CA2206259A1

CA2206259A1 - Drug releasing surgical implant or dressing material

Info

Publication number: CA2206259A1
Application number: CA002206259A
Authority: CA
Inventors: Duncan H. Haynes; Mark D. Kline; Ben H. Boedeker
Original assignee: Individual
Current assignee: US Department of Army
Priority date: 1994-11-28
Filing date: 1995-11-28
Publication date: 1996-06-06
Also published as: EP0790823A1; DE69531254D1; US5972366A; US5660854A; JPH10511019A; EP0790823B1; AU4364096A; WO1996016643A1; ATE244561T1; KR100382987B1; MX9703912A; DE69531254T2; RU2176525C2; EP0790823A4; DK0790823T3; PT790823E; AU698113B2; ES2202382T3

Abstract

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 microparticulate 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.

Description

CA 022062~9 1997-0~-28 I)RUG l~LEASING SURGICAL IMPLANT Ol~ DRESSING MATERIAL

Field of the Invention The present invention relates to implantable absorbable sponges or 5 externally applied dressing materials, and more particularly to implants or dressing materials having the capability to deliver ph~rm~re~ltir~l~ or the like to the wound or implant site.

Back~rolmd of the Invention In order to improve the effectiveness and functionality of wound dressings and surgical implants, various all~ have been made to incorporate them with a variety of m~lir~m~nt~ such as antibiotics, analgesics, and the like.
Examples of antibacterial wound dressings are disclosed in U.S. Patent No.
4,191,743 to Klemm et al., U.S. Patent No. 2,804,424 to Stirn et al., and U.S.
15 Patent No. 2,809,149 to Cusumano. Similarly, U.S. Patent No. 3,987,797 to Stephenson discloses a suture rendered antimicrobial.
Dressings which attempt to promote wound healing are disclosed in U.S.
Patent No. 5,124,155 to Reich. Most prior art surgical bandages and dressings which incorporate mP~lir~tions are made by soaking the material in an aqueous 20 solution of the medicine. This can render the carrier brittle and inflexible upon drying. Moreover, it is difficult to control the rate of release of the mr-lir~mt-nt, or its effect on peripheral tissues, when it is applied to the carrier dissolved in a liquid state. Also, many important medicines are water insoluble and cannot be applied by this technique. AlL~ alively, the medicament is applied to the dressing or implant 25 as a powder or dust which is quickly released and possesses a danger that large drug particles may irritate tissue or enter the circulatory system where they can block capillaries.
In addition to externally applied dressings, it is also known to impregnate an implantable surgical material with a me~lic~ment. For example, U.S. Patent No.

CA 022062~9 1997-0~-28 5,197,977 to Hoffman Jr. et al. disclose a synthetic vascular graft that is impregnated with collagen and a me~lie~mf~nt Additionally, Boyes-Varley et al. in Int. J. and MaJcillafac.Surg. 1988;
17:138-141, describe the use in an animal study of a the Gelfoam~ brand sponge S with a saline solution of m~(lic~m~nt~. However, the Physicians' Desk Reference, (Medical Economics, Co., Oradell, NJ) 1992 edition warns that "it is not recommended that Gelfoam~ be saturated with an antibiotic solution or dusted with antibiotic powder. " A similar warning is provided with the entry of another popular surgical implant -- the Surgicel~ brand absorbable hemostat -- which states that "the 10 Surgicel~ hemostat should not be impregnated with anti-infective agents. "
It would be desirable to have a method for safely and effectively impregnating externally applied dressings as well as implantable sponges and hemostats, especially the popular Gelfoam~ and Surgicel~ brands. More particularly, it would be desirable to impregnate the dressings or implants with15 me-lir,~ment in neither a solute nor a powder form, but a form which permits the drug concentration and release rate to be controlled.

Summary and Objeets of the Invention In view of the foregoing limitations and shortcomings of the prior art 20 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 asurgical impl~nt and external wound dressing which can safely and effectively deliver any of a number of ph~rm~rellticals (or drugs) to targeted tissue at a controlled rate, while m~int~ining its hemostatic function. It is, therefore, a primary 25 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, miclo~alLiculate form with the advantage that the drug concentration and release can 30 be controlled.

CA 022062~9 1997-0~-28 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 5 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 tlimini~h 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 micropal~iculate 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 15 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-infl~mm~tories, local 20 anesthetics, tissue growth promoters, or tissue destruction inhibitors to a wound or surgical site, including both soft tissue and bone, for the purpose of providinghemostasis, relief of pain, control of infection, hastened regrowth, decreased infl~mm~tion, 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 ph~rm~celltical composition in solid 0 microparticlulate or microcrystalline form, and an adjuvant coating to improve the adherence of the ph~rm~ceutical particles to the carrier and to control the rate of release and the concentration of the pharm~celltic~l to the wound site.

CA 022062~9 1997-0~-28 The carrier material of the present invention may be made of any of a variety of materials which are ph~rm~celltir~lly acceptable (non-toxic and non-allergenic), adhere to or within the target tissue, and incorporate the pharm~re lti~l composition. Preferably the carrier is fibrous, such as a fabric dressing and S suture or a cross-linked solid foam adsorbable implant, wherein the fibers support the drug particles.
The types of ph~rm~re~ltir~l~ which may be employed include antiseptics, antibiotics, anti-infl~mm~tories, local anesthetics, analgesics, tissue growth promoters, and tissue destruction inhibitors, for example. The ph~rm~relltical 10 composition is preferably a crystalline or miclo~~alLiculate, water-insoluble drug reduced ~o microscopic dimensions (20 nm - 30,u) by sonication, microflllitli7~tion (Example 1) and other methods of high-shear homogeni7~tion such as the Gaulin orRannie Homogenizers (APV Gaulin/Rannie, St. Paul, MN), or other processes.
The microcrystals are suspended in an aqueous solution by coating the crystals with 15 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, efffux of drug and ingrowth of tissue. Also storage of the drug in microparticulate or microcrystalline form 20 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 ~ullounding tissue at rates and durations chosen for optimal therapeutic effect.25 Some embotlimP-nt~ 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, CA 022062~9 1997-0~-28 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 simlllt~n~ously control bleeding and deliver a 5 drug to adjacent tissue in a sustained lllamlel. In particular, contemplated uses include implantation of compositions cont~ining drugs and approl)liate factors to provide pain relief, to control infl~mm~tion, to accelerate tissue or bone regrowth and to control infection.
The present invention provides a means of giving continuous treatment of a 10 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 n~e-le~, but in the form of drug micl~al~icle with controlled association 15 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. Accolll~allyhlg 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.
Brief Description of the D.~wi..~
FIG. 1 is a schem~ti7~l drawing made from microscopic observations of Lecithin-Oxytetracycline-Collagen Matrix and Lecithin-Oxytetracycline-Cellulose Matrix at 10x and 40x.
FIG. 2 presents reproductions of 800x photomicrographs of a collagen fibril tli~secte~l from a Lecithin-Oxytetracycline-Collagen Matrix. Panel A is from a transmission photomicrograph. Panel B depicts the yellow-green fluorescence (represented as white) arising from the associated oxytetracycline microcrystals in 30 the identical specimen when illllmin~tecl by ultra-violet light. Panels C and D are CA 022062~9 1997-0~-28 from photo- and fluorescent micrographs (respectively) of another specimen afterhydration with aqueous buffer.

FIG. 3 shows the time course of oxytetracycline release from four forms of 5 o~y~eLlacycline-impregnated Collagen Matrix. Details of the experiment are given in Examples 10-12.

