Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-09-24
2001-07-31
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S469000, C424S470000, C424S474000, C514S770000, C514S779000, C514S781000, C514S782000
Reexamination Certificate
active
06267986
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for the preparation of a controlled release pharmaceutical composition comprising two discrete zones wherein the first discrete zone comprises therapeutically effective amount of pseudoephedrine or its pharmaceutically acceptable salt as active ingredient and the second discrete zone comprises a therapeutically effective amount of a long-acting antihistamine selected from the group consisting of loratadine, azatidine, fexofenadine, terfenadine, cetirizine, astemizole, and levocabastine, or their pharmaceutically acceptable salt as active ingredient.
BACKGROUND OF THE INVENTION
Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a non-sedating antihistamine useful, for example, in alleviation of seasonal allergic rhinitis symptoms such as sneezing and itching, and in the treatment of chronic idiopathic urticaria in patients six years or older. Loratadine is available in the form of conventional tablets that release loratadine in a conventional manner by the processes of disintegration and dissolution such that loratadine begins to elicit its antihistaminic effect within 1 to 3 hrs and the effect lasts in excess of 24 hrs. The tablets are thus orally administered only once daily.
Azatadine is disclosed in Belgian Patent No. 647,043 and in corresponding U.S. Pat. Nos. 3,326,924 and 3,419,565. The elimination half-life is reported to be 9-12 hrs. Terfenadine and fexofenadine are disclosed in U.S. Pat. No. 3,878,217 and have a duration of action of 12 to 24 hrs, and >24 hrs., respectively.
Cetirizine disclosed in U.S. Pat. No. 4,525,358; astemizole in U.S. Pat. No. 4,219,559, and levocabastine in U.S. Pat. No. 4,369,184; have a duration of action of 12 to 24 hrs, >24 hrs, and 16 to 24 hrs; respectively.
Pseudoephedrine and its pharmaceutically acceptable salts are well recognized by those skilled in the art as safe and effective nasal decongestants. Pseudoephedrine or its pharmaceutically acceptable salt when formulated as conventional tablets are commonly administered orally three or four times a day for the relief of nasal congestion. However, sustained release or controlled release tablets that release pseudoephedrine or its pharmaceutically acceptable salt at a controlled slow rate such that they may be administered twice-daily or once-daily are also commonly available.
It is well known to those skilled in the art that controlled delivery results in a decrease in the frequency of drug administration thereby improving patient compliance. Furthermore, controlled drug delivery systems produce constant therapeutic plasma levels of active ingredients as compared to fluctuations seen when multiple doses of a conventional formulation are given. Thus, controlled drug delivery systems may decrease the severity and frequency of side effects.
A decongestant is commonly administered orally in combination with an antihistamine for relieving nasal congestion associated with allergic rhinitis. It is quite apparent from the above stated facts that when the decongestant is pseudoephedrine or its pharmaceutically acceptable salt, and the antihistamine is a long-acting antihistamine, then the dosage form should preferably be designed such that the long acting antihistamine is released in a conventional manner and pseudoephedrine is released at a controlled rate such that the pharmaceutical composition is suitable for twice-daily or once-daily administration.
U.S. Pat. No. 4,996,061 discloses a pharmaceutical composition in the form of a multiple-compression tablet comprising of two discrete zones. The first discrete zone is made with formulation (A) comprising a therapeutically effective decongestant amount of a sympathomimetic drug, one or more pharmaceutically acceptable water-soluble non-ionic cellulose ethers in an amount from about 18% to about 50% by weight of formulation (A), and one or more pharmaceutically acceptable excipients. The second discrete zone is made with formulation (B) comprising a therapeutically effective antihistaminic amount of a piperidinoalkanol, calcium carbonate in an amount from about 0.5% to about 25% by weight of formulation (B), one or more pharmaceutically acceptable anionic surfactants in an amount from about 1% to about 10% by weight of formulation (B), and one or more pharmaceutically acceptable excipients. Formulation (B) may optionally contain a therapeutically effective decongestant amount of a sympathomimetic drug.
U.S. Pat. No. 4,792,452 discloses a tablet formulation composed of up to about 45% by weight of a pH-dependent salt of alginic acid, up to about 35% by weight of a pH-independent hydrocolloid gelling agent, binder and excipients. Release of the drug is therefore affected by the varying pH of the gastrointestinal Tract.
It is an object of the present invention to provide an oral controlled release pharmaceutical composition that releases the drug unaffected by the varying pH of the gastrointestinal Tract. The pharmaceutical composition in the form of tablets comprise a therapeutically effective amount of pseudoephedrine or its pharmaceutically acceptable salt and a therapeutically effective amount of a long-acting antihistamine selected from the group consisting of loratadine, azatadi, fexofenadine terfenadine, cetirizine, astemizole and levocabastine or their pharmaceutically acceptable salt such that the long-acting antihistamine or its pharmaceutically acceptable salt is released at a rapid rate, and pseudoephedrine or its pharmaceutically acceptable salt is released at a controlled rate.
Accordingly, the present invention provides a pharmaceutical composition in the form of a tablet comprising two discrete zones wherein the first zone comprises a therapeutically effective amount of pseudoephedrine or its pharmaceutically effective salt, one or more hydrophilic polymer(s) as herein described, a salt of a polyuronic acid, and a pharmaceutically acceptable salt of a group II metal ion; the second discrete zone comprises a therapeutically effective amount of a long-acting antihistamine selected from the group consisting of loratadine, azatidine, fexofenadine, terfenadine, cetirizine, astemizole, and levocabastine or their pharmaceutically acceptable salt with at least one pharmaceutically acceptable excipient. Optionally, the blend may be converted into granules by conventional means. Also optionally, the blend or the granulated blend may be compressed onto the first discrete zone. Further optionally, the blend may be coated onto the first discrete zone with the aid of a binder solution.
According to the present invention, the first discrete zone comprises one or more hydrophilic polymer(s). The hydrophilic polymer(s) that may be used in the present invention include cellulose ethers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, or other water soluble or swellable polymers such as sodium carboxymethyl cellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum, alginates, gelatin, albumin and the like. The hydrophilic polymers used may also be polyacrylate polymers such as homopolymers based on acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, or copolymer based on acrylic acid and long chain (C
10
-C
30
) alkyl acrylates and cross-linked with allylpentaerythritol.
The preferred hydrophilic polymers are selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, xanthan gum and mixtures thereof. The hydrophilic polymers may be present in an amount from about 0.1% to 90%, more preferably from about 20% to 50%, by weight of the total weight of the first discrete zone.
According to a more preferred embodiment of the present invention, the hydrophilic polymer is a mixture of a hydroxypropyl methylcellulose and hydroxypropylcellulose.
Examples of hydroxypropyl methylcellulose polymers that may be used in the present invention include those available from Dow Chemical Co. under the brand name Methocel, such as, Methocel K15M, Methocel K100M, and the like. Hydroxypropylcellulose polymers that may be used in
Jain Girish Kumar
Rampal Ashok
Sen Himadri
Deshmukh Esq. Jayadeep R.
Ranbaxy Laboratories Limited
Spear James M.
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