KR100505899B1 - Pharmaceutical capsule compositions containing loratadine and pseudoephedrine - Google Patents

Abstract

The present invention comprises immediate release pellets (Pellet A) containing loratadine and pseudoephedrine or pharmaceutically acceptable salts thereof, and pseudoephedrine or pharmaceutically acceptable salts thereof, and include water-insoluble polymers and wet-blocking agents. It relates to an oral capsule composition comprising a sustained release pellet (pellet B) coated with an agent).

Description

Capsule composition containing loratadine and pseudoephedrine {PHARMACEUTICAL CAPSULE COMPOSITIONS CONTAINING LORATADINE AND PSEUDOEPHEDRINE}

The present invention relates to a capsule composition containing loratadine and pseudoephedrine, and more particularly to immediate release pellets (pellet A) and pseudoephedrine or pharmaceutically acceptable containing loratadine and pseudoephedrine or pharmaceutically acceptable salts thereof. An oral capsule composition comprising a salt thereof and comprising a sustained release pellet (pellet B) coated with a water-insoluble polymer and a wet-blocking agent.

Pseudoephedrine, a sympathetic neurostimulant, or a pharmaceutically acceptable salt thereof, such as pseudoephedrine sulfate, is known as a decongestant, and loratadine is a non-sleeping antihistamine that is used for allergic rhinitis, allergic skin diseases, and acute hay fever. It is a drug. Therefore, the combination of the two drugs can exert an excellent effect on colds and allergic rhinitis (US Pat. No. 5,314,697).

However, Pseudoephedrine sulfate has a half-life of 6.3 hours, which is much shorter than that of loratadine, while loratadine is absorbed from the gastrointestinal tract and binds to plasma proteins, so the half-life of the body is long, 12-15 hours. It has a slow dissolution rate. Due to the characteristics of these two drugs, when the two drugs are prepared as a simple compound, there is a problem in maintaining both drugs at the same time in the effective blood concentration range.

In order to solve this problem, U.S. Patent No. 5,314,697 discloses a film coated tablet having sudoephedrine sulfate as a sustained release matrix core together with a hydrophilic gel and then having a coating layer containing loratadine thereon. After taking the agent, loratadine with a long half-life is first eluted from the coating layer after taking it, and then pseudodoped sulfate with a short half-life is eluted from the sustained-release matrix core.

However, in a high pH environment, since solubility and dissolution rate of loratadine are drastically reduced, there is a problem that dissolution deviation occurs due to delayed dissolution of pseudoephedrine sulfate from the sustained-release matrix core. That is, since the elution of pseudoephedrine sulfate is greatly influenced by the wetting and elution of loratadine in the outer layer, the sulfuric acid according to the pH change of gastrointestinal fluid varies according to various factors such as the type and amount of food. The elution pattern of pseudoephedrine is changed irregularly.

U.S. Patent No. 5,807,579 also discloses tablets prepared by dispersing sustained-release pellets containing pseudoephedrine or salts thereof in a matrix containing antihistamines that may contain pseudoephedrine or salts thereof, even in this case high pH. Due to the low wettability of loratadine under conditions, the dissolution of pseudoephedrine may change, resulting in a loss of the desired dissolution pattern.

Accordingly, the present inventors have conducted studies to solve the above problems, and as a result, immediate release pellets containing loratadine and pseudoephedrine or salts thereof, and pseudoephedrine or salts thereof, and water-insoluble polymers and wet-blocking agents The present invention was completed by discovering that the capsule composition including the sustained-release pellet coated with) has not only the above-mentioned problems but also shows a preferable dissolution of the two components.

It is therefore an object of the present invention to provide an improved oral capsule composition containing loratadine and pseudoephedrine or a pharmaceutically acceptable salt thereof.

According to the invention, an immediate release pellet containing (a) (i) a therapeutically effective amount of loratadine, (ii) pseudoephedrine or a pharmaceutically acceptable salt thereof, and (iii) one or more pharmaceutically acceptable additives ( Pellet A) and

(b) sustained-release pellets (pellet B) containing (i) pseudoephedrine or a pharmaceutically acceptable salt thereof and (ii) at least one pharmaceutically acceptable additive, wherein 2-30% by weight relative to the total weight of pellet B Water insoluble polymers; And a sustained release pellet (pellet B) coated with 2 to 30% by weight of a wet-blocking agent selected from the group consisting of magnesium stearate, talc, fatty acid esters, or mixtures thereof. This is provided.