Detailed Description of the Invention The present invention generally comprises a fibrous carrier matrix, which 10 functions as a wound dressing, sponge, absorbable surgical implant or the like, a ph~ celltir~l composition in solid microparticlulate or microcrystalline form, and an adjuvant coating to improve the adherence of the ph~rm~e~ tical particles to the carrier and to improve control over the concentration and rate release action of the ph~ eutical.
Starting Materials Carrier Matr~x The carrier of the present invention may be made of any of a variety of materials which are pharm~ce~tir~lly acceptable (non-toxic and non-allergenic), 20 which can adhere to or be implanted within the target tissue, and which can be made to incorporate the ph~ eutical composition. The carrier is preferably fibrous, such as textiles, filaments, cross-linked solid foam, gels, etc. Exemplary materials include, but is not limited to, collagen, chemically cross-linked collagen or gelatin, cellulose, oxidized cellulose; cellulose acetate in fibrous form, especially 25 those with a low degree of acetylation; ethyl cellulose, methyl cellulose, cellulose ethyl hydroxyethyl ether in fibrous form; poly-D,L-lactate; pyrrolidone polymers in fibrous form; acrylic resins, including polyacrylate, polymethacrylate, and their copolymers, poly-hydro~ybu~yldte, poly-hydroxyvalerate and their copolymers, in fibrous form; polyglycolic acid (Dexon), poly(D~L-lactic-co-glycolic acid); and 30 polyglactin (Vicryl). The l l~r~lled carrier material contains microscopically-CA 022062~9 1997-0~-28 W O96/16643 PCTrUS9S/14559 dimensioned empty space, allowing for hydration, efflux of drug and ingrowth of tissue.
As used herein, the term "matrix" or "matrix material" describes the carrier material in a three dimensional configuration (fabrics, piled fibers, solid foams, 5 etc.). The matrix of the present invention functions not only as a carrier for the ph~rm~reutical but also as a wound dressing, implantable hemostat, or the like.
Accordingly, it is preferable to utilize as the carrier matrix a wound dressing or implantable hemostat which is commercially available and deterrnined to be safe and effectively loaded with antibiotics and other ph~rm~ce~ltir~lc.
An example of a surgically implantable material which may be employed is the Gelfoam~ brand absorbable gelatin sterile sponge ( Upjohn Company, K~l~m~7.oo, MI) which is widely used in ~Ulg~ly and dentistry. This product is described in the Physicians Desk Reference, 1992 ed. at page 2338 as a "water-insoluble, off-white, nonelastic, porous pliable product prepared from purified pork 15 skin gelatin USP granules". It functions as a hemostat which is able to absorb and hcld within its interstices, many times its weight of blood and other fluids. The directions for use state that Gelfoam~ may be left in place and the wound may beclosed over it. Under "Precautions", it is stated that "It is not recommended that Gelfoam~ be saturated with an antibiotic solution or dusted with antibiotic powder. "
It is a particular feature of the present invention that this and similar materials are modified to be safely and effectively loaded with antibiotics and other pharm~r,e~ltic~l.c .
Another example of a surgically implantable material which may be employed is the Surgicel~ Absorbable Hemostat (Johnson & Johnson Medical, Inc., Arlington TX). This product comprises knitted fabric strips of oxidized regenerated cellulose, sterile-packaged in various sizes described in the Physician's Desk Reference, 1992 ed. at page 1151 as having both hemostatic and bactericidal properties. Instructions are given for use as both a removable dressing and as an implantable material when applied in small qll~ntitiPs. Under "Warnings", it is 30 stated that "Surgicel~ hemostat should not be impregnated with anti-infective agents = - -CA 022062s9 1997-0~-28 W O96/16643 PCTrUS9S/14S59 or with other materials such as burr~lhlg or hemostatic substances. " However, the method of the present invention modifies this and related products made of cellulose fibers so as to deliver drugs.
Other fiber-based surgical materials to which the present invention is 5 applicable, including calcium-alginate in fibrous form (Lubet-Moncla, U.S. Pat. No.
3,431,907, 1969), materials incorporating cross-linked gelatin, carboxy-methyl cellulose or pectin, Pawelchak et al., U.S. Pat. No. 4,292,972, 1981, and prior art discussion therein, and flocc~ te~l or chPmir~lly cross-linked fibronectin (Reich, U.S. Pat. No. 5,124,155, 1992). This listing is for illustrative purposes, and is not 10 considered limiting.
The carrier may be sized and shaped in any manner suitable to conform to the particular body cavity or tissue to which it will be applied. The bulk density of the carrier matrix should be sufficiently low to allow adequate amounts of the pharmaceutical to be incorporated, while m~int~ining the structural integrity. For 15 implantation, the carrier matrix should be biodegradable and non-allergenic. The microscopic size of the carrier material is limited only by the size of the cavity to be packed and the burden of material to be resorbed. The lower limit of size is likewise determined by considerations of retention in the cavity. The size and density of individual fibers in a fabric or solid foam is limited by considerations of 20 mechanical strength and porosity. Generally, the larger the microscopic size and the lower the porosity, the slower will be the drug release.

Pharmaceuticals The ph~rm~elltir.~l component (or drug) of the present invention may be any 25 of a variety of substances including antiseptics, antibiotics, anti-infl~mm~tories, local anesthetics, tissue growth promoters, and tissue destruction inhibitors which are solid in the pure state at and below 37~C. Most preferably, the drug substance is reduced to < 10~m or submicron dimensions in an aqueous medium by sonication process, microfluidization, or homogenization described in U.S. Patent Nos.
30 5,091,187 and 5,091,188 to Haynes, both incorporated herein by reference. In the CA 022062~9 1997-0~-28 Haynes process, water-insoluble drugs are rendered injectable by formulation as aqueous suspensions of phospholipid-coated microcrystals. The crystalline drug is reduced to 50 nm to 10 ,~m dimensions by sonication or other processes inducing high shear in the presence of phospholipid or other membrane-forming amphipathic5 lipid. The membrane-forming lipid stabilizes the microcrystal by both hydrophobic and hydrophilic interactions, coating and enveloping it and thus protecting it from coalescence, and rendering the drug substance in solid form less irritating to tissue.
The ph~ ceutical composition is preferably a crystalline or microparticulate, water-insoluble drug reduced to microscopic dimensions (20 nm -10 30 ~m) by sonication, microfluidization, homoge~ lion, wet grinding or airimpact, or other processes. The microcrystals, which may be water insoluble, are suspended in an aqueous solution by coating the crystals with an amphipathic, membrane-forming lipid. The drug microparticles are ~tt~t'.h~-l to the carrier material by non-covalent means, using an adjuvant material. The loaded carrier 15 material preferably comprises microscopically-dimensioned empty space, allowing for hydration, efflux of drug and ingrowth of tissue.
In ~l~relled embodiments of the invention, the selected drug will be substantially water-insoluble ( < 20 mg/ml at physiological pH). Thus, diffusible drug monomers will be present at only low concentration when the carrier matrix is 20 hydrated. Water-insolubility is also associated with slow dissolution rates. The res-lltin~ slow release is desirable for most therapeutic use.
In cases where incorporation and slow release of a water-soluble drug is required, the drug may be rendered water-insoluble by complexation with an oppositely-charged cation or anion as described in the next paragraph.
25 Alternatively, the release of water-soluble drugs can be slowed by coating their drug microparticles with lecithin or other membrane-forming lipids.
As described by Haynes (U.S. Patent Nos. 5,091,187,; 5,091,188) many water-soluble drugs can be held in drug microcrystal form by complexation with anions and cations. These include 2-naphthylenesulfonate (napsylate), gluconate,30 1,1 ' methylene bis (2-hydroxy-3-naphthalene) carboxylic acid (pamoate), CA 022062~9 l997-0~-28 tolylsulfonate (tosylate), mPth~n~s~llfonate (mersylate), glucoheptanoate (gluceptate), bitartrate, polygl~lt~mic acid, succinate, carboxylic acids of various chain lengths from acetate to behenate, bromide, iodide, phosphate, nitrate, calcium, magnesium, their 1: 1 fatty acid or phosphate complexes, and with various amines, including5 dibenzylethylenP~ min~ (be~ hill~), N,N' (dihydroabietyl)ethylene ~ min~
(hydrabamine) or polymers such as polylysine. The choice of these counterions ismade largely on an empirical basis, with stability of the derived crystals and their compatibility with water being primary criteria. As described by Haynes (U.S.
Patent No. 5,246,707) these principles can also be used to render biological 10 molecules insoluble. It is also applicable to water-soluble drugs, particularly those which can be rendered water-insoluble or which do not cross lipid bilayer membranes.
As previously stated in U.S. Pat. Nos. 5,091,187, 5,091,188 and 5,246,707 to Haynes, the size of the drug microparticles can vary within large limits which 15 are set by the desired rates of release of the drug and by physical stability and mech~nic~l properties of the final product. The size of the drug microparticles can be chosen to optimize the rate of release of the drug. Generally smaller particles give faster release. The dimensions of the drug microparticles can vary between 30 ,um and 20 nm. Preferred is when the upper limit of drug mi.;lopallicle size is 10 20 ,Lcm so that capillary blockage will not occur in the event that drug microparticles are released to the circulation. A most ~rerclled range is between 2 ,L~m and 100 nm, which is largely determined by the size relationship between the drug microparticle and the fibers of the carrier material and the desire for pliability of the final product.
Generally, the smaller the drug particles, the smaller will be the rate of release. In 25 actual practice, optimal particle size is determined empirically by testing a range of sizes and noting physical and release characteristics of the product.
If the incorporated drug is not bacteriostatic or bactericidal, additional agents may be incorporated. A wide range of preservatives can be incorporated. These include, but are not limited to, benzalkonium chloride, benzethonium chloride, 30 propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenol, sodium CA 022062~9 1997-0~-28 benzoate, EDTA, etc. The product may be terminally sterilized by gamma irradiation or, in some cases, by ethylene oxide or heat.

