Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-05-28
2001-01-09
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S480000
Reexamination Certificate
active
06171618
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to dosage forms comprising cetirizine and pseudoephedrine, containing both a sustained release and an immediate release component.
BACKGROUND OF THE INVENTION
and is a member of the class of compounds termed 2-[4-(diphenylmethyl)-1-piperazinyl]acetic acids. These compounds are useful as antiallergens, spasmolytics, and antihistamines which are generally non-sedating. See U.S. Pat. No. 4,525,358 and
The Merck Index,
Eleventh Edition, 1989, page 310, entry 2013.
Pseudoephedrine, as well as pharmaceutically acceptable acid addition salts thereof such as the hydrochloride and sulfate salts, is a sympathomimetic drug known by those skilled in the art as a safe therapeutic agent for treating nasal congestion. It is commonly administered orally and concomitantly with an antihistamine for treatment of nasal congestion for the treatment of allergic rhinitis.
Cetirizine and pseudoephedrine can be administered together. The general schedule for administering the two drugs together involves one 10 mg cetirizine tablet per day, plus eight 30 mg immediate-release pseudoephedrine tablets divided into four doses over the course of a day. It is well known, however, that patient compliance with a multiple dose daily administration schedule can be affected by the inconvenience of having to remember to take medicine at numerous, appropriately spaced intervals. It would accordingly be useful if patients could take cetirizine plus pseudoephedrine as a unitary dosage form, such as a tablet, say once-daily or twice-daily, to improve convenience and better ensure patient compliance.
SUMMARY OF THE INVENTION
In one aspect, this invention provides a solid dosage form comprising cetirizine and pseudoephedrine
wherein at least a portion of said pseudoephedrine is contained in a core comprising said portion of pseudoephedrine, whereby release of said pseudoephedrine into an environment of use is sustained;
wherein said cetirizine is contained as an immediate-release component in said dosage form; and
wherein said dosage form is substantially free of alcohols having a molecular weight lower than 100 and reactive derivatives thereof.
In a preferred embodiment, this invention provides a solid dosage form comprising cetirizine and pseudoephedrine,
wherein at least a portion of said pseudoephedrine is contained in a core comprising said portion of pseudoephedrine, said core being surrounded by a permeable membrane, whereby release of said pseudoephedrine into an environment of use is sustained;
wherein said cetirizine is contained as an immediate-release component in said dosage form; and
wherein said dosage form is substantially free of alcohols having a molecular weight lower than 100 and reactive derivatives thereof.
In a preferred embodiment, the dosage form is substantially free of alcohols having a molecular weight less than 250, and reactive derivatives thereof. In a more preferred embodiment, the dosage form is substantially free of alcohols having a molecular weight less than 500 and reactive derivatives thereof. In a still more preferred embodiment, the dosage form is substantially free of alcohols having a molecular weight less than 1000 and reactive derivatives thereof.
This invention further provides a process for making a solid dosage form containing cetirizine and pseudoephedrine, comprising
coating a shaped sustained release core comprising pseudoephedrine with an immediate release layer comprising cetirizine and a water soluble film forming polymer, said core and said immediate-release layer being substantially free of alcohols having a molecular weight lower than 100 and reactive derivatives thereof.
In a preferred embodiment this invention provides a preferred process for making a solid dosage form containing cetirizine and pseudoephedrine, comprising the steps of
coating a shaped composition comprising pseudoephedrine with a permeable membrane
coating said permeable membrane with an immediate release layer comprising cetirizine and a water soluble film forming polymer,
said composition, said membrane, and said layer being substantially free of alcohols having a molecular weight lower than 100 and reactive derivatives thereof.
“Cetirizine” as employed herein is intended to Include not only the free compound of formula (I) but also any pharmaceutically acceptable salt thereof. Preferred are acid addition salts, especially the dihydrochloride (referred to also herein as the “hydrochloride”). “Cetirizine” is also intended to cover individual enantiomers as well as the racemate.
“Pseudoephedrine” as employed herein is intended to be inclusive of the free base and also of any pharmaceutically acceptable acid addition salt. Preferred for use in this invention are the sulfate and hydrochloride salts.
The term “alcohols” is used generically to mean any compound having one or more hydroxyl (—OH) groups reactive toward cetirizine. The term is thus inclusive of diols and polyols as well as mono-alcohols which are reactive toward cetirizine under normal conditions of processing and storage.
A “reactive derivative” as used herein includes those materials having alcohol (—OH) groups which have been esterified and which can react with cetirizine by transesterification.
“Shaped” usually means round or roughly spherical, but can also mean any other shape that tablet cores can be made in.
The invention provides a dosage form containing both cetirizine and pseudoephedrine. The cetirizine is contained in an immediate-release component from which it starts to be delivered or released substantially Immediately upon ingestion (i.e., upon swallowing). No mechanism has been incorporated into the dosage form to delay the release which would otherwise take place upon exposure to a use environment, such as the luminal fluid of the gastrointestinal (GI) tract. Generally the cetirizine should be at least 80% released from the dosage form within an hour after administration.
The pseudoephedrine, by contrast, releases in a sustained fashion, at least about 75% of the drug contained in the dosage form releasing over a period of 4 to 36 hours, preferably about 8 to about 24 hours, although the period of sustained release can be tailored to have an immediate release component, as disclosed further below. The term “about” as used above and elsewhere herein means plus or minus 10% for each of the numerical limits. The sustained release pseudoephedrine is contained in a core which can be engineered in a variety of ways and embodiments to implement sustained release. For example, the pseudoephedrine can be incorporated into a sustained release matrix that meters pseudoephedrine out over a period of 4 to 36 hours, the matrix thus constituting the core. Alternatively, the pseudoephedrine core can comprise a shaped pseudoephedrine immediate release composition and a surrounding, rate limiting membrane which imparts sustained release behavior to the core.
In the final product dosage form (i.e., the dosage form intended to be sold or administered), and during processing when making the dosage form, it is important to avoid contact of cetirizine with alcohols having a molecular weight less than 100 since such contact can result in a reaction with cetirizine, usually esterification, and thereby damage the dosage form by reacting with the active medicinal agent. Thus, the dosage form should be substantially free of such reactive components at the time the immediate-release cetirizine component is introduced into the dosage form, and thereafter. Alcohols and other reactive components can be employed during processing, so long as they are removed to reduce or eliminate their presence prior to introducing cetirizine. Not employing alcohols at all during processing, or removing them prior to introducing cetirizine into the dosage form, is what is meant by the phrase “substantially free of alcohols having a molecular weight less than . . . ”. Some level of alcohols which are reactive with cetirizine can be tolerated in the final dosage form, the exact level depending on the particular
Johnson Barbara A.
Korsmeyer Richard W.
Oksanen Cynthia A.
Benson Gregg C.
Jones James T.
Kulkosky Peter F.
Pfizer Inc.
Richardson Peter C.
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