(a) Field of the Invention
This invention relates to a novel therapeutic dosage form of etodolac which provides drug plasma levels over a twenty-four hour period. More particularly, the sustained release dosage form is a tablet comprising as essential ingredients etodolac, hydroxypropylmethylcellulose, ethylcellulose and a release rate modifying agent such as dibasic sodium phosphate.
(b) Prior Art
The active agent of this invention, 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b] indole-1-acetic acid or a therapeutically acceptable salt thereof, is disclosed in U.S. Pat. No. 3,939,178. This active agent, hereinafter designated by its generic name, etodolac, has been reported to have analgesic and anti-inflammatory properties. It has been further reported to be active in the treatment of adjuvant arthirtis, a model of inflammatory arthritis sensitive to treatment with nonsteroidal anti-inflammatory drugs, in U.S. Pat. No. 4,533,551.
Hydroxypropylmethylcellulose alone and in combination with ethylcellulose has been proposed as an ingredient in a sustained release formulation for twenty-four hour administration or therapeutic agents. See U.S. Pat. No. 4,369,172, issued Jan. 18, 1983 which describes dosage forms as a carrier base material a particular hydroxypropylmethylcellulose, i.e. having a hydroxypropoxyl content of 9-12 weight percent, a methoxyl content of 27-30 weight percent and a number average molecular weight of less than 50,000 with up to 30% by weight of the mixture of ethylcellulose. The patent describes comparative dissolution tests run with tablets made with this carrier base material and with a carrier base material made with a hydroxypropylmethylcellulose having a hydroxypropoxyl content of 8% by weight. The dissolution tests shown in Examples 1-4 of the patent indicate that the tablets made from the 8% hydroxypropxyl content material dissolve faster and release drug more rapidly than tablets made from 10.3% hydroxypropoxyl material.
Another patent, U.S. Pat. No. 4,389,393, describes controlled release dosage forms having as a carrier base material a hydroxypropylmethylcellulose having a hydroxypropoxyl content of 4-32 weight percent, a methoxyl content of 16-24 weight percent and a number average molecular weight of at least 50,000 with up to 30% by weight of the mixture of ethyl cellulose.
U.S. Pat. No. 3,954,959 issued May 4, 1976 describes dosage forms in which the medicine is admixed with a buffer, shaped into small particles and subsequently coated with a film forming material such as ethylcellulose for diffusion of gastrointestinal juices.
Sustained action medications effective for 24 hours or once-a-day dosage present formulation problems because of the relatively short period of time they are present in the gastro-intestinal tract prior to elimination. This is especially true for medications with short half-lives (i.e. less than 6 hours) that normally would be administered in divided doses two or more times a day. The window period for medication release into the patient's system and hence into the blood stream varies from patient to patient but normally averages 10 to 12 hours. Thus after the window period of about 10-12 hours during which the drug enters the bloodstream, half of that present is metabolized every half-life and hence concentration of the drug in the blood tapers off after about 16-18 hours. Additional formulation problems are presented when the medication is one having a relatively short elimination half-life and whose solubility shows a great degree of pH dependency. Etodolac is a medicine with a half-life of about eight hours and an aqueous solubility which is very low and pH independent below pH 3. The solubility then gradually increases with rising pH up to 5 and linearly increases with increasing pH to 7. A thirty fold difference in solubility between pH 5 to 7 has been observed.
USPTO Backgrounds
USPTO Backgrounds