Adjuvant S A particular feature of the present invention is its use of adjuvant materials to control the mode of association between the drug microparticles and the carrier material. The adjuvant aids the incorporation of the drug microparticles in the carrier material by at least one of two mech~ni~m~: (a) by ~imlllt~n~ously coating the drug miclopalLicles and the fibers of the carrier material to promote their 10 association, and/or (b) by aiding in the elllla~lllent of drug miclu~alLicles between fibers of the carrier material while the two are being subjected to physical or physico-ch~-mi~l manipulations (not forming covalent ch~.mic~l bonds). It is possible for an adjuvant to work by both mech~ni.~m~. Membrane forming phospholipids such as lecithin can ~imlllt~n~ously envelope the drug micloL~alLicles 15 and fibers of the carrier material. Fiber-forming materials such as solubilized collagen will coat both the drug miclopalLicles and fibers of carrier material.
The mode of association between the drug micropalLicle and the carrier material can be:
(a) by binding of the drug miclopallicle to the carrier material by means of 20 the adjuvant which has ch~mic~l affinity for both, (b) by ellLla~lllent of the drug microparticle between fibers of the carrier material, facilitated by physical or non-covalent chemiçal manipulations of the carrier material together with the drug microparticle in the presence or absence of adjuvant, (c) by the naturally occurring chemical affinity which may occur between the surfaces of the drug microparticles and the fibers of the carrier material in selected cases. This can be determined by adding drug microparticles to single fibers of the carrier material and observing their interactions under a microscope.
These forces can include hydrophobic interaction, hydrogen bonding and ionic CA 022062s9 l997-05-28 I

W O96/16643 PCT~US95/14559 interactions. When strong binding forces are present, and an adjuvant will not be needed.
Membrane-forming adjuvants which may be used include the phospholipids, inclll~ing lecithin (phosphatidyl choline), phosphatidyl glycerol, phosphatidic acid, 5 phosphatidyl serine, phosphatidyl inositol, cardiolipin (diphosphatidyl glycerol), phosphatidyl ethanolamine; sphingomyelin; and mono-glycerides, including monop~lmitin, monostearin, monocaprylin and monoolein. As described in U.S.
Patent No. 5,091,188, other lipid materials can be inr.luc1ed with them to modify the properties of the resulting membranes. Also, water-soluble and water-suspendable10 adjuvants include collagen (several types); gelatin; carboxymethylcellulose, hydroxyethyl cellulose, hydro~ypro~yl cellulose, hydroxypropyl methylcellulose, povidone, benzalkonium chloride and benzethonium chloride. Non-ionic surf~rt~3ntc can also be used as adjuvants to aid drug microparticle loading and release, and for their anti-bacterial properties. These include polyoxamers such as polyoxyl 10 oleyl 15 ether, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil; polyoxyl stearates, polysorbates; poly~lopyleneglycol; sorbitan monolaurate, sorbitan monooleate, sorbitan monop~lmit~te and -monostearate. Miscellaneous adjuvants include cholesterol, calcium stearate, magnesium stearate; sodium salts of fatty acids such as sodium stearate; sodium lauryl sulfate; and glycerol monstearate.
Selection of Secondary Adjuvant:
Water-soluble macromolecules capable of binding drug monomers can be incorporated in the preparation to increase the total concentration of the drug in the aqueous microphase and speed the release of the drug. These include serum 25 albumin and cyclodextrans (alpha, beta and gamma). Alternatively, carboxymethylcellulose, dextrans and other water-soluble polymers can be added to the preparation to increase the viscosity of the aqueous phase, and thus slow the rate of diffusion of drug monomers and drug miclopalLicles in the aqueous microphase.It is believed that the present invention is superior to prior art modes of 30 association of particulate drug which neither involve adjuvants nor rely on specific CA 022062~9 1997-0~-28 interaction between the drug particle and the fibers of the carrier material. such as simple retention of drug particles in the interstices of an unperturbed solid foam or fabric of the carrier material by simple "dusting in" or by air flow (as in elllldplllellL
of dust particles in air filters). Materials which can be "blown in" can also beS shaken out during transport and h~n(llin~. Furthermore, our invention does not rely on binding of monomeric drug molecules to the carrier material or the adjuvant, although such tendencies may slow or speed the release of the drug (respectively).
Thus, a particular feature of the present invention is that it relies on a specific physical association between drug microparticle and the solid carrier matrix.
10 We achieve this by use of the adjuvant or by specific manipulations of the carrier material in the presence of the drug micropalLicles. This provides a surgical material in which the drug micfo~dlLicles remain homogeneously distributed in storage, during transport and when the material is cut and worked.

15 Methods of Manufacture and Use ~ r~mlfa~t lre of the present invention begins with selecting a fibrous carrier material, such as an implantable absorbable sponge or hemostat, selecting a drugand selecting the adjuvant (membrane forming, water soluble, etc.).
There are two pl~felled methods of introducing the drug and adjuvant into 20 the carrier material: (a) by soaking the carrier material with a suspension of water insoluble drug microparticles in the presence of the adjuvant, or (b) by soaking the carrier material in a solution of the drug in the presence of adjuvant, followed by removal of solvent, thereby producing miclol.alLicles. Method (a) is particularly applicable where the drug is poorly soluble in the chosen solvent and where a high 25 degrees of drug loading and pliability of the finich~cl product are desired.
In Method (a), when the solvent is water, the ~lefelled method of removal of the solvent is freeze-drying (lyophilization), particularly for an aqueous solvent (Examples 2-3). Removal of water in the frozen state avoids rearrangement of thedrug microparticles and deposition of solubilized drug as a continuous phase 30 between the miclopalLicles, which results in hardening of the dressing or implant.

CA 022062~9 l997-0~-28 WO 96/16643 PCT/US95/~4559 Method (b) is applicable when lower degrees of loading are required and when ease of production is important. In this case freeze-drying is not generally advantageous over simple solvent evaporation. It is possible to do the coating by several stages of soaking and evaporation (Example 8).
S The choice between these two methods can be based on sy~ ie investigation with the desired drug and adjuvant combination. Our experimentation has given indications that addition of drug microparticles to hydrated carrier material enh~nrçs their subsequent ellL,~lllent between the fibers. Also, the interaction of the drug microparticle with the fibers of the carrier material is strengthened by the 10 subsequent dehydration, particularly in the presence of a suitable adjuvant.
Adjuvants which have affinity for both the drug micropalLicle and the carrier material are most suitable for producing tight association of the latter two.
When pliable materials are desired, it is important that the drug microparticles or dissolved drug not form a continuous drug phase within the 15 preparation. This can occur when the solvent removal is from a liquid state and when the carrier material acts as a wick.
It is also possible to introduce the drug to the carrier material by spraying ona solution or suspension of drug, in the presence or absence of adjuvant. This method is particularly applicable when high degrees of drug loading are not 20 nf~Ce~s~ry and when ease of m~mlf~rt~lre is important.

Rate of Release of the Drug:
Mech~ni~ms by which the drug can be released from the carrier include: (a) diffusion or flow of drug monomers and (b) diffusion or flow of drug microparticles 25 from the carrier matrix. Mech~ni~m (a) is most important when the drug microparticles are firmly attached to the carrier material or are entrapped therein. It is illustrated by examples 5, 11 and 17 in which oxytetracycline (OTC), a water-insoluble drug, was released very slowly. The higher the number of grams of water-insoluble drug per liter volume of matrix, the slower will be its release rate in 30 terms of fraction per hour.

