Opiates in various forms, including opium, heroine and morphine which derive from the opium poppy, have very powerful analgesic properties and have seen widespread use for anesthesia as well the treatment of pain, especially where the pain is very severe. In addition to these natural opiates, many synthetic opioids have since been synthesized including fentanyl and congeners of fentanyl such as sufentanil, alfentanil, lofentanil, carfentanil, remifentanil, etc., which are many times more potent than morphine.
At present, the dosage form with the most widespread use is still morphine administered orally, although opioids can also be delivered by intravenous infusion (see, e.g., Scholz et al. 1996 Clin. Pharmacokinet. 31:275–92; White 1989 Anesth. Analg. 68:161–71), oral administration, (see, e.g., U.S. Pat. Nos. 4,769,372; 5,202,128; and 5,378,474), epidural or intrathecal administration (see, e.g., Vercauteren et al. 1998 Anaesthesia 53:1022–7; Stephens 1997 Am. Fam. Physician 56:463–70), transdermal application (e.g., using a transdermal patch (see, e.g., U.S. Pat. No. 4,588,580)), or subcutaneous injection (see, e.g., Paix et al. 1995 Pain 63:263–9; Bruera et al. 1988 Cancer 62:407–11; Moulin et al. 1992 Can. Med. Assoc. J. 146:891–7). For a review, see, e.g., Clotz et al. 1991 Clin. Pharm. 10:581–93; and Anderson et al. 1998 J. Pharm. Care Pain Symptom Control 6:5–21.
Unfortunately, oral administration of morphine meets with several disadvantages. Many extremely ill patients can no longer take drugs orally for a variety of reasons, such as the inability to swallow or gastrointestinal obstruction. Furthermore, long-term oral administration often necessitates the ingestion of multiple pills or tablets many times a day, a dosing scheme commonly associated with poor compliance. For these and other reasons, parenteral administration of opioids can be a preferred alternative to oral administration.
However, parenteral administration of opioids meets with several challenges. Many patients, especially those with chronic-pain or diseases, require long-term treatment with opioids, e.g., for days, months, years and sometimes for the lifetime of the patient, and therefore require large quantities of drug to be administered over time. Also, many patients with severe pain require high doses of opioids to control pain, oftentimes with escalating requirements due to progression of the underlying disease state or development of tolerance to the opioid. Furthermore, in order to provide convenient, long-term or high-dosage pain treatment, opioids may need to be infused continuously and for long duration, usually by means of an infusion pump which can be an implantable or external pump. In order to provide acceptable convenience and mobility to patients, infusion pumps must be limited in size which in turn limits the volume of drug formulation that can be contained within. When opioids are administered for long durations using conventional formulations of opioids, the limited size of the drug reservoir of the pumps requires such pumps to be frequently refilled or exchanged which, besides being inconvenient, also requires the attention of a skilled health care worker and exposes the patient to possible infection.
Besides limitations imposed by pump size, the absorption capacity of the tissue into which the drug formulation is infused can limit the amount of volume of drug formulation that can be absorbed. For example, the absorptive capacity of the subcutaneous tissue is generally a maximum of 10 ml per hour (see e.g., Anderson et al., supra). Furthermore, infusions of large amounts of fluid into certain tissue can cause tissue edema which causes discomfort to the patient.
Currently available opioid formulations are too dilute to meet the needs of patients requiring long term treatment or large drug doses to control pain. For example, sufentanil citrate is currently available in an aqueous solution at a concentration of 50 μg/mL; morphine at 1 mg/mL; morphine sulfate at 20 mg/mL; fentanyl citrate at 20 μg/ml and alfentanil at 500 μg/mL. Simply adding more drug to conventional aqueous formulations is not a viable solution to creating more concentrated formulations as the opioid compound, especially those which are lipophilic such as fentanyl and its congeners, may precipitate out of solution which leads to, for example inconsistent delivery rates, reduced drug absorption, reduced tissue response and clogging of the drug delivery device or other points along the infusion pathway.
For the foregoing discussion, it is evident that there is a need in the art for more concentrated opioid formulations that permit convenient long-term or high dose delivery yet is stable over time and safe for parenteral use. The present invention addresses this need, and provides related advantages as well.