Erythromycin and its derivatives are known for their antibacterial activity against a number of organisms. An example of an erythromycin derivative is 6-O-methoxyerythromycin A, better known as clarithromycin.
The erythromycin compositions have been typically administered at least two to three times daily as immediate release compositions. Clarithromycin, for example, has to be administered at least twice daily for optimal effects.
Sustained release formulations, however, are preferred. Well-absorbed oral sustained or slow release therapeutic drug dosage forms have inherent advantages over conventional, immediate release dosage forms. A less frequent dosing of a medicament, as is required by a sustained release dosage form, increases the resultant patient regime compliance, provides a more sustained drug blood level response, and effects therapeutic action with less ingestion of a drug, thereby mitigating many potential side effects. By providing a slow and steady release of a medicament over time, absorbed drug concentration spikes are mitigated or eliminated by effecting a smoother and more sustained blood level response.
Even in a sustained release formulation, the daily dose of the drug is 1000 mg. The daily dose of 1000 mg is presently administered to patients in two tablets. The 500 mg tablet currently marketed is quite large with a tablet weight of about 1000 mg. Thus, there is a need in the marketplace to make a smaller tablet containing 500 mg clarithromycin and/or to make a 1000 mg tablet which is not unacceptably large.
Various sustained release formulations containing clarithromycin have been described. For example, U.S. Pat. No. 5,705,190 to Broad, et al. describes controlled release formulations for sparingly soluble basic drugs, such as erythromycin derivatives, including clarithromycin, comprising the drug in association with a water soluble alginate salt, a complex salt of alginic acid, and an organic carboxylic acid to facilitate dissolution of the drug at higher pH. However, the total tablet weight of each tablet containing 500 mg drug as described in the examples is more than 900 mg, as substantial amounts of polymers are required for controlling the rate of drug release. Thus, a single tablet containing 1,000 mg drug made in accordance with the teachings therein would be at least 1,800 mg. This would be unacceptably large for human consumption.
U.S. Pat. No. 6,010,718 to Al-Razzak, et al. describes an extended release pharmaceutical dosage for erythromycin derivatives, such as clarithromycin using from about 5 to about 50% by weight of a pharmaceutically acceptable polymer, such as a water soluble polymer, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, and derivatives and mixtures thereof. However, the total weight of each tablet containing 500 mg drug, as described in the examples, is close to 1000 mg. Once again a single tablet would be unacceptably large at 2000 mg, thus necessitating the administration of two tablets of 500 mg strength, each for delivering the daily dose of 100 mg clarithromycin.
These prior art formulations require a high concentration of polymer, such as 10-30% by weight to be used to control the release of the drug. Not only is this a large amount of polymer, but also this tends to make the oral dosage form quite large. Additionally, sticking and picking of tablets are common problems with this drug. Moreover, the tableting characteristics of these formulations are quite poor, and additional excipients are added to improve the tableting characteristics.
However, the present inventor has found another method of preparing a sustained release formulation in which sustained release hydrophilic polymers or alginic acid or salts thereof are not required. Moreover, the present inventor has found a means of preparing a sustained release formulation comprising erythromycin derivatives such as clarithromycin, in which the drug is present in at least 75% by weight of the oral dosage form.
More specifically, the present inventor has found that erythromycin derivatives, such as clarithromycin can form a tablet matrix by itself in combination with a lubricant when placed in aqueous medium and can achieve slow release without the aid of controlled release polymers, especially hydrophilic controlled release polymers or alginic acid or salts thereof. The matrix thus formed does not disintegrate, and is quite stable in aqueous solution, and the inventor has found that it releases the drug by erosion. Using the methodology of the present invention, a sustained release formulation in tablet form can be prepared containing a high concentration of an erythromycin derivative, such as clarithromycin. Thus, for example, a tablet with a concentration of an erythromycin derivative, such as clarithromycin as high as 90% by weight or higher can be prepared.