Publication Date: 2014-Dec-01
The IP.com Prior Art Database
The present invention is related to pharmaceutical compositions and dosage forms of 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione.
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 Thalidomide is represented by formula (I), and is chemically known as 2-(2,6- dioxopiperidin-3-yl-1H-isoindole-1,3(2H)-dione or α-(N-phthalimido) glutarimide (CAS number 50-35-1). It was first described by Chemie Grünenthal GmbH in GB 768821 along with a process for its preparation.
 Thalidomide is an effective treatment for several inflammatory and autoimmune disorders including erythema nodosum leprosum (an inflammatory cutaneous and systemic complication of leprosy), Behcet's syndrome, discoid lupus erythematosus, and Crohn's disease. Thalidomide is believed to exert its anti-inflammatory effects, at least in part, by inhibiting tumor necrosis factor-α (TNF-α) production by monocytes. It also inhibits the growth of new blood vessels (angiogenesis), which also means it is useful in treating macular degeneration and other diseases.
 Most recently, thalidomide has been outlined as selective inhibitor of TNF-α for the treatment of patients with specific types of cancer such as newly diagnosed multiple myeloma (a type of blood cancer in which immature malignant plasma cells accumulate in end eventually destroy the bone marrow), refractory multiple myeloma, brain, melanoma, breast and renal cell carcinoma.
 Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25 °C in dimethylsulfoxide and sparingly soluble in water and ethanol. Preferred pharmaceutical compositions of thalidomide are dosage forms for oral administration, such as capsules, tablets, troches, lozenges, dispersions, granules, a solution or a suspension.
 Thalidomide was approved by FDA in 1998 in the form of size #0 capsule shell containing 12.5 % w/w of this active ingredient. The capsule fill weight was 400 mg, so only 50 mg of thalidomide were included per capsule. As several diseases, such as cancer, require a 200 to 800 mg dosage regime, patients had to ingest 4 to 16 capsules of thalidomide to receive a therapeutically effective amount of the drug, which significantly hindered patient compliance.
 EP1562556 B1 tries to solve this problem by describing single unit dosage forms comprising thalidomide and an excipient, wherein the oral dosage form contains thalidomide in an amount of 35-45% by weight of the oral dosage form and the excipient in an amount of 55-65% by weight of the total oral dosage form, wherein the excipient is a carrier, diluent or filler, and wherein the carrier, diluent or filler is pregelatinized starch.
 Further to this European patent, a preferred dosage form further includes a lubricant or glidant in an amount of from about 0.01% to about 4% by weight, and more preferably in an amount from about 0.1% to about 1%. Table 2 in this document discloses one example of 200
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mg thalidomide capsule formulation, wherein magnesium stearate is apparently used as lubricant or...