CA 022062~9 1997-0~-28 Rates of release by mech~nicm (a) will be lowest for drugs which are intrinsically water insoluble. However, low rates of release of water-soluble drugs can also be achieved if they are rendered water-insoluble by complexation with suitable cationic or anionic agents or by secondary adjuvants (described above) to 5 make drug microcrystals. Also, the rates of release of water-soluble drugs can be decreased if they are intrinsically membrane impermeable and are encapsulated within membrane vesicles of lecithin or other membrane-forming lipids firmly attached to the carrier material.
The rate of release of a water-insoluble drug via m~ch~nicm (a) can be 10 increased by inclusion of water-soluble macromolecules such as serum albumin or cyclodextrin which have appreciable ability to bind the drug monomers (secondaryadjuvants). After the matrix is implanted within the body and becomes hydrated, these molecules will bind drug monomers, thus increasing their total concentration in the aqueous diffusion pathways within quiescent matrix. This will allow for more 15 rapid delivery of the drug from the matrix interior to the tissue boundary.
When mech~ni.cm (b) is operative, the rate of loss of the drug is dependent upon the rate of release of the drug micropalLicles from the carrier material. In examples 13, 14, 15 and 16, oxytetracycline microparticles were released by thismech~nicm The rate of release of drug miclopalLicles is dependent upon the 20 firmness of ~ chm~nt to (or ellLl~lllent within) the carrier material, which can be controlled by selection of primary adjuvant materials. Since diffusion of large particles is slow, the rate of release is dependent on the amount of tidal flow resulting from sql1eç7.ing and releasing of the preparation in the medium in which it is placed. Thus the inclusion of secondary adjuvants which increase the viscosity of 25 the aqueous microphases within the hydrated matrix can be used to decrease the rate of release by mechanism (b).
The design of a particular product will start by deciding on the amount of drug to be loaded and on the rate at which it is to be released. Then the physico-chemical and solubility characteristics of the drug compound will be considered.30 Then a combination of carrier material and adjuvants will be chosen to favor or CA 022062~9 1997-0~-28 disfavor mech~ni~m~ (a) and (b) to obtain the desired release rate. For example, if the drug is intrinsically water-insoluble and slow rates of release are desired~ then a carrier material/adjuvant combination favoring ellLldplllent and release by mech~ni~m (a) will be selected (examples 5, 11 and 17~. But in the case where it5 was desired to release the same drug more rapidly, a carrier material/adjuvantcombination favoring ~3tt~chm~nt by coating and release by mechanism (b) will beselected (examples 13, 14, 15 and 16).
If a water-soluble drug is used, the principles are dirrel~lll. In this case adjuvants are chosen which will encapsulate the drug and/or render it insoluble. As 10 an example, hydrophilic, water-soluble drugs which bear net charge at neutral pH
can be entrapped within vesicular structures produced by membrane-forming phospholipids. Also, many water-soluble drugs bearing net charge can be renderedinsoluble by a counterion of opposite charge. Both of these principles can be combined to hold a water-insolubilized drug inside lecithin vesicular structures15 attached to or entrapped within the carrier material.

~)esign of Final Pr~duct.
The design of the final product will depend upon how the product is to be used (dressing vs implant), the desired size and shape of the material, and the 20 desired release rate and duration of release. The functioning of the product depends on six variables listed below, with brief illustrations following in parentheses:
a. Carrier material (biodegradable for implantation; pliable for application to soft tissue, stiff for implantation in bone; porosity).
b. Size of drug microparticle or microcrystal (less than 10 ~m for 25 implantation; dimensions less than ~ m~t~r of fibers for optimal coating;
dimensions comparable with interstices of carrier material for optimal ellLla~lllent;
small dimensions for more rapid dissolution).
c. Adjuvant (to coat or aid in entrapment of the drug miclopallicle; choice of mechanism (a) or nl~ch~ni~m (b) for release of drug).

CA 022062~9 l997-0~-28 Wo 96/16643 PCT/US95/14559 d. Method of solvent removal (lyophili7~tion or simple evaporation determined by economics and stiffn~ss and homogeneity requirements of fini~h~l product).
e. Degree of drug loading, density of preparation (gm drug/ml hydrated 5 matrix and gm drug/gm carrier material + adjuvant; determined by potency of the drug and desired number of hours of sustained release).
f. Secondary adjuvants (to increase or decrease the solubility of the drug or alter the viscosity of the bulk material in the hydrated state, thus altering rate of drug release).
In describing the various embodiments of our invention, we will use the following notation:
(Adjuvant)-(Drug)-(Matrix Material).

Thus the composition of Example 2 is Lecithin-Flurbiprofen-Collagen 15 Matrix.
The following examples are given to show the manner by which our invention is carried out. All parts and percentages reported herein are by weight (w/w) or weight/volume (w/v) percentage, in which the weight or volume in the denominator represents the total weight or volume of the system. We also report 20 drug loading in terms of gm drug per gm of matrix material. Concentrations ofwater soluble constituents in aqueous solution (e.g. glucose) are given in millimolar concentration (mM = millimoles per liter) referred to the volume of water in thesystem. All temperatures are reported in degrees Celsius. Diameters or dimensions are given in millimt~.ters (mm = 10-3 meters), micrometers (~ = 10-6 meters) or 25 nanometers (nm--10-9 meters). The compositions of the invention can comprise,consist essentially of or consist of the materials set forth and the process or method can comprise, consist essentially of or consist of the steps set forth with suchmaterials.

CA 022062~9 1997-0~-28 Gelfoam~ impregnated with aqueous suspension of l~ecithin-Coated Flzc,~ cJlen Microcrystals.
This example describes soaking Gelfoam~ with an aqueous suspension of S microcrystals to obtain a product lacking sustained release or specific association of the drug with the carrier material. Lecithin-coated microcrystals of ~lulbip~ofen were prepared by the method described in U.S. Patents 5,091,187 and 5,091,188 toHaynes which are incorporated herein by lef~ ce~ Briefly, 75 gm egg lecithin (Pfanstiehl Laboratories, Waukegan, IL), Phospholipids, egg, #P-123, Lot 21097, 10 Drug Masterfiled) was added to 225 ml with 300 mM glucose, 2 mM sodium phosphate buffer, pH 7Ø The mixture was allowed to hydrate and was then dispersed with a Brinkman Polytron PR 10/35 appalalus (Bnnkman Instruments, Westbury, NY). Then 75 gm of ~lu~bi~lofen (SST Corp, Clifton, NJ) were added and further dispersed. The suspension was then degassed by sonication and was 15 passed a total of 7 times through an M-llOF Microfluidizer (Microfluidics, Inc., Newton, MA) to creàte an aqueous suspension of lecithin-coated microcrystals of flull~i~LoI~ll (20% (w/v) nLnbi~lofen, 20% (w/v) lecithin). The pH was adjusted to 7.2.
The preparation was ex~rnin~cl under a fluorescence microscope (Carl Zeiss, 20 #4725631, "West Germany") at 800-fold m~gnifi-~tion in fluorescent and in normal mode. Small free-flowing microcrystals of approx. 0.5 ,um ~im~n~ion were visualized by their refraction and by their greenish fluorescence. We estimate that less than 1 % of the particles were greater than 1.0 ,um dimension, and essentially none were greater than 10 ,um . Analysis with a Coulter N4 Particle Sizer (Coulter 25 Electronics, Hialeah, PL) in the "intensity" mode gave an average diameter of 521 +62 nm for 100% of the particles, and 0% > 3 ~m .
Samples of Gelfoam~ (NDC 0009-0342-01, Gelfoam, Sterile Sponge, absorbable gelatin sponge, USP (Upjohn Colly?ally, K~l~m~7.oo, MI) were cut into 7 mm x 7 mm x 10 mm pieces. The volume of the cut samples was estimated as 30 approx. 0.5 cm3 from their dimensions. The samples were weighed and then CA 022062~9 1997-0~-28 immersed in aliquots of the 20% (w/v) flurbiprofen, 20~ (w/v) lecithin-coated microcrystal suspension described above and were subjected to three sql1eç7.in~/reexpansion cycles. The samples were then removed by means of a surgical forceps and allowed to drip. The h~nging samples retained approx. 0.1 ml 5 (cm3) of the microcrystal suspension as determined weighing. The volume of thesample was estimated to be less than 0.25 ml. Some of the samples were introduced into vials cont~ining m~nnitol solution and were observed to return to their original volumes of 0.5 cm3. Additionally, the nulbil)lofen microcrystals could be readily removed by squeez.ing, indicating a lack of specific association with the collagen 10 carrier material.
The resulting product colls~i~ul~s a hemostatic plug which can be introduced into tooth sockets after tooth extraction for the purpose of controlling bleeding and delivering the non-steroidal anti-infl~mm~tory analgesic drug to the tissue for the control of pain. The material can be removed days after surgery or a gum flap can 15 be sewn over, enclosing the material which will eventually be resorbed. This material can also be used for many other types of surgery where fairly rapid release of the drug is desired.

