Title:  Pain management with liposome-encapsulated analgesic drugs

United States Patent:  RE38,407

Issued:  January 27, 2004

Inventors:  Mezel; Michael (Nova Scotia, CA); Hung; Orlando (Nova Scotia, CA)

Assignee:  Delex Therapeutics Inc. (Mississauga, CA)

Appl. No.:  880054

Filed:  June 14, 2001

Abstract

Liposome-encapsulated opioid analgesic agents delivered by the pulmonary route provide local, or systemic analgesia superior to that produced by the solution form of these agents administered by parentral (intravenous, intramuscular, or subcutaneous injection) or oral routes.

DESCRIPTION OF THE INVENTION

The present invention broadly relates to the use of liposome encapsulation to improve the analgesic effects of opioid analgesic agents administered to an individual via the pulmonary system. A major advantage of this invention is the obtainment of a sustained analgesic effect using a noninvasive method of drug delivery. Because of the noninvasive nature of this drug delivery system, it is particularly suitable for certain patient populations, such as small children where other delivery systems are problematic. The present invention may be used to provide systemic analgesic treatment both for human and veterinary purposes. Analgesic agents, such as opioids, are good candidates for liposome encapsulation.

The amount of the opioid analgesic agent or drug to be included in the liposomal preparation is not, per se, critical and can vary within wide limits depending inter alia on the particular agent, the intended application and the lipid used. Generally, the opioid analgesic agent may be included in an amount of between about 0.005 to 10% by wt. of the liposomal preparation and more usually may be included in an amount of between 0.01 and 0.1% by wt.

Inhaled liposome-encapsulated opioid analgesic agents are expected to have less variability than other routes of drug delivery (e.g. transdermal administered fentanyl), will not require a functioning bowel, can provide rapid onset of analgesic action suitable for acute pain management, and will be inexpensive to manufacture. In other words, inhalation of liposome-encapsulated opioid analgesic agents offers the following benefits as a method of analgesic drug administration: (1) a simple and noninvasive route of administration; (2) a rapid onset of analgesia from absorption of free opioid (in the range of 10-20% of the opioid dose); (3) a sustained analgesia from continued release of liposome-encapsulated opioid (approximately 80-90% of the opioid dose) and (4) a low cost. Thus, inhaled liposome-encapsulated fentanyl may provide a significant advance in our therapeutic armamentarium against acute and chronic pain, at lower cost than currently available therapies.

The sustained release property of the liposomal product can be regulated by the nature of the lipid membrane and by the inclusion of other excipients in the composition of the liposomal products. Decades of research in liposome technology permits a reasonable prediction on the rate of drug release based on the composition of the liposome formulation. The rate of drag release is primarily dependent on the nature of the phospholipids, e.g. hydrogenated (--H) or unhydrogenated (--G), or the phospholipid/cholesterol ratio (the higher this ratio, the faster the rate of release), the hydrophilic/lipophilic properties of the active ingredients and by the method of liposome manufacturing.

Materials and procedures for forming liposomes are well-known to those skilled in the art and need not be described herein in detail. Reference is made to U.S. Pat. Nos. 4,485,054, 4,761,288 and 4,937,078, the disclosures of which are hereby incorporated by reference, for the disclosure of suitable liposome preparation techniques. As described therein, the liposomes can be prepared as multilamellar lipid vesicles (MLV), unilamellar lipid vesicles, including small unilamellar vesicles (SUV) and large unilamellar vesicles (LUC) and as multivesicular liposomes. Many other liposome manufacturing techniques also can be used to make the final liposomal product containing the appropriate active ingredient, lipids, and other excipients as will be understood by those skilled in the art. For example, suitable liposomes also can be prepared using the known ethanol or ether injection methods. Suitable active ingredients are opioid analgesic agents including such opioid agents as alfentanil, anileridine, codiene, diamorphine, fentanyl, hydrocodone, hydromorphone, meperidine (pethidine), morphine, oxycodone, oxymorphone, propoxyphene and sufentanil and the opioid agonists and antagonists pentazocine and nalbuphine. Lipid components are usually phospholipids and cholesterol; excipients are tocopherol, antioxidants, viscosity inducing agents, and/or preservatives.

