HORSHAM, Penn--Sparta Pharmaceuticals, Inc. has completed a phase I clinical trial of Spartaject busulfan, an injectable form of busulfan, an agent that is poorly water soluble and currently available only in tablet form.

The Spartaject technology accommodates poorly water soluble and water insoluble compounds by encapsulating fine particles of the drug with a phospholipid layer, thereby permitting the creation of a suspension of the drug, rather than a solution, and avoiding the use of potentially toxic solubilizing agents (see figure).

The phase I trial of Spartaject busulfan was conducted at Johns Hopkins Oncol-ogy Center and Duke University. Louise Grochow, MD, of Johns Hopkins, led the study, and, together with Lori Hollis, PharmD, presented interim data from the trial at the American Association for Cancer Research 1998 meeting.

Patients in the study received oral and intravenous busulfan for myeloablation prior to bone marrow transplantation for the treatment of various types of cancer. Safety and bioavailability at low and high doses were assessed. Results showed that busulfan blood levels were less variable after IV busulfan than after oral busulfan.

The variability seen after oral dosing may contribute to toxicity or problems with bone marrow engraftment, the researchers said. Furthermore, oral dosing requires patients to take as many as 100 tablets a day for 4 days.

In her presentation, Dr. Grochow said that "parenteral administration of busulfan may permit more consistent drug exposure, simplify drug administration and therapeutic monitoring, and further reduce the incidence of venoocclusive disease."

In an interview, Martin Rose, MD, JD, Sparta’s vice president for clinical and regulatory affairs, said that the FDA has accepted the company’s plans to begin pivotal phase II/III clinical trials of Spartaject busulfan as preparative therapy for adult cancer patients treated with bone marrow transplantation. The agent has also received orphan drug designation for that indication.

Two other phase I trials of the agent are in progress, Dr. Rose said. At Duke University Medical Center, in a study led by Henry Friedman, MD, Spartaject busulfan is being injected intrathecally for the treatment of neoplastic meningitis in adults and children. At St. Jude Children’s Research Hospital, Spartaject busulfan will be given to pediatric patients being prepared for bone marrow transplantation. Principal investigator for this study is John Rodman, PharmD.

Dr. Rose also noted that Sparta has licensed its Spartaject drug delivery technology to Schering-Plough for use with the company’s anticancer agent Temodal (temozolomide). Schering-Plough submitted a new drug application (NDA) to the FDA in August 1998 for the use of orally administered Temodal to treat recurrent malignant gliomas.

In the interview, Dr. Rose pointed out a number of differences between Sparta-ject technology and liposomal techniques for creating injectable agents. He said that the Spartaject technology can be applied to agents that are completely water insoluble, whereas liposomes are used primarily for drugs that are at least slightly water soluble.

The drug:lipid ratio with Spartaject is approximately 1:1, compared with approximately 1:20 with some liposomes, "a lot more lipid and a lot less drug than with Spartaject," he said. "Our particle size is in the 2 to 5 micron range, less than the size of a red blood cell," he added, "and our particles are distributed evenly in the circulation, whereas liposomes are taken up preferentially by certain tissues such as the liver, spleen, and reticuloendothelial system."

He noted that Spartaject busulfan is a stable product with a shelf-life of at least 1 year, and that reconstitution of the drug is a simple process. "You just add water for injection and shake it up," he said, "whereas with liposomes it can be more complicated."

Dr. Rose said that, in addition to allowing IV delivery of existing oral drugs, the technology can potentially be used to improve existing injectable drugs by reducing formulation toxicities, and permit the renewed development of anti-cancer and antiviral agents whose development may have been halted because of formulation difficulties attributable to poor solubility.