Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-15
2003-02-04
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S444000, C424S448000, C424S449000, C424S457000, C424S468000, C424S474000, C424S490000
Reexamination Certificate
active
06515010
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a pharmaceutically active compound, compositions containing the compound and methods of using the compound in the treatment of certain disease states in mammals, in particular man. More specifically, the present invention relates to carvedilol methanesulfonate, which is the methanesulfonate salt of 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, compositions containing this compound, and methods of using carvedilol methanesulfonate to treat hypertension, congestive heart failure and angina.
BACKGROUND OF THE INVENTION
U.S. Pat. No 4,503,067 describes a compound which is known as carvedilol. This compound is a novel multiple action drug useful in the treatment of hypertension and angina. Carvedilol is known to be both a competitive non-selective &bgr;-adrenoceptor antagonist and a vasodilator. The vasodilatory actions of carvedilol result primarily from &agr;
1
-adrenoceptor blockade, whereas the &bgr;-adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug. Also, carvedilol, as a consequence of its antioxidant action in attenuating oxygen free radical-initiated lipid peroxidation, is useful in organ protection, in particular, cardioprotection. Additionally, carvedilol is useful in the treatment of congestive heart failure.
The currently marketed formulation of carvedilol is a conventional, swallow tablet and prescribed as a twice-a-day medication in the United States. This formulation is in immediate release form; that is to say the nature of the formulation is such that by the time carvedilol leaves the stomach, it is either in solution or it is in the form of a suspension of fine particles, i.e. a form from which carvedilol can be readily absorbed.
Carvedilol, a free base with one pKa of 7.6, exhibits a predictable solubility behavior in neutral or alkaline media, i.e. above pH 9.0, the solubility is relatively low (<1 ug/mL). The solubility increases with decreasing pH and eventually reaches a plateau with a broad peak (~0.2 mg/mL) at a pH of 4-5. At acidic pHs of 1 to 4 in buffers, the solubility is limited by the solubility of the protonated form of carvedilol or its salt formed in-situ. The hydrochloride salt form formed in-situ in an acidic medium, such as simulated gastric fluid, is less soluble in water than carvedilol itself.
Surprisingly, it has been found that unlike carvedilol or certain salt forms of carvedilol, carvedilol methanesulfonate exhibits a solubility of >8.0 mg/ml in purified water at 25° C. Thus, carvedilol methanesulfonate may result in a dosage form from which the drug substance becomes available for bioabsorption throughout the gastrointestinal tract. Hence, it may be possible to develop controlled release once-a-day (uid) and twice-a-day (bid) dosage forms, delayed release or pulsatile release dosage forms. Also, carvedilol methanesulfonate may be formulated in an injectible form or as a transdermal patch. The high solubility feature of carvedilol methanesulfonate is particularly important when formulating this compound for therapeutic use.
SUMMARY OF THE INVENTION
The present invention provides a novel salt form of carvedilol, namely carvedilol methanesulfonate.
The present invention also provides pharmaceutical compositions containing carvedilol methanesulfonate and the use of this compound in the treatment of hypertension, congestive heart failure and angina.
DETAILED DESCRIPTION OF THE INVENTION 1-(Carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol is known as carvedilol. This compound has the following structure:
and is claimed in U.S. Pat. No. 4,503,067 (assigned to Boehringer Mannheim, GmbH, Mannheim-Waldhof, Fed. Rep. of Germany), issued Mar. 5, 1985. Reference should be made to said patent for its full disclosure, including the methods of preparing and using this compound. The entire disclosure of the '067 patent is incorporated herein by reference.
In accordance with the present invention, it has been unexpectedly found that a novel salt form of carvedilol, namely the methanesulfonate salt, exhibits a significantly higher aqueous solubility than the corresponding free base or other prepared salts. The aqueous solubility data for carvedilol and its salt forms determined at 25° C. are presented in Table 1.
TABLE 1
Aqueous Solubility (mg/mL) at 25° C. for Carvedilol and its Salt Forms
Carvedilol
Methanesul-
Time, hr
(ug/mL)*
Hydrochloride
Adipate
Tartrate
fonate
0.5
5.0
1.65
0.46
0.71
8.17
1
9.8
1.63
0.42
0.70
8.40
4
1.37
0.25
0.56
8.67
24
11.6
8.70
70
1.06
0.28
0.68
11.2
*Note:
the solubility of carvedilol is given in micrograms per milliliter.
The data from Table 1 demonstrates that the methanesulfonate salt of carvedilol exhibits an aqueous solubility in excess of 8 mg/ml, while the hydrochloride, adipate and tartrate salt forms are poorly soluble in water. Thus, the methanesulfonate salt of carvedilol provides for the development of bioenhanced dosage forms and patient-compliant injectible dosage forms.
Carvedilol methanesulfonate salt form can be formulated in accordance with the present invention in an injectible form, an oral solid dosage form (as an immediate release or modified release [i.e. controlled release, delayed release or pulsatile release] capsule or tablet) or as a transdermal patch, in particular, in pharmaceutical compositions for the treatment of congestive heart failure, hypertension and angina.
By controlled release is meant any formulation that achieves slow release of drug over an extended period of time. In the controlled release formulations of the instant invention, a portion of the carvedilol methanesulfonate in the formulation is made available as a priming dose and the remainder is released in a sustained fashion. Examples of controlled release systems are a matrix tablet or bead formulation, and a barrier film coated tablet or bead/pellet formulation.
By delayed release is meant any formulation wherein the release of the drug is delayed for certain time or minimum under acidic conditions but rapid above a certain pH depending on the polymer used for the barrier film coat. Examples of delayed release systems include timed-release tablets and capsules and enteric-coated tablets and beads.
By pulsatile release is meant any multi-unit tablet or capsule formulation where in individual mini-tablets or particulates/pellets/beads are polymer barrier film coated, that utilizes intermittent pulsatile dosings of carvedilol methanesulfonate from one or more units as a function of time.
Such modified release formulations are preferably formulated in a manner such that release of carvedilol methanesulfonate is affected predominantly during the passage through the stomach and the small intestine to the colon.
Examples of controlled release, pulsatile release and delayed release formulations which are suitable for incorporating carvedilol methanesulfonate are described in:
Sustained Release Medications, Chemical Technology, Review No. 177, Ed. J. C. Johnson, Noyes Data Corporation (1980);
Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition, Eds. J. R. Robinson, V. H. L. Lee, Mercel Dekkes Inc., New York (1987);
Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack Publishing Company (1980); and
Solubility Considerations and Design of Controlled Release Dosage Forms, by G. M. Venkatesh, Polymer Preprint, Volume 40, pp 322, 1999 (American Chemical Society).
The process for preparing the solid dosage forms in accordance with the present invention may be carried out using a combination of a planetary mixture, a V-blender, a high shear granulator, a fluid bed granulator, a slugging press, a roller compactor, a cummunuting mill, sieving equipment, or a tableting machine. Optionally, the granulation of the hydrated or anhydrous form of carvedilol methanesulfonate, produced using a conventional
Franchini Miriam
Venkatesh Gopadi M.
Kinzig Charles M.
McCarthy Mary E.
Powers Fiona T.
SmithKline Beecham Corporation
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