, binders, disintegrants and lubricants. Wherein the filler may be: starch, microcrystalline cellulose, lactose, dextrin, compressible starch, mannitol, etc. Wherein the binder can be povidone, hypromellose, methylcellulose, sodium carmellose, starch slurry, gelatin slurry, etc. Its disintegrant can be sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, cross-linked carmellose sodium and cross-linked povidone. Lubricants can be: micronized silica gel, magnesium stearate, talc and macrogol 4000 or 6000.

The polymer materials and auxiliary materials required to make sustained-release preparations can be cellulose derivatives, acrylic resins, vinyl polymers, waxy materials, natural polymer gums such as zein, sodium alginate, gum arabic, yellow Raw gum, etc.

The preparation method of the pharmaceutical composition of the present invention: take an appropriate amount of levocetirizine, starch, lactose, sodium carboxymethyl starch and color lake in the prescribed amount, mix them evenly, place them in a high-speed stirring granulator, and add an appropriate amount of adhesive , cutting, granulating, sieving, drying at 50-60°C, adding an appropriate amount of magnesium stearate, and setting aside; take the prescribed amount of pseudoephedrine, mix it with hypromellose and microcrystalline cellulose in an appropriate amount, and place it in a high-speed In the stirring granulator, add water, cut, granulate, sieve, dry at 50-60°C, add an appropriate amount of micropowder silica gel and magnesium stearate, and place the levocetirizine granules prepared above in a double-layer press Tablets are compressed in a tablet machine, and the product is obtained.

Example 1

Levocetirizine rapid release layer

Ingredient mg/composition

Levocetirizine 2.5

Starch 30.0

Lactose 70.0

Sodium carboxymethyl starch 5.0

5% hypromellose solution Appropriate amount

Color Lake 0.1

Magnesium stearate 1.0

Pseudoephedrine Sustained Release Layer

Ingredients mg/component

Pseudoephedrine 120

Hypromellose K100M 120

Microcrystalline Cellulose 60

Alcohol Appropriate amount

Appropriate amount of pure water

Micropowder silica gel 0.6

Magnesium Stearate 3

Preparation process: take an appropriate amount of levocetirizine, starch, lactose, carboxymethyl starch sodium and color lake in the prescribed amount, mix well, place in a high-speed stirring granulator, add an appropriate amount of binder, cut, granulate, pass Sieve, dry at 50-60°C, add an appropriate amount of magnesium stearate, and set aside; take the prescribed amount of pseudoephedrine, mix it with hypromellose and microcrystalline cellulose in an appropriate amount, place it in a high-speed stirring granulator, add water , cutting, granulating, sieving, drying at 50-60°C, adding an appropriate amount of micropowder silica gel and magnesium stearate, and placing the above-mentioned prepared levocetirizine granules in a double-layer tablet press for tableting, namely have to.

Example 2

Levocetirizine Hydrochloride Rapid Release Layer

Ingredient mg/composition

Levocetirizine hydrochloride 2.5

Starch 30.0

Lactose 70.0

Sodium carboxymethyl starch 5.0

5% hypromellose solution Appropriate amount

Color Lake 0.1

Magnesium stearate 1.0

Pseudoephedrine Hydrochloride Sustained Release Layer

Ingredients mg/component

Pseudoephedrine hydrochloride 120

Hypromellose K100M 120

Microcrystalline Cellulose 60

Alcohol Appropriate amount

Appropriate amount of pure water

Micropowder silica gel 0.6

Magnesium stearate 3

Preparation process: Take the prescribed amount of levocetirizine hydrochloride, starch, lactose, sodium carboxymethyl starch and appropriate amount of color lake, mix well, place in a high-speed stirring granulator, add appropriate amount of binder, cut, granulate, Sieve, dry at 50-60°C, add an appropriate amount of magnesium stearate, and set aside; take the prescribed amount of pseudoephedrine hydrochloride, mix it with hypromellose and microcrystalline cellulose, and place it in a high-speed stirring granulator , add water, cut, granulate, sieve, dry at 50-60°C, add appropriate amount of micropowder silica gel and magnesium stearate, and place the levocetirizine hydrochloride granules prepared above in a double-layer tablet press Slices, ready to serve.

