Casein hydrolysate as a rapid and/or enteric dissolving additive for oral drugs.
Two types of casein hydrolysates, casein A (mean peptide length 3.3) and casein B (mean peptide length 17.4) were prepared by the enzymatic hydrolysis of casein, and their effects on in vitro dissolution rates and oral bioavailability of drugs were evaluated. The in vitro dissolution behavior of the kneaded mixture of three drugs (diclofenac acid, diazepam, and prednisolone) with caseins A and B were significantly improved compared to the drugs alone, even at 1:1 weight ratio of drug and casein hydrolysate, even though casein A and casein B did not interact with drug molecules in the kneaded mixture. Only diclofenac, an acidic drug, showed an increased dissolution rate with added casein hydrolysates, and a more rapid dissolution with casein A than with casein B was observed. When the dissolution of prednisolone from kneaded mixture was compared at pH 1.2 and 6.8, the dissolution rate of prednisolone from the casein A kneaded mixture was considerably higher than that of prednisolone powder at both pHs, and the rate from the casein B kneaded mixture was higher only at pH 6.8. The plasma concentration-time profile showed that prednisolone was completely and rapidly absorbed from the casein A kneaded mixture as well as the prednisolone solution. In addition, prednisolone in the kneaded mixture with casein B was more difficult to absorb up to 1 hr after administration in comparison to prednisolone powder. The slow and lowered absorption of prednisolone by casein B might be explained by conversion of casein B to a shorter soluble peptide in the gastrointestinal tract and by the slow dissolution of prednisolone at acidic conditions. The toxicological tests revealed that casein hydrolysate is a safe drug carrier. Consequently, casein hydrolysates might be safely used to control the dissolution rate and bioavailability of a variety of drugs, depending on the peptide length of the casein fragments.
Imai
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Nishiyama
T
T
Shameem
M
M
Otagiri
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D001835:Body Weight / Q000187:drug effects; D002364:Caseins / Q000737:chemistry*; D004285:Dogs; D005079:Excipients / Q000737:chemistry* / Q000633:toxicity; D005260:Female; D007408:Intestinal Absorption; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011492:Protein Hydrolysates / Q000737:chemistry* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
D000893:Anti-Inflammatory Agents; D002364:Caseins; D005079:Excipients; D011492:Protein Hydrolysates; D011239:Prednisolone