1. Field of the Invention
This invention relates to a sustained release systemic fluoride drug product for treatment or prevention of osteoporosis or other bone disease. More particularly, this invention relates to the use of sodium monofluorophosphate, alone or in combination with another fluorine compound, together with an estrogen-containing substance and, if desired, a calcium containing substance, in a sustained release solid unit dosage form, suitable for use in the treatment and prevention of osteoporosis, alveolar bone loss or other bone diseases where systemic fluoride ion is efficacious and further treating hormonal imbalance and enhancing utilization of the fluoride ion by introduction of estrogen.
2. Description of the Prior Art
Fluoride stimulates the activity of bone-forming cells and, together with calcium and phosphate, the two major mineral components of bone is also stored in the bone structure. Fluoride seems to directly stimulate the proliferation of osteoblasts resulting in an increase in bone formation.
U.S. Pat. No. 3,287,219 discloses the oral administration of sodium fluoride to promote bone healing.
The role of fluoride in strengthening the teeth and in imparting acid resistance and preventing caries in dental treatment is well documented. The use of sodium fluoride tablets and liquids for infants and young children in areas where the drinking water is not or is only insufficiently fluoridated is well known. For this purpose, fluoride ion from NaF is administered in dosages of about 0.25 to about 1 mg per day. Representative patents in this area include U.S. Pat. Nos. 3,306,824, 4,265,877 and 4,397,837 (toothpaste). The use of sodium monofluorophosphate (MFP) in dental products, particularly toothpaste products, as an anticaries fluoride additive is also well known and is mentioned in U.S. Pat. No. 4,397,837, cited above. The MFP is slowly metabolized by an intestinal enzyme, MFPase or alkaline phosphatase into free fluoride ion which, in turn, is absorbed into the blood stream, some of the MFP being directly absorbed in the liver and converted therein to F ion.
More recently, the use of NaF or MFP for the treatment of bone disease to promote bone formation and strengthen bone has received wide attention. In fact, although not yet approved for use in the United States, both NaF and MFP products for the treatment and prevention of osteoporosis are available in Europe. Thus, Flurexal.RTM. is an enteric coated tablet containing 22 mg sodium fluoride (10 mgF) sold by Zyma SA Nyon Suisse; Tridin.RTM. is a chewable tablet containing 38 mg sodium monofluorophosphate (5 mg F), 500 mg calcium gluconate monohydrate, 500 mg calcium citrate tetrahydrate, 200 mg carboxymethyl cellulose, available from Opfermann Arzneimittel GmbH.
According to the directions for use provided with the medications, Flurexal.RTM. should be taken three times each day, while Tridin.RTM. should be taken one to two tablets three times a day for treatment or one tablet three times a day for prevention of steriod-osteoporosis. In general, the typical recommended dosage for F ion is in the order of from about 20 to 50 mg per day for a human adult.
The literature provided with Tridin.RTM. states that gastric and intestinal irritation is seldom observed. To the same effect, Yngve Ericsson, "Monofluorophosphate Physiology: General Considerations," Caries Res. 17 (Suppl. 1), pages 46-55 (1983), reported that "neither in patients nor in numerous experiments with laboratory workers has any subjective discomfort been recorded with doses up to 30 mg F as MFP." However, as discussed in U.S. Pat. Nos. 4,859,467 and 4,861,590 to Baylink and Grodberg, gastric and intestinal distress is in fact a significant occurrence.
Attempts to solve the adverse side effects of gastrointestinal (GI) tract symptoms by minimizing the availability of F ion in the stomach by providing NaF in a sustained release form have only been partially effective in avoiding GI irritation. More particularly, it has been observed that, while slow release sodium fluoride is well tolerated by approximately 70% of patients, there is adverse gastrointestinal effects in the other approximate 30% of patients.