As used herein, "pellet" refers to drug-containing particles having a diameter in the range of about 300 to 1500 micron. "Rapid release" refers to the nature of the pharmaceutical composition in which the total dose of the active ingredient is biologically available without significant delay. "Sustained release" refers to the nature of a pharmaceutical composition in which the active ingredient becomes biologically available over an extended period of time after administration, as described in USP XXIV, 1999.

As used herein, "therapeutically effective amount" of loratadine and pseudoephedrine refers to the amount necessary to obtain the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining the therapeutically effective amount, various factors are contemplated, such as the bioavailability characteristics of the pharmaceutical composition administered, the dosage regimen and the like. For example, the effective dosages of loratadine and pseudoephedrine sulfate may be 10 mg / day and 240 mg / day, respectively, and for unit dosages administered twice daily, the amounts of loratadine and pseudoephedrine sulfate may be 5 mg and 120 mg, respectively. have.

Immediate release pellets (pellets A) contained in the composition according to the invention contain a therapeutically effective amount of loratadine, pseudoephedrine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable additives. When the composition of the present invention is administered, the dissolution rate of loratadine is obtained by dissolving pseudoephedrine or a salt thereof, which is soluble in water, from the immediate release pellet and simultaneously dissolving the loratadine into an aqueous gastric environment. Increase and rapidly reach the therapeutic initial concentration of pseudoephedrine or its salts.

The pseudoephedrine or salt thereof contained in pellet A is an amount sufficient to obtain a therapeutically effective initial concentration, and the content thereof is preferably 5 to 50% by weight based on the total pseudoephedrine or salt thereof contained in pellets A and B.

Immediate release pellets of the compositions according to the invention may contain one or more pharmaceutically acceptable additives, for example disintegrants, binders, or glidants.

Disintegrants that can be used for the elution improvement of loratadine include microcrystalline cellulose, low-substituted hydroxypropyl cellulose (US Pharmacopoeia XXIV, 1999), sugars, crospovidone, sodium starch glycolate or mixtures thereof, Of these, crospovidone, low-substituted hydroxypropyl cellulose or mixtures thereof are more preferred. The content of these disintegrants is preferably 5 to 50% by weight relative to the total weight of the rapid release pellet, and 10 to 30% by weight is more preferable since a satisfactory elution phase of loratadine can be obtained.

The immediate release pellets may also contain binders such as polyvinylpyrrolidone, hydroxypropyl cellulose, gelatin and the like, and glidants such as colloidal silicon dioxide, silicon dioxide and talc.

Immediate release pellets can be obtained from the Extrusion & Spheronizing method (Pharmaceutical Pelletization Technology, 1989, p187-216), Solution & Suspension layering method, Drug Dev.Ind. Pharm., 1989, 15 (8), p1137-1159) and dry powder layering method (Dry powder layering method, Pharmaceutical Pelletization Technology, 1989, p187-216).

For example, when rapid-release pellets are prepared by dry powder delamination, crystalline sucrose seeds and microcrystalline cellulose seeds (e.g., Celphere ™, Asahi Chemical, etc.) in a centrifugal graulator The rapid-release pellet of the present invention can be prepared by spraying a binding solution onto an inert carrier such as) and simultaneously dispersing a mixed powder of loratadine, pseudoephedrine or a salt thereof, and a pharmaceutically acceptable additive in the inert carrier.

Sustained-release pellets (pellets B) contained in the composition according to the invention contain pseudoephedrine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives, and contain 2-30% by weight of the total weight of pellet B 2-30% by weight of a wet-blocking agent based on the total weight of pellet B selected from the group consisting of insoluble polymers and magnesium stearate, fatty acid esters, talc, or mixtures thereof.

Since elution of pseudoephedrine from the sustained-release pellets is not affected by the elution pattern of loratadine, a desired elution pattern can be obtained.

Sustained release pellets, or pellets B, can be prepared by coating a core pellet containing pseudoephedrine or a salt thereof with a water insoluble polymer and an anti-wetting agent, or dispersing the pseudoephedrine or its salt in a water insoluble polymer matrix containing an anti-smearing agent. have.

When a core pellet containing pseudoephedrine is coated with a water-insoluble polymer and a wetting-preventing agent to form a coating, the desired dissolution pattern of pseudoephedrine (sig) is easily controlled regardless of the pH of the gastrointestinal fluid by easily adjusting the composition and / or thickness of the coating film of pellet B A sigmoidal dissolution profile can be obtained. Therefore, the coated pellets are more preferable as the sustained release pellets of the present invention.

