Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-02-22
2001-06-26
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S457000, C424S458000
Reexamination Certificate
active
06251427
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical capsule composition containing loratadine and pseudoephedrine, and more particularly, to a pharmaceutical capsule composition for oral administration, which comprises rapid-release pellets (pellets A) containing loratadine and pseudoephedrine or a pharmaceutically acceptable salt thereof and extended-release pellets (pellets B) containing pseudoephedrine or a pharmaceutically acceptable salt thereof, wherein the pellets B are coated with a water-insoluble polymer and a wet-blocking agent.
BACKGROUND OF THE INVENTION
Pseudoephedrine or a pharmaceutically acceptable salt thereof, e.g., pseudoephedrine sulfate, has been recognized by those skilled in the art as a sympathomimetic drug effective for treating nasal congestion. Loratadine, a non-sedating antihistaminic agent, is also known to be useful as an anti-allergy agent for the treatment of seasonal allergic rhinitis symptoms such as sneezing and itching. Therefore, an oral dosage composition containing both loratadine and pseudoephedrine or a pharmaceutically acceptable salt thereof is useful for treating patients showing the sign and symptoms associated with upper respiratory diseases and allergic rhinitis (see U.S. Pat. No. 5,314,697)
However, the biological half-life of pseudoephedrine sulfate is only about 6.3 hours, while loratadine, which combines with plasma proteins after being absorbed through the gastrointestinal tract, has a much longer biological half life of 12 to 15 hours. Further, loratadine has a poor water-solubility and exhibits a very low dissolution rate. Therefore, a conventional formulation prepared by simply mixing loratadine and pseudoephedrine or its salts is not capable of maintaining therapeutically effective blood concentrations of both ingredients at the same time for a prescribed period.
In order to solve the above problem, U.S. Pat. No. 5,314,697 suggests a film-coated tablet comprising an extended-release matrix core containing pseudoephedrine sulfate and a hydrophilic gel, a coating layer containing loratadine being formed on said core. When this formulation is ingested, loratadine having a longer biological half-life is released from the coating layer before the dissolution of pseudoephedrine sulfate having a shorter biological half-life from the extended-release matrix core.
However, the solubility and dissolution rate of loratadine from the outer layer decrease markedly in a high pH environment, and for this reason, the dissolution of pseudoephedrine sulfate from the extended-release matrix core may be unduly delayed. That is, the dissolution of pseudoephedrine sulfate is highly affected by the degree of wetting and dissolution of loratadine in the outer layer, and therefore, the release profile of pseudoephedrine sulfate fluctuates in an unpredictable manner with the pH of the gastrointestinal fluid which varies widely depending on various factors such as the amount and kind of ingested food.
Further, U.S. Pat. No. 5,807,579 discloses a tablet composition comprising extended-release pellets containing pseudoephedrine or its salts that are dispersed in a matrix containing an antihistaminic agent and optional pseudoephedrine or its salts. However, this composition also suffers from the problem of poor wetting of loratadine at a high pH condition, which may lead to an unsatisfactory mode of pseudoephedrine delivery.
The present inventors have carried out extensive research to solve the aforementioned problems; and, have discovered that a pharmaceutical capsule composition, which comprises rapid-release pellets containing loratadine and pseudoephedrine or a salt thereof, and extended-release pellets containing pseudoephedrine or a salt thereof, which are coated with a water-insoluble polymer and a wet-blocking agent, are free of above problems and exhibit controllable, satisfactory release profiles of both ingredients.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an improved pharmaceutical capsule composition for oral administration containing loratadine and pseudoephedrine or a pharmaceutically acceptable salt thereof.
In accordance with the present invention, there is provided a pharmaceutical capsule composition for oral administration, which comprises:
(a) a plurality of rapid-release pellets (pellets A), each pellet containing (i) a therapeutically effective amount of loratadine, (ii) pseudoephedrine or a pharmaceutically acceptable salt thereof, and (iii) one or more pharmaceutically acceptable excipients; and
(b) a plurality of extended-release pellets (pellets B), each pellet containing (i) pseudoephedrine or a pharmaceutically acceptable salt thereof and (ii) one or more pharmaceutically acceptable excipients, which are coated with a water-insoluble polymer in an amount ranging from 2 to 30 wt % and a wet-blocking agent selected from the group consisting of magnesium stearate, talc, fatty acid ester and a mixture thereof in an amount ranging from 2 to 30 wt %, based on the total weight of pellets B.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “pellets” means pharmaceutical-containing particles having a diameter ranging from about 300 to 1500 microns. The term “rapid-release” refers to a property of the pharmaceutical composition wherein the entire dose of active medicament becomes bioavailable without substantial delay. The term “extended-release” is as expressed in the U.S. Pharmacopoeia (USPXXIV, 1999) and refers to a property of the pharmaceutical composition wherein the contained active medicament becomes bioavailable over an extended period of time after being ingested.
As used herein, the term “therapeutically effective amount” of loratadine and pseudoephedrine refers to the amount required to produce the desired therapeutic response upon the oral administration and can be readily determined by one skilled in the art. In determining the therapeutically effective amount, a number of factors are considered, but not limited to: the bioavailability characteristics of the pharmaceutical composition administered, the dose regimen selected, and other relevant circumstances. For example, the effective doses of loratadine and pseudoephedrine sulfate may be 10 mg and 240 mg per day, respectively. Further, in case of a twice-a-day unit dosage form, the amounts of loratadine and pseudoephedrine sulfate may be 5 mg and 120 mg, respectively.
The rapid-release pellets (pellets A) of the pharmaceutical capsule composition according to the present invention contain a therapeutically effective amount of loratadine, pseudoephedrine or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. When the composition of the present invention is administered, the highly water-soluble pseudoephedrine or its salt is readily leached out from the rapid-release pellets upon which the pellets are disintegrated to release loratadine particles to the aqueous gastric environment, thereby enhancing the dissolution rate of loratadine, while a therapeutically effective blood level of pseudoephedrine or its salts is attained rapidly from the beginning.
Pellets A contain pseudoephedrine or its salt in an amount sufficient to produce a therapeutically effective initial concentration of pseudoephedrine and that amount may range from 5 to 50 wt % based on the total amount of pseudoephedrine or its salt in pellets A and B.
The rapid-release pellets of the pharmaceutical composition according to the present invention may contain one or more pharmaceutically acceptable excipients, including a disintegrant, a binder, or a lubricant.
Suitable disintegrants, which may be used to improve the dissolution rate of loratadine, include microcrystalline cellulose, low-substituted hydroxypropyl cellulose (USPXXIV, 1999), sucrose, crospovidone, sodium starch glycolate, and mixtures thereof. Among the disintegrants, preferred are crospovidone, low-substituted hydroxypropyl cellulose and a mixture thereof. The disintegrants may be used in an amount ranging fro
Jo Hang-Bum
Kim Hyun-Soo
Park Young-Joon
Fubara Blessing
Page Thurman K.
Rosenman & Colin LLP
Yuhan Corporation
LandOfFree
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