Lecithin-Flurbiprofen-Collagen Matrix This example shows how freezing and lyophilization of the product of Example 1 results in specific association between the flurbiprofen microcrystals and the collagen fibers as described for our invention. The impregnated material of Example 1 was placed in glass ampules, sealed, and was quickly frozen by partialimmersion of the ampules in CO2-acetone. Then the ampules were uncapped and introduced into a lyophilizer. After reaching dryness, the ampules were removed,capped and terminally sterilized by gamma irradiation (1.5 mega Rad).
Some of the ampules were opened and the contents were analyzed. The sponges m~int~inPtl their shape but were reduced in volume to less than 0.2 cm3.30 They were slightly more rigid than before impregnation and lyophilization. They CA 022062~9 1997-0~-28 were slightly tacky. When gently compressed and released they returned to their original shape. When compressed under high pressure they did not return to theiroriginal dimensions. Compression did not cause the drug to be lost from the matrix.
Some samples were cut with crossed scalpels and were e~min~d under the 5 fluorescent microscope at 800-fold m~gnifir~tion in fluorescent and normal modes.
Collagen fibers were discernible by a very weak greenish fluorescence in the drystate. These were coated with approx. 0.5 ~m crystals of oxytetracycline OTC
(strong yellow-green fluorescence) closely associated with the fibers. Occasionally the crystals occurred in clusters, also closely associated with the fibers.
Buffer (300 mM m~nnitol, 2 mM sodium phosphate, pH 7.0) was added to the microscope slides and the process of rehydration was observed. The drug microcrystals rem~in~l associated with the fibers. In the first phases of the rehydration process, lamellar structures coating the fibers in association with the microcrystalline drug became prominent. These lamellar structures are similar to15 what is observed when solid lecithin is hydrated under similar conditions. Upon agitation of the hydrated samples by manipulation of the cover slip, some clusters of microcrystals could be made to detach from the carrier material.
One 10 mm x 7 mm x 7 mm Lecithin-Flurbiprofen-Collagen matrix composition was introduced into an ampule cont~ining an excess of mannitol buffer.
20 The matrix returned to its original 0.5 cm3 volume within a few mimlt~s. In contrast to Example 1, sqllee7.in~ does not release nu~ rofen microcrystals. After 2 hrs of rehydration, it was removed and blotted onto a microscope slide. Distinct 0.5 ,um to 4 ,um lecithin-coated flurbiprofen microcrystals were observed. The blot contained a small amount of collagen which could be detected by its weak green 25 fluorescence. The sponge was torn apart and a fragment was viewed on a slide. It contained 0.5 ~m to 4 ,um lecithin-coated microcrystals of flurbiprofen, identified by its strong green fluorescence, within a continuous collagen matrix. The properties of the lecithin-flurbiprofen-collagen matrix in the dry state are shown below in TABLE 1.

CA 022062~9 l997-0~-28 Approx. volume 0.5 ml Gelfoam~ weight 5.9+0.4 mg S Flurbiprofen weight 25.6+4.3 mg Physical state Pliable, solid foam Color Yellow/light brown Flurbiprofen MC dist. Homogeneous (Macroscopic) 10 FlL~lbiplofen MC assn. Very Close Rehydration time Approx. 1 min Physical characteristics Sponge after rehydration Drug behavior after rehydration Remains in sponge The resnlting product constitutes a sterile hemostatic plug which can be conveniently introduced into tooth sockets after tooth extraction for the purpose of controlling bleeding and for delivering the non-steroidal anti-infl~,ll",~to~y analgesic 20 drug to the tissue for the control of pain. The material can be removed days after surgery. Alternatively, a gum flap can be sewn over, enclosing the material which will eventually be resorbed. This material can be used for many other types of ~ulgely in which fairly rapid release of the drug in miclopalLiculate form (cf. FIG.
3) is desired.

Table 2 presents the results for preparations of surgical materials incorporating the antibiotic oxytetracycline (OTC) using Gelfoam~ or cellulose gauze (Johnson & Johnson, New Brunswick, NJ) as the matrix material. In addition to 30 being a useful antibiotic, OTC has an intrinsic fluorescence which aids in vi~ li7ing its deposition in the dressing. The left-hand column describes the method of m~nllf~ctllre of the product. OTC microcrystals (20%) were coated with either lecithin (20%) or with nothing ("slurry") or were exposed to 2% collagen, to 1%
polyethylene glycol (PEG), or to 1% carboxymethyl-cellulose (CMC). Solvent was 35 removed using either heat (36~C), vacuum at room temperature or lyophilization (freeze drying under vacuum). Preparations were also made with a 2% OTC
solution in ethanol (EtOH) removed under vacuum with or without lecithin. More information on the method of preparation is given in the corresponding examples.Each row of Table 2 describes the properties of a separate product.

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CA 022062~9 1997-0~-28 Wo 96/16643 PCT/USg5/14559 Table 2 describes the fini~h~cl product in terms of the following properties:

~ Weights of carrier matrix (by weighing) and OTC (by analysis). Averages +
5 SD were obtained from 5 samples.

"Physical state" describes the appearance and mech~nical properties of the Matrix. These varied from pliable to crusty to hard (hrd.) to shriveled (shr.). "Dark."
in(lic~t~s the OTC had darkened.
"OTC dist. (macro.)" describes the macroscopic OTC distribution of OTC in the Matrix after ~lic~ectin~ it and observing it in cross section under an ultra-violet light. It was rated as grossly homogeneous (homog.) if OTC was observed in all portions of the Matrix and as heterogeneous (heterog.) when it was not.
"Assoc (micro.)" describes the microscopic distribution of OTC in relation to the fibers. It was de~ illed using a fluorescent microscope, observing dry samples and their behavior upon re-wetting. The following modes of association were observed:

Very loose association (VLA): OTC Microcrystals have few discernible points of contact with fibers under microscopic ex~min~tion. In these cases OTC dust isreleased when the preparation is torn apart or shaken.

Loose association (LA): Microscopic ex~min~tion shows that the OTC
25 Microcrystals have few points of contact with fibers. Under microscopic ex~min~tion the Microcrystals invariably become dislodged when water is added to isolated fibers.

Close association (CA): Microscopic ex~min~tions shows that the OTC
Microcrystals are in intim~fe contact with fibers. No space can not be discerned . ~
CA 022062~9 1997-0~-28 between Microcrystals and the fibers to which they are bound. Under microscopic e~min~tion the Microcrystals could be dislodged from isolated fibers after water was added and the fibers were ~,git~t~l Continuous close association (CCA): Observations were the same as CA except that the complete surface area of the fiber is covered with OTC.

Very close association (VCL): Tntim~te contact as in CA but OTC
Microcrystals could not be dislodged from isolated fibers by soaking and agitation.
Solid continuous block (SCB): Microcrystals of OTC coat the fibers and fill much of the space between the fibers.

Table 2 also describes the rate of release of Drug MiclopalLicles from the hydrated 15 Matrix observed under the microscope (Examples 13-20).

Lecithin-Oxvtetracvcline-Collagen Matrix and Lecithin-Oxytetracvcline-Cellulose Matrix An aqueous suspension of 20% (w/v) oxytetracycline (OTC), 20% (w/v) lecithin 20 microcrystals was prepared by the process described in Example 1 except that the source of lecithin was OvothinR 120 (Lucas Meyer, Decatur, IL) and the final pH was 5Ø Gelfoam~ and cellulose fiber gauze (from "Non-Stick Pad", Johnson & Johnson, New Brunswick, NJ) were cut, measured. They were then impregnated with the abovesuspension by manipulation (squeezing and allowing to reform). The excess liquid was 25 removed by blotting and the samples were dried by heat tre~tm~nt or lyophili7~ti- n as indicated. With the Gelfoam~ samples, the relationships between initial volume, hydrated, dried and rehydrated volume were similar to those described in Example 2.
For the cellulose fiber gauze samples, the original dimensions were 3 x 10 x 15 mm (0.45 cm3). With addition of lecithin-coated OTC microcrystals they increased CA 022062.,9 1 997 - o., - 28 thickness by approx. 50% (0.675 cm3) and held this volume when suspended by a surgical forceps. Upon lyophilization they retained this volume. The volume was unchanged upon rehydration.
Figure 1 presents schem~tic representations of fr~gment~ of the pl~pal~lions cut5 from the samples based on observations under the microscope at 10x and 40x. Material was deposited on and between the fibers of the carrier materials within the matrix.
The characteristics of the fini.~hP~l products are given in the first grouping in Table 2. Lyophilization gave pliable products with homogeneous distribution of oxytetracycline (OTC) throughout the dressing, with close association between the 10 microcrystals and the fibers. Under the microscope, individual OTC Microcrystals with 0.5 to 2 ,~ dimensions could be easily discerned from their strong yellow-green fluorescence. Panel A of Fig. 2 is a reproduction of a tr~n~mi~sion photomicrograph of a coated collagen fibril tli~sectecl from the preparation and viewed at 800 power. Panel B of Fig. 2 shows exactly the same field illllmin~tecl in the ultra-violet which causes OTC to give off yellow-green fluorescence depicted as white in this reproduction.
In this Example the OTC/carrier weight ratios were 3.14+0.35 gm/gm for Gelfoam~ and 2.29+0.44 gm/gm for the cellulose gauze. The products are suitable for both insertion into surgical sites and as external wound dressings. The Gelfoam~material can be loaded with OTC to approx. 4.0 gm/gm and still retain this property.
Removal of water by warm drying in air caused the Gelfoam~-based preparation to become shriveled and hard, and caused the gauze-based preparation to darken.