Water insoluble polymers usable in the present invention include ethylcellulose, methacrylic acid copolymers (e.g., Eudragit L, Eudragit RS, Eudragit RL, Eudragit S, etc.), hydrogenated castor oils. , Shellac, and mixtures thereof.

Core pellets of sustained-release pellets include the Extrusion & Spheronizing method, Pharmaceutical Pelletization Technology, 1989, p187-216, Solution & Suspension layering method, Drug Dev. Ind. Pharm., 1989, 15 (8), p1137-1159) and dry powder layering method (Dry powder layering method, Pharmaceutical Pelletization Technology, 1989, p187-216).

For example, when prepared by dry powder delamination, inert crystalline sucrose seeds and microcrystalline cellulose seeds (e.g., Celphere ™, Asahi Chemical) in CF granules The core pellets of the sustained-release pellets of the present invention can be prepared by spraying a binder solution on a carrier and simultaneously dispersing a mixed powder of pseudoephedrine or a salt thereof and a pharmaceutical additive in an inert carrier. The core pellets may be coated with a water-insoluble polymer and a wetting-preventer solution again dissolved in a suitable solvent to prepare the sustained release pellets of the present invention. Suitable solvents usable in the present invention include acetone, ethanol, isopropyl alcohol, methylene chloride, and mixtures thereof.

Pharmaceutical additives that can be used in the sustained-release pellets of the present invention include, for example, plasticizers such as polyethylene glycol 6000, diethyl phthalate and diethicebacate; Excipients such as microcrystalline cellulose and powdered sugar; Disintegrants such as low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, and mixtures thereof; Binders such as polyvinylpyrrolidone, hydroxypropyl cellulose and gelatin; It may contain one or more known additives such as lubricants such as colloidal silicon dioxide, silicon dioxide, magnesium stearate, talc and the like.

The capsule composition of the present invention can be easily formulated in a capsule form by filling the above-mentioned immediate release pellets and sustained release pellets in an appropriate capsule.

When orally administering the capsule composition of the present invention, loratadine is easily eluted from the capsule composition of the present invention at a higher rate than the conventional tablet composition.

In addition, pseudoephedrine or a salt thereof having a half-life shorter than that of loratadine is first eluted from the immediate release pellet and then eluted from the sustained release pellet, thereby enabling rapid and continuous dissolution transport of pseudoephedrine. Sustained-release pellets are coated with a water-insoluble polymer to have an effective sustained release property. In particular, the coating of the sustained-release pellets has a wetting-preventing agent to exhibit a pseudo-multiple dissolution profile.

Therefore, the capsule composition of the present invention exhibits a rapid and sustained effect upon administration, regardless of various factors related to the gastrointestinal tract environment.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, this does not limit the present invention.

Example 1. Preparation of immediate release pellets containing loratadine and pseudoephedrine sulfate.

A binder solution was prepared by dissolving 5.0 g of polyvinylpyrrolidone in 120 g of water. 25 g of loratadine, 180 g of pseudoephedrine sulfate, 25 g of microcrystalline cellulose, 75 g of low-substituted hydroxypropyl cellulose, 75 g of crospovidone, and 1.5 g of colloidal silicon dioxide were mixed and appled with a sieve of 20 mesh to prepare a mixed powder. It was. While spraying the binder solution to 250 g of the crystalline sucrose seeds in the CF granulator, the mixed powder was dispersed in the crystalline sucrose seeds to prepare pellets. (Rotating speed: 140-200 rpm, bonding liquid spray amount: 2-20 ml / min, spray air pressure: 1-2 kg / cm ² , air volume: 5-300 L / min, powder injection speed: 5-30 g / min )

Examples 2 and 3. Preparation of immediate release pellets containing loratadine and pseudoephedrine sulfate.

Except for varying the content of the ingredients as shown in Table 1, the procedure of Example 1 was repeated to prepare immediate release pellets containing loratadine and pseudoephedrine sulfate.

