Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-23
2002-06-11
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S411000
Reexamination Certificate
active
06403579
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention is concerned with pharmaceutical combination preparations that are suitable for treating cardiac and cardiovascular disorders and the illnesses associated therewith. Specifically, the present invention relates to pharmaceutical combination preparations containing carvedilol and hydrochlorothiazide as active substances.
2. Description
Carvedilol, a compound of the formula:
is a &bgr;-blocker with additional &agr;
1
-blocking activity, which has been commercially available for several years under the trade name Coreg® in the United States and Dilatrend™ outside the United States.
Hydrochlorothiazide, a compound of the formula:
is a diuretic, which has been marketed for decades.
The combination of a &bgr;-blocker with a diuretic has been used successfully for treating cardiac and circulatory disorders such as hypertension, angina pectoris, cardiac insufficiency and illnesses associated therewith. Many studies have investigated the advantages of combination therapy using carvedilol and hydrochlorothiazide (e.g. Widmann et al., 1990, Eur J Clin Pharmacol 38(2):143-146; van der Does et al., 1990, Eur J Clin Pharmacol 38(2):147-152; McTavish et al., 1993, Drugs 45(2): 232-258). In all of these studies, the two active substances carvedilol and hydrochlorothiazide were sequentially administered in the form of individual tablets. A fixed combination of the two active substances could not be realized until the present invention.
A combined product was not earlier developed because the two active substances, carvedilol and hydrochlorothiazide, have different solubilities and, when granulated together, gave end products with inadequate active substance release and bioavailability. Thus, it was problematic to provide the two active substances as a combination preparation, such as a tablet. An object of the invention is to provide a solution to these problems.
SUMMARY OF THE INVENTION
The subject invention provides a pharmaceutical combination preparation containing the active substances (i) carvedilol, or a pharmaceutically acceptable salt thereof, and (ii) hydrochlorothiazide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable additive.
The preferred weight ratio of (i) hydrochlorothiazide, or a pharmaceutically acceptable salt thereof, to (ii) carvedilol, or a pharmaceutically acceptable salt thereof, is between about 1:0.5 and about 1:10. Typically, the preparation is in dosage form containing (i) about 10 mg to about 50 mg of carvedilol, or a pharmaceutically acceptable salt thereof, and (ii) about 5 mg to about 30 mg of hydrochlorothiazide, or a pharmaceutically acceptable salt thereof. The acceptable additive includes binders, disintegrants, glidants, adsorption agents, separating agents, fillers, and carriers. A more preferred pharmaceutical combination preparation contains about 0 weight % to about 50 weight % lactose, about 0 weight % to about 50 weight % saccharose, about 0 weight % to about 10 weight % magnesium stearate, about 0 weight % to about 30 weight % cellulose, about 0 weight % to about 10 weight % polyvinylpyrrolidone, about 0 weight to about 10 weight % polymeric cellulose compounds, about 0 weight % to about 10 weight % highly dispersed silicon dioxide and about 0 weight % to about 20 weight % cross-linked polyvinylpyrrolidone. Most preferably, the preparation is in solid dosage form.
The subject invention also provides method for treating of cardiac and circulatory disorders which comprises administering an effective amount of a pharmaceutical combination preparation in dosage form containing the active substances (i) carvedilol, or a pharmaceutically acceptable salt thereof, and (ii) hydrochlorothiazide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable additive.
Another aspect of the subject invention is a process for producing a solid dosage form pharmaceutical combination preparation containing carvedilol, or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide, or a pharmaceutically acceptable salt thereof. The process comprises (i) forming a press mass containing a carvedilol, or pharmaceutically acceptable salt thereof, granulate and a hydrochlorothiazide carvedilol, or pharmaceutically acceptable salt thereof, granulate and (ii) compressing the press mass to form the solid dosage form pharmaceutical combination preparation. The two granulates each having a granulate moisture content between about 6% and about 20% and a bulk density between about 0.1 g/ml and about 1.5 g/ml. The granuate moisture content and the bulk density of the two granulates do not vary from each other by more than about 30%.
The granulate moisture content of the carvedilol, or pharmaceutically acceptable salt thereof, granulate and the hydrochlorothiazide, or pharmaceutically acceptable salt thereof, granulate is preferably between about 10% and about 15%. The bulk density of both the carvedilol, or pharmaceutically acceptable salt thereof, granulate and the hydrochlorothiazide, or pharmaceutically acceptable salt thereof, granulate is preferably between about 0.4 g/ml and about 0.75 g/ml. Compressing is generally accomplished using a tablet press to form tablets. The process can further comprise coating the solid dosage form with a pharmaceutically acceptable aqueous film suspension. The coating of the solid dosage form is typically first performed at a rate of about 30 g to about 50 g of film suspension per minute during the first about 30 minutes to about 70 minutes and then performed at a rate of about 60 g to about 90 g of film suspension per minute until the film coating has finished. Pharmaceutically acceptable solid dosage form combination preparations prepared using the described process are also part of the invention. The amount of the disintegrant in the dosage form is typically at least 5 weight %.
Another aspect of the invention is a light-protecting film suspension for use in coating solid dosage form pharmaceutical preparations. This light-protecting film preferably comprises: about 10 weight % to about 50 weight % poly(ethyl acrylate, methyl acrylate) 2:1, 800,000; about 1 weight % to about 10 weight % sodium citrate; about 1 weight % to about 25 weight % methylhydroxypropylcellulose; about 0 weight % to about 20 weight % macrogol 10,000; about 5 weight % to about 40 weight % talc; about 2 weight % to about 25 weight % titanium dioxide; about 0 weight % to about 10 weight % indigocarmine color lacquer; about 0 weight % to about 2 weight % polysorbate; and about 0 weight % to about 1.0 weight % dimethicone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be considered limiting.
The present invention is concerned with pharmaceutical combination preparations containing the active substances carvedilol, or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide, or a pharmaceutically acceptable salt thereof, as well as pharmaceutically usual additives. Moreover, the present invention is concerned with the use of this combination preparation for the treatment of cardiac and circulatory disorders such as hypertension, angina pectoris, cardiac insufficiency and illnesses associated therewith.
The term “pharmaceutical combination preparation” refers to a pharmaceutically acceptable dosage form which simultaneously contains two or more active substances.
Pharmaceutically acceptable salts of the compounds of the formulas (I) and (II) include alkali salts, such as Na or K salts, alkaline earth metal salts, such as Ca and Mg salts, as well as salts with organic or inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid or toluenesulphonic acid, which are non-toxic for living organisms.
The phr
Henley III Raymond
Hoffman-La Roche Inc.
Johnston George W.
Parise John P.
LandOfFree
Pharmaceutical compositions containing carvedilol and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical compositions containing carvedilol and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical compositions containing carvedilol and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2921225