OTC-Collagen Matrix and OTC-Cellulose Matrix This is a comparative example, showing the effect of omitting lecithin (or otheradjuvant). The procedure of Example 3 was repeated except that lecithin was omitted and sonication (Sonifier~Cell Disrupter, Mod. W 185D, Heat System and Ultrasonics, Plainview, NY) was used for particle size reduction. In attempt to minimi7~o crystal reaggregation, the Gelfoam~ and gauze samples were rapidly impregnated. Volume CA 022062~9 l997-0~-28 relationships were similar to those described in Examples 2 and 3, for Gelfoam~ and gauze, respectively. As shown in the second glvupillg of Table 2, the distribution of OTC within the two types of matrix was heterogeneous. The microcrystals were loosely or very loosely associated with the collagen matrix and cellulose matrix, 5 respectively. A lower degree of OTC incorporation was obtained for the GelfoamR-based preparation. The samples were pliable, and are suitable for external wounddressings. However, the samples are not resistant to continuous vibration.

EXAMPLE S
Collagen-O~C-Collagen Matrix and C~llag~n-OTC-Cellulose Matrix Oxytetracycline (OTC) was sonicated in buffer in the presence of 2% (w/v) collagen (Insoluble Type I Bovine Achilles Tendon, C-9879, Lot 21F-8000, Sigma Chemical Co., St. Louis, MO). The sonication was performed for 60 min. at 3040~C.
Gelfoam~samples were impregnated and lyophilized. Volume relationships were 15 similar to those described in Example 2 except that the sample did not swell to its original volume when it was rehydrated. It rem~inPd at its low volume (<0.2 cm3, or <40% original volume) for at least 15 hrs.
The lyophilized sample was a crusty and hard. The matrix could be shaped by compression and could be easily torn apart or trimmed without loss of OTC. Under20 microscopic e~min~tion, the Gelfoam~-based preparation had clumps of 2-5 ~m microcrystals (strong yellow-green fluorescence) entrapped between the original and added collagen. This material is suitable for implantation in bone.
When cellulose gauze was used as a carrier material, a crusty and hard material was also obtained. Volume relationships were as described in Example 3. Microscopic 25 e~min~tion revealed clumps of 2-5 ~m OTC Microcrystals (yellow-green fluorescence) embedded in flakes of collagen loosely adhering to the cellulose fibers. This emphasizes the need for the adjuvant to have affinity for both the drug microparticle and the carrier m~teri~l CA 022062~9 l997-0~-28 PEG-OTC-Collagen Matrix and P~G-OTC-Cellulose Matrix OTC was sonicated at 20% (w/v) in the presence of 1 % (w/v) polyethylene glycol (PEG) (m.w. 3,350, P-3640, Lot 127F-0214, Sigma Chemical Co., St. Louis, MO). For 5 Gelfoam(~), inclusion of this non-ionic surfactant did not improve the adhesion of the OTC-Microparticles, but produced a less pliable product in the dry state (Table 2). For the gauze pl~dLion7 inclusion of PEG did not improve the adhesion of the OTC-Microparticles and did not change the pliability of the product. Volume relationships were as described in Examples 2 and 3, respectively.

CMC-OTC-Collagen Matrix and CMC-OTC-Cellulose-Cellulose Matrix The procedure of Example 4 was repeated, except that the sonication was done in the presence of 1% (w/v) carboxymethylcellulose (CMC) (sodium salt, C-8758, Lot 67F-lS 0527, Sigma Chemical Co., St. Louis, MO). Treatment of Gelfoam~ and gauze m~t~ri~l~with this macromolecule increased the hardness of the m~1eri~l and did not improve the adhesion of the OTC-Microparticles (Table 2). Volume relationships were as described in Examples 2 and 3, respectively.

Lecithin-OTC-Collagen Matrix and Lecithin-OTC-Cellulose Matrix f~om an ethanol medium An ethanolic solution of 2% (w/v) OTC and 2% (w/v) lecithin was made and the Gelfoam~ and gauze samples were wetted with this solution and dried at room 25 temperature under vacuum. This cycle was repeated for a total of 5 times. The procedure resulted in homogeneous OTC distribution in the finished collagen matrix and cellulose matrix. Under the microscope, 1-4 ~m microcrystals were observed. Some were in clumps, but all were in close or very close association with the cellulose fibers or collagen fibers, respectively. The products are pliable and are suitable for both insertion into CA 022062~9 1997-0~-28 surgical sites and for use as extern~l wound dressings. The degrees of OTC loading were lower than in Examples 3 and 4. The volumes of the samples did not change with immersion in ethanol solution, dehydration or rehydration.

OTC-Collagen Matrix and OTC-Cellulose Matrix~om an ethanol medium Example 8 was repeated, except that lecithin was not included. This also resulted in pliable finished products with low degrees of loading, and with looser association between the drug and fibers. The volumes of the samples did not change with immersion 10 in ethanol solution, evaporation or hydration.

Drug Release. Macroscopic Observations In these examples, materials from previous examples were tested for the rate of 15 release of oxytetracycline. The samples were introduced into vials cont~ining 2.0 ml of 300 mM mannitol, 2 mM phosphate buffer, pH 7Ø The samples became completely hydrated within 1-15 minl~t~s Gelfoam(~-based samples expanded from their dry volume (< 0.2 cm3) to their pre-impregn~te~7 volumes of approx. 0.50 cm3. The exception was collagen-OTC-Gelfoam~) which did not expand. All the gauze-based sarnples retained 20 the volumes of their treated states ( 1.5 times original volume).
After several minutes of hydration the samples were compressed once (to approx.
1/1 0th of their original volume) against the wall of the container to squeeze out any oxytetracycline which was not associated with the carrier material. The samples were then removed and introduced into a new vials with new buffer and the process was25 repeated at the end of 3-hour intervals for up to 15 hours. The cumulative amount of oxytetracycline released was calculated. The data are shown in Fig. 3.

-CA 022062~9 1997-0~-28 WO 96/166~13 PCT/US95/14559 OTC release from Lecithin-OTC-Collagen Mafrix and PEG-OTC-Collagen Matrix The top kace of Fig. 3 is a control experiment which shows that when Gelfoam~ issimply impregnated with an aqueous suspension of lecithin-coated OTC microcrystals, S but not dried or lyophilized, the OTC is released quickly. The center trace in Fig. 3 shows that Lecithin-OTC-Gelfoam prepared by lyophilization in Example 3 releases its OTC
slowly. In this test, 6 hours are required to release 70% of the OTC. Similar results were obtained with samples which had been dried at 36~C. The comparison shows that the lyophili7~tion or drying has caused the lecithin-coated OTC microcrystals to be bound to 10 the collagen fibers of the collagen matrix.
Figure 3 shows that PEG-OTC-collagen matrix (lyophili7~o~1) releases OTC very rapidly, indicating that PEG does not provide a firm att~chment of the OTC to the collagen matrix.
The above experiments also showed that the release of OTC was by release of 15 OTC microparticles (Mechanism B). When the carrier material was squeezed the solution became cloudy, indicating that colloidal material was released. Also, the amounts of OTC
released into certain 2.0 ml aliquots (approx. 10 mg) exceeded the solubility of OTC (1.1 mg/ml at pH 7.0).