Example 2 Example 3 Medicine Loratadine 25 g 25 g Pseudoephedrine Sulfate 240 g 270 g Excipient Microcrystalline cellulose 25 g 25 g Disintegrant Low Substitution Hydroxypropyl Cellulose 75 g 50 g Crospovidone 75 g 50 g Lubricant Colloidal silicon dioxide 1.5 g 1.5 g Binder Polyvinylpyrrolidone 5.0 g 5.0 g Inert carrier Crystalline Sucrose Seeds 250 g 250 g

Example 4 Preparation of Pseudo-Ephedrine Sulfate-Containing Core Pellets

A binder solution was prepared by dissolving 20 g of hydroxypropyl cellulose in 480 g of water. 1200 g of pseudoephedrine and 3 g of colloidal silicon dioxide were mixed and apples were sieved through 20 mesh to prepare a mixed powder. While spraying a binder solution onto 600 g of crystalline sucrose seeds in a CF granulator, the mixed powder was scattered onto the crystalline sucrose seeds to prepare pellets. The obtained pellets were dried at 50 ° C. until the water content was 2% or less using a ket moisture meter to prepare a core pellet containing pseudoephedrine sulfate.

Examples 5 and 6. Preparation of Pseudosulphate-containing Core Pellets.

The core pellets containing Pseudosulphate Pseudosulphate were prepared by repeating the process of Example 4 except that the content of the ingredients was changed as shown in Table 2.

Example 5 Example 6 Medicine Pseudoephedrine Sulfate 1200 g 1200 g Binder Hydroxypropyl cellulose - 20 g Polyvinylpyrrolidone 20 g - Lubricant Colloidal Silicon Oxide 3 g 3 g Magnesium Stearate - 240 g Inert carrier Crystalline Sucrose Seeds 600 g 600 g

Examples 7-10. Preparation of Pseudosulphate-containing Sustained-Release Pellets.

Using the core pellets prepared in Example 4 and the components described in Table 3, sustained-release pellets containing pseudoephedrine sulfate were prepared as follows.

A suspension of acetone and isopropyl alcohol mixtures of water-insoluble polymers, magnesium stearate, and other components was sprayed onto a pseudoephedrine-containing core pellet in a CF-360 granulator, followed by a water content of 2% at 50 ° C. It dried to below, and produced the sustained-release pellet containing suede sulfate.

Example 11. Preparation of Pseudosulphate-containing Sustained Release Pellets.

The sustained-release pellet was prepared by repeating the procedure of Examples 7 to 10 using the core pellet prepared in Example 6 and the components shown in Table 3.

Example 7 Example 8 Example 9 Example 10 Example 11 Pseudosulphatephedrine core pellets 280 280 280 280 280 Ethyl Cellulose 15 30 - 26 15 Eudragit RS - - 40 13 - Diethylphthalate 1.5 3.0 4.0 3.9 1.5 Magnesium stearate 18 - - 13 - Talc - 10 10 - - Acetone 150 300 400 390 150 Isopropyl Alcohol 150 300 400 390 150

Example 12 Preparation of Capsule

127.3 g, 139.3 g, and 135.3 g of the immediate release pellets prepared in Examples 1, 2, and 3, respectively, were mixed with 143.3 g, 122.9 g, and 112.6 g of the sustained release pellets prepared in Example 7, and then No. 1 The capsules of Examples 12, 13, and 14 were prepared by filling the capsules, respectively. In addition, 127.3 g of the rapid-release pellet prepared in Example 1 was mixed with 153.1 g of the sustained-release pellet prepared in Example 10, and then filled into capsule No. 1 to prepare a capsule of Example 15. The final composition is shown in Table 4 below.

ingredient Example 12 (Example 1 + 7) Example 13 (Example 2 + 7) Example 14 (Example 3 + 7) Example 15 (Example 1 + 10) Loratadine 5 5 5 5 Pseudoephedrine Sulfate Immediate release pellets 36 48 54 36 Sustained release pellets 84 72 66 84 Microcrystalline cellulose 5 8.6 8.6 8.6 Low Substituted Hydroxypropyl Cellulose 15 15 15 15 Crospovidone 15 15 15 15 Colloidal Silicon Oxide 0.5 0.48 0.47 0.5 Hydroxypropyl cellulose 1.4 1.2 1.1 1.4 Polyvinylpyrrolidone One One One One Ethyl Cellulose 7.5 15 - 13 Eudragit RS - - 20 6.5 Diethylphthalate 0.75 1.5 2.0 3.9 Magnesium stearate 9 - - 6.5 Talc - 5 5 -

Test Example 1. Dissolution Test (1)

Each of the sustained-release pellets prepared in Examples 7 to 11 was placed in a basket, and the dissolution test was performed under the following conditions. The results are shown in Table 5.