Phospholipids are particularly useful, such as those selected from the group consisting of phosphatidylchloines, lysophosphatidylchloines, phosphatidylserines, phosphatidylethanolamines, and phosphatidylinositols. As noted, such phospholipids often are modified using for example, a modifying agent selected from the group consisting of cholesterols, stearylamines, stearic acid, and tocopherols. The lipid typically is dissolved in a solvent and the solvent then is evaporated, typically under a reduced pressure, to yield a thin lipid film containing any lipophilic analgesic agent. Afterwards, the film is hydrated, with agitation, using an aqueous phase containing any desired electrolytes and any hydrophilic analgesic agent, and lipid vesicles entrapping the analgesic agent are produced. As recognized by those skilled in the art, while certain materials and procedures may give better results with certain drugs, the use of particular materials and procedures are not narrowly critical and optimum conditions can be determined using routine testing. Additionally, as also noted, a preservative or antioxidant often will be added to the preparation.

In summary, the pharmacokinetic profiles of this new noninvasive method of opioid delivery indicate that pulmonary administration of the liposome-encapsulated opioid analgesic agents offers significant advantages over the conventional parenteral opioid administration as a method of analgesic drug administration with rapid onset and sustained analgesic effect.

The liposome-encapsulated opioid analgesic agents normally are administered to a human patient in an amount to provide an accepted and necessary level of therapeutic postoperative analgesic plasma concentration, commonly agreed to be in the range of 0.2 to 1.2 ng/ml. As will be recognized by those skilled in the art, the required amount of encapsulated opioid in a single dose will depend on a variety of factors including inter alia body weight, lung capacity, lung function and the like. Inhalation of between about 1000 .mu.g to 4000 .mu.g per dose will be suitable in many cases. Of course, within the broad practice of the present invention the dose amount can be varied as needed to obtain any desired effect.

In accordance with the present invention, the liposome-encapsulated opioid analgesic agents can be delivered by direct inhalation of an aerosol using any of the variety of known methods for delivering drugs through the pulmonary system.

The bioavailability or the amount of drug delivered to the lungs can be improved with the use of a large initial volume of solution placed in the nebulizer, a higher compressed gas flow rate (12 I.min^-1) to produce a higher percentage of small droplets (1-5.mu.), deep inhalation with breath holding, and the use of positive expiratory pressure (Resistex .TM., D. C. Lung Co. Inc., Sebastopol, Calif., U.S.A.) during the aerosol therapy (Newman S. P.: Chest 88(2):152s-160s, 1985 and Anderson J. B., et al: Eur J Resp Dis 63(suppl) 119:97-100, 1982).

The following examples are illustrated of the present invention, and are not to be regarded as limiting. In the following examples, representative active ingredients: fentanyl, alfentanil, sufentanil and morphine were encapsulated into uni- and multi-lamellar liposomes using a procedure described by Mesei M., et al: U.S. Pat. No. 4,485,054. Briefly, the phospholipids, cholesterol and lipophilic opioid analgesic agents (and other lipid soluble agents, if present in the formula) were dissolved in chloroform/methanol mixture in a pear shape flask containing glass beads. The solvent was then evaporated to dryness in a rotary evaporator under reduced pressure at 30^oC. until a smooth, thin lipid film was obtained on the surface of the flask and glass beads. The film was then hydrated with a sterile aqueous solution containing any water soluble (hydrophilic) opioid analgesic agents (this would include most salt forms of the analgesic compounds), at the transition temperature of the phospholipid, by shaking 30 minutes in a Lab Line Orbit Environment-Shaker. The sterile water may contain some electrolytes, e.g., sodium chloride, sodium bicarbonate, and/or calcium chloride in an amount that renders the final product isotonic and yields a pH near 7.4. In the following examples, the ethanol was generally added to the aqueous phase before forming the liposomes or to the finished liposomal product. The liposomes were then separated from the glass beads by filtering through a Buchner funnel without filter paper. In some cases, where a low solubility of the active ingredient limited higher drug concentration in the final liposomal product, or where it is desired to increase the level of opioid analgesic agent initially absorbed as free opioid, the multiphase liposomal drug delivery system described and claimed in Mezei in U.S. Pat. No. 4,761,288; can be utilized to advantage. Both the base and salt forms of the active ingredient have been used for preparing the liposomal-encapsulated product.

OPIOID FORMULAS FOR INHALATION

Claim 1 of 25 Claims

We claim:

1. A method of managing pain in a patient comprising administering to said patient a composition containing a liposome-encapsulated opioid analgesic agent through said patient's pulmonary system.

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