Title:  Biodegradable polymer matrices for sustained delivery of local anesthetic agents

United States Patent:  6,214,387

Assignee:  Children's Medical Center Corporation (Boston, MA)

Filed:  September 17, 1997

Biodegradable controlled release microspheres for the prolonged administration of a local anesthetic agent, and a method for the manufacture thereof are disclosed. The microspheres are formed of a biodegradable polymer degrading significantly within a month, with at least 50% of the polymer degrading into non-toxic residues which are removed by the body within a two week period. Useful polymers include polyanhydrides, polylactic acid-glycolic acid copolymers and polyorthoesters containing a catalyst; polylactic acid-glycolic acid copolymers are preferred. Local anesthetics are incorporated into the polymer using a method that yields a uniform dispersion, preferably solvent casting. Prolonged release is obtained by incorporation of a glucocorticoid into the polymeric matrix or by co-administration of the glucocorticoid with the microspheres. The type of anesthetic and the quantity are selected based on the known pharmaceutical properties of these compounds.

DETAILED DESCRIPTION OF THE INVENTION

Microsphere systems for the controlled and prolonged delivery of a local anesthetic agent to a targeted area are provided. These systems can be used for the management of various forms of persistent pain, such as postoperative pain, sympathetically maintained pain, or certain forms of chronic pain such as the pain associated with many types of cancer.

Polymers

It is important that the polymer degrade in vivo over a period of less than a year, with at least 50% of the polymer degrading within six months or less. More preferably, the polymer will degrade significantly within a month, with at least 50% of the polymer degrading into non-toxic residues which are removed by the body, and 100% of the drug being released within a two week period. Polymers should also degrade by hydrolysis by surface erosion, rather than by bulk erosion, so that release is not only sustained but also linear. Polymers which meet this criteria include some of the polyanhydrides, co-polymers of lactic acid and glycolic acid wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e., 80% or less lactic acid to 20% or more glycolic acid by weight), and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Other polymers include protein polymers such as gelatin and fibrin and polysaccharides such as hyaluronic acid. Polylactic acid is not useful since it takes at least one year to degrade in vivo.

The polymers should be biocompatible. Biocompatibility is enhanced by recrystallization of either the monomers forming the polymer and/or the polymer using standard techniques.

Anesthetics

The systems employ biodegradable polymer matrices which provide controlled release of local anesthetics. As used herein, the term "local anesthetic" means a drug which provides local numbness or pain relief. A number of different local anesthetics can be used, including dibucaine, bupivacaine, etidocaine, tetracaine, lidocaine, and xylocaine. The preferred anesthetic is bupivacaine or dibucaine, most preferably in the form of a salt, for example, the hydrochloride, bromide, acetate, citrate, or sulfate. Compared to the free base form of these drugs, the more hydrophilic hydrochloride salt displays longer and denser nerve block, more complete release from polymer matrices, slower clearance from the targeted nerve area, and less encapsulation. Bupivacaine is a particularly long acting and potent local anesthetic when incorporated into a PLAM. Its other advantages include sufficient sensory anesthesia without significant motor blockage, lower toxicity, and wide availability.

The devices can also be used to administer local anesthetics that produce modality-specific blockade, as reported by Schneider, et al., Anesthesiology, 74:270-281 (1991), or that possess physical-chemical attributes that make them more useful for sustained release then for single injection blockade, as reported by Masters, et al., Soc. Neurosci. Abstr., 18:200 (1992), the teachings of which are incorporated herein.

The anesthetic is incorporated into the polymer in a percent loading of 0.1% to 90% by weight, preferably 5% to 75% by weight. It is possible to tailor a system to deliver a specified loading and subsequent maintenance dose by manipulating the percent drug incorporated in the polymer and the shape of the matrix, in addition to the form of local anesthetic (free base versus salt) and the method of production. The amount of drug released per day increases proportionately with the percentage of drug incorporated into the matrix (for example, from 5 to 10 to 20%). In the preferred embodiment, polymer matrices with about 75% drug incorporated are utilized, although it is possible to incorporate substantially more drug, depending on the drug, the method used for making and loading the device, and the polymer.

Antiinflammatories

Glucocorticoids that are useful to prolong in vivo release include glucocorticocoids such as dexamethasone, cortisone, prednisone, and others routinely administered orally or by injection. Useful loadings are from 0.01 to 30% by weight, preferably between 0.05 and 0.5%. The dosage must be low enough to avoid toxicity.

The examples demonstrate that glucocortocoids such as dexamethasone prolong release in vivo and not in vitro, but do not reduce the intensity of the nerve block generated by the release of anesthetic from the polymer, and do not affect the recovery of sensation and strength. Other compounds do not prolong release.

Methods of Manufacture

The microspheres are preferably manufactured using a method that evenly disperses the anesthetic throughout the device, such as solvent casting, spray drying or hot melt, rather than a method such as compression molding. Microparticles, microspheres, and microcapsules are collectively referred to herein as "microspheres". A desired release profile can be achieved by using a mixture of microspheres formed of polymers having different release rates, for example, polymers releasing in one day, three days, and one week, so that linear release is achieved even when each polymer per se does not release linearly over the same time period.

Methods for manufacture of microspheres are well known and are typified in the following examples. In the preferred embodiment for administration by injection, the microspheres have a diameter of between approximately 10 and 200 microns, more preferably between 20 and 120 microns.

Methods of Administration

In the preferred method of administration, the microspheres are administered by injection at the site where pain relief is to be achieved. The microspheres may be injected through a trochar, or the pellets or slabs may be surgically placed adjacent to nerves.

As described below, the microspheres can be administered alone or in combination with a solution including a steroidal anti-inflammatory or other glucocorticoids in an amount effective to prolong release of anesthetic from the microspheres. Alternatively, the microspheres include an amount of steroidal anti-inflammatory effective to prolong release of anesthetic from the microspheres.

Potential applications include two to five day intercostal blockade for thoracotomy, or longer term intercostal blockade for thoracic post-therapeutic neuralgia, lumbar sympathetic blockade for reflex sympathetic dystrophy, or three-day ilioinguinal/iliohypogastric blockade for hernia repair.

Claim 1 of 32 Claims

What is claimed is:

1. A method for prolonged nerve blockade, local numbness, or pain relief at a site in a patient comprising

administering at the site a multiparticulate unit dose of a local anesthetic selected from the group consisting of bupivacaine, dibucaine, etidocaine, tetracaine, lidocaine, xylocaine and salts thereof incorporated into particles of a biocompatible, biodegradable polymer selected from the group consisting of polymers of lactic acid, glycolic acid, and copolymers thereof, the particles being selected from the group consisting of microparticles, microspheres, and microcapsules, wherein the local anesthetic is included in the unit dose in an amount effective to achieve nerve blockade, local numbness, or pain relief at the site and is incorporated into the particles in a percent loading of between 5 and 90% by weight, and an amount of a glucocorticoid effective to prolong the nerve blockade or pain relief provided by the local anesthetic for a time period greater than that obtained by the use of the local anesthetic incorporated in the polymer in the absence of the glucocorticoid.

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