Atorvastatin was one of NanoCelle’s greatest challenges due to the calcium salt. To improve Atorvastatin dosing with NanoCelle®, we had to cleave off the calcium salt.

Background

Atorvastatin is selected because of its chemical structure. Atorvastatin (as calcium) belongs to the class of medicines known as “statins”, more specifically called HMG-CoA reductase inhibitors. HMG-CoA reductase is an enzyme involved in regulating cholesterol levels in your body. Statins are used along with changes to exercise and diet to help control the amount of cholesterol produced by the body. A standard 20 mg atorvastatin oral tablet contains more the 80% of excipients; only 14% is the active ingredient. The poor water solubility of Atorvastatin calcium and the intrinsic drawbacks of oral route administration make the bioavailability of atorvastatin only 12%.

Studies - ethics approved and published

A series of human studies were undertaken to produce a NanoCelle® Atorvastatin that had improved bioavailability and bypassed first-pass metabolism. In all cases, a comparator being 20mg oral Atorvastatin branded as Lipitor was used.

Earlier studies utilised a 1mg/0.3mL NanoCelle® Atorvastatin and provided mixed results.

Later studies utilised a single-dose, open-label, balanced,  two-treatment, two-period, two-sequence, two-way crossover format.

The Results

Studies confirmed that calcium-bound salt was not ideal for enhanced delivery. By removing the calcium salt, we were able to increase the compound’s pH to 6.4

Later human studies showed significant improvement with dosing of the NanoCelle® Atorvastatin at 1mg/0.15mL (or 2mg/0.3mL) calcium-free and with a pH of 6.2 in the finished formulation. With bloods collected at baseline, 15 min, 30 min, and 45 min, peak plasma levels were demonstrated at the 30 min mark.

Final work demonstrated product optimisation of the NanoCelle® Atorvastatin at 2mg/0.15mL (or 4mg/0.3mL) with pH at 6.2, again showing peak concentration at 30 minutes, and elimination just under 9 hours.