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Opioid formulationsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical FormOpioid formulations description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070014820, Opioid formulations. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The invention relates to high-concentration formulations of opioids to alleviate pain. BACKGROUND OF THE INVENTION [0002] 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. [0003] 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. [0004] 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. [0005] 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. [0006] 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. [0007] 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 .mu.g/mL; morphine at 1 mg/mL; morphine sulfate at 20 mg/mL; fentanyl citrate at 20 .mu.g/ml and alfentanil at 500 .mu.g/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. [0008] 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. SUMMARY OF THE INVENTION [0009] The present invention provides opioid formulations suitable for long-term delivery to a subject. The formulation of the invention comprises fentanyl or a fentanyl congener, and a solvent in which the fentanyl or fentanyl congener can be provided in concentrations significantly in excess of conventional formulations, e.g., on the order about 2-fold to about 10,000-fold greater than conventional formulations, e.g., currently commercially available formulations. In the present invention, concentrated opioid formulations useful for parenteral delivery are created by solubilizing in non-aqueous solutions extremely potent opioid compounds, e.g., fentanyl and its congeners, which are hundreds to thousands of times more potent than morphine. The formulations of the invention are especially useful for high-dose delivery, or long-term delivery, e.g., several hours, weeks, months, or even years. Long-term delivery can be achieved using various external or implanted devices. [0010] The invention further provides a sustained release dosage form comprising a formulation of the invention. The dosage form can be an external, partially implanted, or implanted device (e.g., biodegradable implants or pumps), which can be based on, for example, drug diffusion systems, electrochemical systems, electromechanical systems, osmotic pumps, electrodiffusion systems, electroosmosis systems, vapor pressure pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps, erosion-based systems, diffusive systems and the like. [0011] The invention further provides methods of treating pain in a subject, comprising delivering from a drug delivery device a fentanyl or fentanyl congener formulation of the invention to a site in the body of the subject. Delivery of the formulation is generally continuous, and can be for a pre-selected administration period ranging from several hours, one to several weeks, one to several months, up to one or more years. [0012] Pain amenable to alleviation includes all types of acute or chronic pain, e.g., cancer pain, chronic inflammatory disease pain, neuropathic pain, post-operative pain, iatrogenic pain, complex regional pain syndrome, failed-back pain, soft tissue pain, joint pain, bone pain, central pain, injury pain, arthritic pain, hereditary disease, infectious disease, headache, causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, and denervation. [0013] A primary advantage of the present invention is that very potent and concentrated opioid formulations can be achieved by solubilizing very potent opioids in a small volume of solvent. This makes it possible to provide therapeutic amounts of drug to a subject in the case where the delivery device is relatively small (e.g., an implantable system), where delivery is required for a relatively long duration, or where high effective doses of drug are required to achieve the desired therapeutic effect. [0014] Thus, it is possible to deliver a consistent amount of drug over an extended period of time without the need to refill or replace the delivery device, thereby reducing risk of infection and tissue damage, increasing patient compliance, and achieving consistent, accurate dosing. [0015] A primary advantage of the formulations of the invention is that high concentrations of fentanyl or fentanyl congener are achieved without substantial precipitation of the drug. [0016] Another important advantage of the formulations of the present invention is that therapeutic amounts of drug (even high doses) can be delivered to internal tissues of the body at a low volume rate. For certain body tissues, e.g., subcutaneous space, low volume delivery can make the delivered formulation more amenable to absorption by the local tissue, and further minimizes local tissue disturbance, trauma, or edema. [0017] A further advantage of the formulations of the invention is that precipitation of the fentanyl/fentanyl congener does not occur when the formulation comes into contact with aqueous environment, such as body fluids. Precipitation of drug is clearly undesirable, since it could lead to local toxic effects, or clogging of the delivery orifice or elsewhere along the delivery route, resulting in uncontrolled delivery or complete stoppage of delivery, which would adversely affect consistency and accuracy of dosing and therefore patient safety. The formulations of the invention avoid these potential problems. [0018] These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below. DETAILED DESCRIPTION OF THE INVENTION [0019] Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. [0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. Continue reading about Opioid formulations... Full patent description for Opioid formulations Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Opioid formulations patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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