OTC release from Collagen-OTC-Collagen Matrix Figure 3 shows that Collagen-OTC-Collagen Matrix prepared by lyophili7~tion gives very slow release of OTC. Only 15% of the incorporated OTC was released in 15 hours. This shows that the addition of collagen increases OTC retention. Microscopic e~min~tion of this preparation showed that microcrystals were physically entrapped in a matrix of solid collagen material. In this experiment, the release was consistent with Mech~ni~m A (release of OTC monomers). No cloudiness was observed in the solution, and the free concentration of OTC in the aliquots was < 0.6 mg/ml which is well below its solubility limit (1.1 mg/ml).

CA 022062~9 1997-0~-28 I,ecithin-OTC-Collagen Matrix and OTC-Collage~z Matrix from ethanol solution The release rates were also determined for the Gelfoam~-based samples of Examples 8 and 9, prepared by impregnation with ethanolic solutions of 2% OTC with or 5 without 2% lecithin, respectively. Under the conditions of Fig. 3, 70% release of OTC
from the lecithin/OTC loaded preparation required 6 hrs. For the ~lepar~Lion without lecithin, 70% release required approx. 14 hr. This difference may relate to the larger size of the OTC crystals obtained in the absence of lecithin.

Drug Release. Microscopic O~servations OTC Release from Lecithin-OTC-Collagen Matrix. Microscopic Observations The fragment of the Lecithin-OTC-Collagen Matrix sample from Example 3 was removed and was mounted between a slide and coverslip, buffered isotonic mannitol was added, and the process of hydration and OTC release was visualized using the fluorescence microscope at 800-fold m~gnification. By switching from ultravioletexcitation to tr~n~mitte~l light, OTC microcrystals could be discerned from lecithin and 20 the collagen carrier material. Within 2-3 mimlte~ of addition of the medium, changes in light tr~n~mi~ion could be observed, with the collagen fibers becoming more diffuse.
Within 5 minntes, some OTC microcrystals were being released from the edge of the preparation, where they exhibited Brownian motion. Lecithin and OTC microcrystals which were intim~tely associated with the collagen fibrils could be observed to bud and 25 swell. Panels C and D of Fig. 2 represent tr~n~mi.~ion and fluorescent photomicrographs of a coated collagen fibril within the pl~p~dLion. The OTC microcrystals are more widely separated.
Close to the edge of the hydrated plepa~dlion immobilized individual OTC
microcrystals could be discerned. Within the center of the 0.1-1.0 mm dimensioned CA 022062~9 1997-0~-28 m~teri~l, OTC microcrystals were at high concentration, were immobilized and individual microcrystals could not be discerned. However, OTC microcrystals could be made to flow out in "rivers" when the sample was squeezed by manipulating the coverslip. The released OTC microcrystals were of fairly ullirol~ll size estim~te~l to be in the 0.3-0.7,um 5 range.
This behavior was graded as slow release. (See Table 2, last column.) OT'' release from PEG-OTC-Collagen Matrix. Microscopic Observations The experiment of Example 13 was repeated using the PEG-OTC-Collagen Matrix pr~aLion of Example 6. The sample changed shape immediately after the addition of aqueous medium. The movement and ~ ~llhlg removed OTC microcrystals within 20 sec. Manipulation of the coverslip showed that the microcrystals could be readily squeezed out, indicating a lack of affinity for the collagen matrix. The released OTC
15 microcrystals ranged in size between an estim~te(1 0.1 and 5.0 ,um.
This behavior was graded as rapid release (see Table 2, last column).

OTC release from CMC-OTC-Collagen Matrix. Microscopic Observations The experiment of Example 13 was repeated using CMC-OTC-Collagen Matrix from Example 7. Rapid release was observed, with observations comparable to those of Example 14.

OTC release~om OTC-Collagen Matrix. Microscopic Observations The experiment of Example 13 was repeated using the OTC-Collagen Matrix preparation of Example 4, lacking adjuvant. As with PEG-OTC-Collagen Matrix (Example 14), microcrystals were rapidly dissociated, indicating a lack of affinity for the collagen matrix. The microcrystals were predomin~ntly 2-5 ~m.

CA 022062~9 1997-0~-28 OTC release from Collagen-OTC-Collagen Matrix. Microscopic Observations The experiment of Example 13 was repeated using the Collagen-OTC-Collagen Matrix of Exarnple 5. The matrix did not change shape or optical properties even 30 5 min~ltes after the addition of aqueous medium. The yellow fluorescence of the OTC
remained within the mass of the collagen matrix, and only occasional 0.5-5.0 ~m microcrystals could be discerned on the edge. Ninety minutes after the addition of the aqueous medium, manipulation of the coverslip did not dislodge OTC microcrystals. This behavior was graded as very slow release (see Table 2, last column). From this, and from 10 the release experiment of Example 11, we concluded tl1at microcrystalline OTC is firmly lodged in the collagen matrix.

OTC release from Lecithin-OTC-Collagen Matrix fethanolpreparation). Microscopic 15 Observations The experiment of Example 13 was repeated using Lecithin-OTC-Collagen Matrix of Example 8 prepared by evaporation of ethanol. Slow release was observed, comparable to that seen in with lyophilized Lecithin-OTC-Collagen Matrix in Example 13.

OTC release from OTC-Collagen Matrix (ethanol preparation). Microscopic Observations The experiment of Example 13 was repeated using OTC-Collagen Matrix of Exarnple 9 prepared by evaporation of ethanol. One-half of the OTC was rapidly released. The rem~in-ler was released slowly as with Lecithin-OTC-Collagen Matrix.

CA 022062~9 1997-0~-28 OTC release from cellulose gauze matrices. Microscopic Observations The experiment~ of Exarnples 13-19 were repeated using the cellulose gauze preparations and the results are tabulated in the final column of Table 2.
S The above examples and teachings show how one skilled in the art can select (1) the carrier material, (2) the drug to be incorporated, (3) the adjuvant, and (4) the method of preparation to get optimal mechanical properties and drug release characteristics for use as a therapeutic wound dressing or implant.
To summarize the plef~lled embodiment of our invention, water-insoluble drugs 10 are reduced to 20 nm - 30 /lm size in aqueous suspension, mixed with defined adjuvant materials and soaked into existing surgical materials con~i~ting of fibers, fabrics or solid foams and water is removed by lyophilization. The finished product constitutes a surgical material capable of delivering large quantities of drug to the surrounding tissue at defined rates. The choice of drug concentration and adjuvant materials and method of 15 incorporation can be used to control the rate of drug release from the surgical material.
The modes of incorporation involve physico-chemical affinity of the adjuvant for both the microcrystalline drug and the surgical m~t~ri~l Alternatively the adjuvant can serve as an aid to enl~ ent of the drug microcrystal between the fibers of the surgical material. The drug-cont~ining material is implantable if the existing surgical material from which it is 20 forrned is implantable. The drug-cont~ining material can also be used as an external dressing. Water-soluble drugs can be incorporated in the surgical materials. Their rates of release can be controlled by encapsulation within phospholipid membranes, by adjuvants which render them insoluble, or by a combination of these principles.
The implant of the present invention may be used in surgical or dental procedures 25 wherein it is desired to simultaneously control bleeding and deliver a drug to adjacent tissue. In particular~ contemplated uses include closing the skin or laceration for pain/infection control; decreasing infl~mm~tion and preventing keloid formation when closing skin; after thoracotomy for pain control to enhance ventilation thereby preventing pneumonia, after herniorraphy when laid upon the ilioinguinal nerve as it is exposed for CA 022062~9 1997-0~-28 pain control; after surgery in a cont~min~ted area to deliver antibiotics; after all types of surgery for infection control; after orthopedic surgery to provide bone growth stim~ ting factors to the site; after orthopedic surgery to provide pain relief, which facilitates joint movement which facilitates recovery; after wounding on the battlefield to provide pain 5 relief, hemostasis, infection control during transport when applied topically or to exposed p~lcllle~al areas of the body.
The present invention provides a pliable, implantable material, suitable for use in surgery and dental practice, which releases a drug or biological agent to the surrounding tissue over a chosen period to achieve a therapeutic effect. Our invention can also be used 10 as a removable wound dressing. Our invention can also provide a semi-rigid material which is suitable for implantation in bone, and which is capable of releasing a drug or biological agent over long periods of time. In particular, contemplated uses include implanting the device during surgery to provide pain relief, implantation duringorthopedic surgery to provide infl~mm~tion relief thereby quickening the rehabilitation 15 process, implantation post dental extraction in the tooth socket for pain control; when impregnated with materials to hasten bone healing it will be implanted along sites of fracture to improve healing of bone; when impregn~te(l with antibiotics it will be implanted during surgery to provide sustained release of antibiotics to the local area; when impregnated with materials to improve clotting it will be implanted during surgery or post 20 dental extraction to facilitate hemostasis; when used topically it will be applied to provide pain relief if impregnated with anesthetics/analgesics; when impregnated with antibiotics it will be applied to prevent or treat infection.
Further aspects of our invention include the ability to control the rate and mode of release of the drug by choice of concentration and type of adjuvant used, as well as the 25 ability to incorporate the drug at high payload (up to 4 gm Drug/gm Carrier Material).
Thus, drugs can be delivered at high concentrations to the adjoining tissue for long durations to prevent the growth of bacteria, to facilitate wound healing and to even give systemic drug delivery, when needed. Additionally, the use of adjuvants to adjust the -CA 022062~9 1997-0~-28 WO 96/16643 PCT/USg5/14559 release rates for water-insoluble and water-soluble drugs is a significant aspect of our mvention.
In conclusion, 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 5 m~t~ri~l, 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 m~teri~l.
With the foregoing and other objects, advantages and features of the invention that will become hereinafter a~palellt, the nature of the invention may be more clearly understood by reference to the following detailed description of the invention, the appended claims and to the several views illustrated in the attached drawings.