Example 3

Levocetirizine Hydrochloride Rapid Release Layer

Ingredient mg/composition

Levocetirizine hydrochloride 5.0

Starch 30.0

Lactose 70.0

Sodium carboxymethyl starch 5.0

5% hypromellose solution 20

Color Lake 0.1

Magnesium stearate 1.0

Pseudoephedrine Hydrochloride Sustained Release Layer

Ingredients mg/component

Pseudoephedrine hydrochloride 240

Hypromellose K100M 200

Microcrystalline Cellulose 60

Ethanol 100

Pure water 50

Micropowder silica gel 1.0

Magnesium Stearate 5.0

Preparation process: Take an appropriate amount of levocetirizine hydrochloride, starch, lactose, sodium carboxymethyl starch and color lake in the prescribed amount, mix evenly, place in a high-speed stirring granulator, add an appropriate amount of adhesive, cut, granulate, Sieve, dry at 50-60°C, add an appropriate amount of magnesium stearate, and set aside; take the prescribed amount of pseudoephedrine hydrochloride, mix it with hypromellose and microcrystalline cellulose, and place it in a high-speed stirring granulator , add water, cut, granulate, sieve, dry at 50-60°C, add appropriate amount of micropowder silica gel and magnesium stearate, and place the levocetirizine hydrochloride granules prepared above in a double-layer tablet press Slices, ready to serve.

The in vitro dissolution properties of the tablets of Examples 1-2 were determined in 0.1N HCl solution at 37°C (first hour) and then in phosphate buffer at pH 6.8. At least 80% of the levocetirizine in the quick-release layer is dissolved within the first 30 minutes, while the pseudoephedrine in the slow-release layer should be released slowly. It was 20-50% in the first hour, 35-75% in the 4th hour, and 75% or more in the 8th hour.

Claims (2)

1. a levocetirizine pseudoephedrine is suppressed double-layer tablet, it is characterized in that:

Levo-cetirizine hydrochloride rapid release layer:

2.5 milligrams of levo-cetirizine hydrochlorides,

30.0 milligrams of starch,

70.0 milligrams of lactose,

5.0 milligrams of carboxymethyl starch sodium,

5% hypromellose solution is an amount of,

0.1 milligram in color lake,

1.0 milligrams of magnesium stearate,

The pseudoephedrine hydrochloride slow release layer:

120 milligrams of pseudoephedrine hydrochlorides,

120 milligrams of hypromellose K100M,

60 milligrams of microcrystalline Cellulose,

Ethanol is an amount of,

Pure water is an amount of,

0.6 milligram of micropowder silica gel,

3 milligrams of magnesium stearate,

Preparation technology: get recipe quantity levo-cetirizine hydrochloride, starch, lactose, carboxymethyl starch is received and the color lake, mixing places High Speed Stirring Machine, adds suitable amount of adhesive, and cutting is granulated, and sieves, and in 50～60 ℃ of oven dry, adds magnesium stearate, and is standby; Get the pseudoephedrine hydrochloride of recipe quantity; with hypromellose and microcrystalline Cellulose mix homogeneously; place High Speed Stirring Machine, add water, cutting; granulate; sieve,, add micropowder silica gel and magnesium stearate in 50～60 ℃ of oven dry; place the bi-layer tablet press tabletting with the above-mentioned levocetirizine dihydrochloride granule that has prepared, promptly.

2. a levocetirizine pseudoephedrine is suppressed double-layer tablet, it is characterized in that:

Levo-cetirizine hydrochloride rapid release layer:

5.0 milligrams of levo-cetirizine hydrochlorides,

30.0 milligrams of starch,

70.0 milligrams of lactose,

5.0 milligrams of carboxymethyl starch sodium,

20 milligrams of 5% hypromellose solution,

0.1 milligram in color lake,

1.0 milligrams of magnesium stearate,

The pseudoephedrine hydrochloride slow release layer:

240 milligrams of pseudoephedrine hydrochlorides,

200 milligrams of hypromellose K100M,

60 milligrams of microcrystalline Cellulose,

100 milligrams of ethanol,

50 milligrams of pure water,

1.0 milligrams of micropowder silica gels,

5.0 milligrams of magnesium stearate,

Preparation technology: get recipe quantity levo-cetirizine hydrochloride, starch, lactose, carboxymethyl starch is received and the color lake, mixing places High Speed Stirring Machine, adds binding agent, and cutting is granulated, and sieves, and in 50～60 ℃ of oven dry, adds magnesium stearate, and is standby; Get the pseudoephedrine hydrochloride of recipe quantity; with hypromellose and microcrystalline Cellulose mix homogeneously; place High Speed Stirring Machine, add water, cutting; granulate; sieve,, add micropowder silica gel and magnesium stearate in 50～60 ℃ of oven dry; place the bi-layer tablet press tabletting with the above-mentioned levocetirizine dihydrochloride granule that has prepared, promptly.