United States Patent:  5,972,366

Assignee:  The Unites States of America as represented by the Secretary of the Army (Washington, DC)

Filed:  September 17, 1996

A surgical implant or external wound dressing which functions as both a hemostat and a device to safely and effectively deliver any of a number of pharmaceuticals to targeted tissue at a controlled rate is disclosed. The device generally comprises a carrier in the form of fibers, sutures, fabrics, cross-linked solid foams or bandages, a pharmaceutical in solid micoparticulate form releasably bound to the carrier fibers, and a lipid adjuvant which aids the binding of the microparticles to the fibers as well as their function in the body.

SUMMARY AND OBJECTS OF THE INVENTION

In view of the foregoing limitations and shortcomings of the prior art methods, materials, and compositions, as well as other disadvantages not specifically mentioned above, it should be apparent that there exists a need in the art for a surgical implant and external wound dressing which can safely and effectively deliver any of a number of pharmaceuticals (or drugs) to targeted tissue at a controlled rate, while maintaining its hemostatic function. It is, therefore, a primary object of this invention to fulfill that need by providing a surgical implant, sponge, or wound dressing with such drug delivery and hemostatic capability.

More particularly, it is an object of this invention to provide an absorbable carrier which is adapted to take up and controllably release a drug in solid, microparticulate form with the advantage that the drug concentration and release can be controlled.

It is another object of the invention to provide a device of the aforesaid type wherein the drug is water insoluble.

It is another object of the invention to provide a device of the aforesaid type wherein the drug can be prevented from entering tissues or circulatory system, if desired.

It is another object of the invention to provide a device of the aforesaid type wherein the drug particles have a diameter of less than 10 microns so as to diminish the likelihood that the particles will irritate tissue if released or block capillaries if the particles enter the circulation

It is another object of the invention to provide a device of the aforesaid type wherein the drug in microparticulate or microcrystalline form is protected against oxidation and possible reaction with the dressing material.

It is another object of the invention to provide a device of the aforesaid type wherein the carrier is adapted to retain as much as 4 grams of drug per gram of carrier.

It is another object of the invention to provide a device of the aforesaid type wherein the carrier remains flexible rather than brittle.

It is another object of the invention to provide a controlled release drug delivery system for dispensing antiseptics, antibiotics, anti-inflammatories, local anesthetics, tissue growth promoters, or tissue destruction inhibitors to a wound or surgical site, including both soft tissue and bone, for the purpose of providing hemostasis, relief of pain, control of infection, hastened regrowth, decreased inflammation, prevention of keloid formation and hastened recovery.

Briefly described, the aforementioned objects are accomplished according to the invention by providing a wound dressing, sponge, or surgical implant material comprising a carrier material, a pharmaceutical composition in solid microparticlulate or microcrystalline form, and an adjuvant coating to improve the adherence of the pharmaceutical particles to the carrier and to control the rate of release and the concentration of the pharmaceutical to the wound site.

The carrier material of the present invention may be made of any of a variety of materials which are pharmaceutically acceptable (non-toxic and non-allergenic), adhere to or within the target tissue, and incorporate the pharmaceutical composition. Preferably the carrier is fibrous, such as a fabric dressing and suture or a cross-linked solid foam adsorbable implant, wherein the fibers support the drug particles.

The types of pharmaceuticals which may be employed include antiseptics, antibiotics, anti-inflammatories, local anesthetics, analgesics, tissue growth promoters, and tissue destruction inhibitors, for example. The pharmaceutical composition is preferably a crystalline or microparticulate, water-insoluble drug reduced to microscopic dimensions (20 nm-30.mu.) by sonication, microfluidization (Example 1) and other methods of high-shear homogenization such as the Gaulin or Rannie Homogenizers (APV Gaulin/Rannie, St. Paul, Minn.), or other processes. The microcrystals are suspended in an aqueous solution by coating the crystals with an amphipathic, membrane-forming lipid. This lipid also acts as an adjuvant allowing the drug microparticles to attach to the carrier material by non-covalent means. The saturated carrier material preferably comprises microscopically-dimensioned empty space, allowing for hydration, efflux of drug and ingrowth of tissue. Also storage of the drug in microparticulate or microcrystalline form protects it against oxidation and possible reaction with the dressing material.

The invention provides a pliable, implantable, as well as externally-applicable surgical material which contains a drug, at high concentration. Upon application to a surgical site or wound, the material releases the drug to the surrounding tissue at rates and durations chosen for optimal therapeutic effect. Some embodiments of the invention produce a semi-solid material suitable for implantation in bone.

The method of making the present invention generally comprises the steps of selecting a carrier material, such as an implantable absorbable sponge or hemostat, preparing a drug to microparticulate form, coating the particles in an adjuvant, modifying the carrier to improve its cohesive characteristics, and applying the coated drug particles to the carrier, and removing the water by lyophilization.

The implant of the present invention may be used in surgical or dental procedures wherein it is desired to simultaneously control bleeding and deliver a drug to adjacent tissue in a sustained manner. In particular, contemplated uses include implantation of compositions containing drugs and appropriate factors to provide pain relief, to control inflammation, to accelerate tissue or bone regrowth and to control infection.

The present invention provides a means of giving continuous treatment of a wound or surgical site with a drug. When used with a resorbable carrier material, our invention provides an implantable sustained delivery device for the drug, achieving local therapeutic benefit while providing hemostasis and a controlled environment for tissue regeneration. It provides a large reservoir of drug at the site where it is needed, but in the form of drug microparticle with controlled association with the carrier matrix material. The present invention is distinctly advantageous over extemporaneous preparations in which macro-particulate drug is "dusted" into wound dressings or surgical materials. Accompanying such practice is the danger that large drug particles may be released to irritate tissue or to enter the circulation where they can block capillaries.

Claim 1 of 10 Claims

1. A drug delivering surgical device for internal or external use comprising:

a carrier comprising a pharmaceutically acceptable porous, fibrous matrix for releasably securing coated drug microparticles therein, said fibers having diameters of between about 0.1 micrometers to about 100 micrometers;

wherein said coated drug microparticles between about 20 nanometers to about 20 micrometers in size, releasably bound to said fibrous matrix by attachment or entrapment therein;

said fibers and said drug microparticles are each coated with a coating agent selected from the group consisting of non-crosslinked collagen and gelatin, carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, povidone, benzalkonium chloride, benzethonium chloride, or long-chain alkylamines.

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