Dosage forms for immediate gastric release of a calcium transport stimulator coupled with delayed gastric release of a bis-phosphonate

An oral pharmaceutical dosage form for administration to a patient to treat bone disease comprising a compacted core containing a therapeutic bis-phosphonate embedded in a shell comprising a vitamin D derivative that stimulates transport of calcium from the intestine into the bloodstream, wherein the shell expands upon contact with gastric fluid to promote retention of the dosage form in the patient's stomach for a prolonged period of time, the vitamin D derivative is released from the shell, the bis-phosphonate is released at least about an hour after the vitamin D derivative is released, and the dosage form degrades into particles too small too cause gastric retention.

An oral pharmaceutical dosage form for administration to a patient to treat bone disease comprising a compacted core containing a therapeutic bis-phosphonate embedded in a gastric retention composition that forms a shell around the core, and a coating of a vitamin D derivative that stimulates transport of calcium from the intestine into the bloodstream applied over the shell, wherein upon contact with gastric fluid the vitamin D derivative is released from the coating, the gastric retention composition swells to promote retention of the dosage form in the patient's stomach for a prolonged period of time, the bis-phosphonate is released at least about an hour after the vitamin D derivative is released and the dosage form degrades into particles too small to cause gastric retention.

An oral pharmaceutical dosage form for administration to a patient disease comprising a capsule enclosing:

• a) a first tablet comprising a compacted core containing a therapeutic bis-phosphonate, and
• b) a second tablet containing a vitamin D derivative that stimulates transport of calcium from the intestine into the bloodstream,
• wherein upon contact with gastric fluid, the capsule dissolves, the vitamin D derivative is released from the second tablet, the first tablet expands to promote retention of the dosage form in the patient's stomach, the bis-phosphonate is released from the core at least one hour after the vitamin D derivative is released and the first tablet degrades into particles too small to cause gastric retention.

An improved combination therapy for treatment of bone disease by repeat administration to a patient of a unit dosage form that releases a calcium transport stimulator in an immediate or uncontrolled manner and, after swelling to a size that prevents passage through the pylorus, and after a delay time period to allow the calcium transport stimulator to deplete the upper GI tract of calcium, releases a therapeutic bis-phosphonate in the stomach.

A combination therapy method for treating bone disease in a patient in need of such treatment by a combination drug regimen comprising the steps of:

• administering to such patient a unit pre-dose of a vitamin D derivative and, about 2 to about 6 hours after administration of the pre-dose, administering a unit dose of a bisphosphonate.