Dissolution test conditions:

Eluent: 900 ml of 0.1N hydrochloric acid

Temperature: 37 ± 0.5 ℃

Method: Basket Law (US Pharmacopoeia)

Elution of Pseudoephedrine Sulfate (%) 1 hours 2 hours 4 hours 6 hours Example 7 15.5 25.5 64.1 82.6 Example 8 21.5 41.9 63.3 84.6 Example 9 15.5 37.8 58.2 78.6 Example 10 19.7 45.4 66.9 88.4 Example 11 15.5 52.1 65.6 79.0

As shown in Table 5, all of the sustained-release pellets of the present invention showed satisfactory dissolution patterns over 6 hours.

Test Example 2 Dissolution Test (2)

The capsules prepared in Example 12-15 were placed in a basket, and the dissolution test was performed under the following conditions. An equal amount of Clarinase (Sheringpurau, USA) was placed in a basket and tested. The results are shown in Table 6 and Table 7.

Dissolution test conditions:

Eluent: 900 ml of 0.1N hydrochloric acid

pH 4.0 acetate buffer 900 ml

pH6.8 phosphate buffer 900ml

Temperature: 37 ± 0.5 ℃

Method: Basket Law (US Pharmacopoeia)

Elution of loratadine (%, 1 hour) pH Comparative example Example 12 Example 13 Example 14 Example 15 1.0 88.5 91.7 94.5 97.2 95.3 4.0 53.4 51.5 52.9 55.1 54.1 6.8 0 10.2 10.9 12.1 9.7

Elution of Pseudoephedrine Sulfate (%) pH 1 hours 2 hours 4 hours 6 hours 1.0 Clarinase 48.8 49.0 n.m. 82.6 Example 12 40.9 47.9 74.8 87.8 Example 13 49.3 55.3 78.4 89.6 Example 14 53.5 59.0 80.2 90.4 Example 15 43.8 61.8 76.8 91.9 4.0 Clarinase 47.4 47.8 n.m. 50.1 Example 12 39.1 49.1 n.m. 84.9 Example 13 48.4 55.1 n.m. 87.9 Example 14 51.3 57.9 n.m. 88.5 Example 15 44.3 60.9 n.m. 92.7 6.8 Clarinase 44.1 48.1 n.m. 49.7 Example 12 40.8 52.3 n.m. 85.1 Example 13 50.1 57.1 n.m. 89.9 Example 14 52.7 59.1 n.m. 87.9 Example 15 46.2 63.7 n.m. 93.1

* n.m. : No measurement

As shown in Table 6, loratadine was easily eluted at pH 1.0. However, elution of loratadine from Clarinase was completely inhibited at pH 4.0 and 6.8.

As shown in Table 7, at pH 1.0, the dissolution rate of pseudoephedrine was not significantly different between compositions. However, the amount of pseudoephedrine sulfate eluted from Clarinase at pH 4.0 and 6.8 was as low as about 50% over 6 hours. This indicates that loratadine, which was not eluted under high pH conditions, prevented elution of pseudoephedrine. In contrast, the dissolution of pseudoephedrine from the composition of the present invention is not affected by pH, and the dissolution pattern is the same at pH 1.0 to 6.8.

It is also particularly preferred that the dissolution pattern of pseudoephedrine sulfate from the composition of the present invention exhibits a sigmoidal curve, as it provides pseudo-multiple administration of pseudoephedrine sulfate.

Claims (3)

immediate release pellets (pellet A) containing (i) a therapeutically effective amount of loratadine, (ii) pseudoephedrine or a pharmaceutically acceptable salt thereof, and (iii) one or more pharmaceutically acceptable additives; (b) sustained-release pellets (pellet B) containing (i) pseudoephedrine or a pharmaceutically acceptable salt thereof and (ii) at least one pharmaceutically acceptable additive, wherein 2-30% by weight relative to the total weight of pellet B Water-insoluble polymers selected from the group consisting of ethylcellulose, methacrylic acid copolymers, hydrogenated castor oil, shellac, and mixtures thereof; And a sustained release pellet (pellet B) coated with 2 to 30% by weight of a wet-blocking agent selected from the group consisting of magnesium stearate, talc, fatty acid esters, or mixtures thereof. . The capsule composition according to claim 1, wherein the pseudoephedrine or a pharmaceutically acceptable salt thereof contained in Pellet A is 5 to 50% by weight based on the total weight of the pseudoephedrine or a pharmaceutically acceptable salt thereof present in the composition. delete