Claims

WHAT IS CLAIMED IS:

1. A surgical implant, wound dressing, or suture, adapted to be applied to human or animal tissue comprising:
a fibrous carrier, solid microparticles of a pharmaceutical of between about 20 nanometers to about30 microns, carried by said fibers, and an adjuvant for adhering said microparticles to said fibers.

2. The surgical implant, wound dressing, or suture of claim 1 wherein said pharmaceutical particles are coated with said adjuvant and said adjuvant comprises a lipid membrane.

3. The surgical implant, wound dressing, or suture of claim 2, wherein said lipid is amphipathic.

4. The surgical implant, wound dressing, or suture of claim 2, wherein said lipid is selected from the group consisting of lecithin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, cardiolipin, phosphatidyl glycerol, phosphatidyl ethanolamine, sphingomyelin, monoglycerides, long-chain alkylamines, fatty acids, cholesterol, triglycerides at room temperature, diglyerides solid at room temperature, waxes, and combinations thereof.

5. The surgical implant, wound dressing, or suture of claim 1, wherein said carrier is an absorbable implant.

6. The surgical implant, wound dressing, or suture of claim 5, wherein said implant comprises a sterile gelatin sponge.

7. The surgical implant, wound dressing, or suture of claim 5, wherein said implant comprises cellulose.

8. The surgical implant, wound dressing, or suture of claim 1, wherein said carrier is a topical dressing 9. The surgical implant, wound dressing, or suture of claim 1, wherein said carrier is a suture.

10. The surgical implant, wound dressing, or suture of claim 1, wherein said pharmaceutical is water-insoluble.

11. The surgical implant, wound dressing, or suture of claim 1, wherein said pharmaceutical is selected from the group consisting of: antiseptics, antibiotics, antiinflammatories, local anaesthetics, tissue growth promoters, tissue destruction inhibitors, and combinations thereof.

12. The surgical implant, wound dressing, or suture of claim 1, wherein said microparticles are microcrystals.

13. The surgical implant, wound dressing, or suture of claim 1, wherein said pharmaceutical particles are less than 10 microns in diameter.

14. The surgical implant, wound dressing, or suture of claim 1, wherein said fibrous carrier retains as much as 4 grams of pharmaceutical per gram of carrier.

15. The surgical implant, wound dressing, or suture of claim 1, further comprising a preservative.

16. The surgical implant, wound dressing, or suture of claim 15, wherein said preservative is taken from the group consisting of benzalkonium chloride, benzethonium chloride, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenol, sodium benzoate, and EDTA.

17. A drug-releasing wound dressing or implant made by a method comprising the steps of:
providing a fibrous carrier material;
providing a suspension of a drug in microparticulate or microcrystalline solid form in a solvent, said microparticles or microcrystals being between about 20 nanometers to about 30 microns;
soaking said carrier material in said suspension; and evaporating said solvent.

18. The drug-releasing wound dressing or implant made by the method of claim 17, wherein said suspension further comprises an adjuvant for coating said drug.
19. The drug-releasing wound dressing or implant made by the method of claim 18, wherein said adjuvant is a lipid selected from the group consisting of lecithin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, caridolipin, phosphatidyl glycerol, phosphatidyl ethanolamine, spingomyelin, monoglycerides, long-chain alkylamines, fatty acids, triglycerides, diglycerides solid at room temperature, and waxes.

20. The dressing or implant made according to the method of claim 17, wherein said microparticles or microcrystals are about 20 nanometers to 30 microns.

21. The dressing or implant made according to the method of claim 17, said microparticles or microcrystals being water-insoluble.

22. The dressing or implant made according to the method of claim 17, wherein said pharmaceutical is selected from the group consisting of antiseptics, antibiotics, antiinflammatories, local anaesthetics, tissue growth promoters, tissue destruction inhibitors, and combinations thereof.

23. A method for controlled delivery of a drug to the tissue to of an animal or human, comprising applying to said tissue the surgical implant, wound dressing or suture of claim 1.

24. A method of administering a drug substance to an animal or human comprising the steps of applying a fibrous wound dressing or surgical implant impregnated with solid particles of a pharmacologically active water-insoluble drug substance, the solid particles being coated with a membrane-forming amphipathic lipid.

25. The method of claim 24, wherein said lipid is selected from the group consisting of lecithin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, cardiolipin, phosphatidyl glycerol, phosphatidyl ethanolamine, sphingomyelin, monoglycerides, long-chain alkylamines, fatty acids, triglycerides, diglyerides solid at room temperature, and waxes.

26. The method of claim 24, wherein said particles are about 20 nanometers to 30 microns.

27. The method of claim 24, wherein said particles are water-insoluble.

28. The surgical implant, wound dressing, or suture of claim 1, wherein said pharmaceutical particles are coated with a water soluble adjuvant selected from the group consisting of: collagen, gelatin, carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, benzalkonium chloride and benzethonium chloride.

29. The drug releasing wound dressing implant made by the method of claim 17, wherein said suspension further comprising a water soluble adjuvant selected from the group consisting of: collagen, gelatin, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, benzalkonium chloride and benzethonium chloride.

--30. A drug delivering surgical implant, dressing, or suture comprising:
a carrier consisting essentially of fibers having diameters of between about 0.1 micrometers to about 100 micrometers, said fibers being coated with a multilamellar, amphiphatic membrane; and, a pharmaceutical releasably bound to said fibers, said pharmaceutical comprising solid microparticles of between about 20 nanometers to about 20 micrometers, said microparticles being coated with a multilamellar, amphiphatic membrane.

31. The drug delivering surgical implant, dressing, or suture of claim 30 wherein said carrier is a porous matrix with said fibers being covalently cross-linked.

32. The drug delivering surgical implant, dressing, or suture of claim 30 wherein said carrier is thread-like and comprises multiple strands of said fibers.

33. The drug delivering surgical implant, dressing, or suture of claim 30, wherein said pharmaceutical is selected from the group consisting of antiseptics, antibiotics, antiinflammatories, local anesthetics, tissue growth promoters, tissue destruction inhibitors, and combinations thereof.

34. The drug delivering surgical implant, dressing, or suture of claim 30, further comprising a preservative.

35. The drug delivering surgical implant, dressing, or suture of claim 34, wherein said preservative is taken from the group consisting of benzalkonium chloride, benzethonium chloride, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenol, sodium benzoate, and EDTA.

36. The drug delivering surgical implant, dressing, or suture of claim 30 wherein said multilamellar, amphiphatic membrane is comprised of a substance selected from the group consisting of lecithin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, caridolipin, phosphatidyl glycerol, phosphatidyl ethanolamine, sphinomyelin and monoglycerides.

37. A drug delivering surgical implant, dressing, or suture comprising:
a carrier consisting essentially of fibers having diameters of between about 0.1 micrometers to about 100 micrometers, and, a pharmaceutical releasably bound to said fibers, said pharmaceutical comprising solid microparticles of between about 20 nanometers to about 20 micrometers, wherein said fibers and said microparticles are each coated with a substance selected from the group consisting of lecithin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, caridolipin, phosphatidyl glycerol, phosphatidyl ethanolamine, sphingomyelin, monoglycerides, long-chain alkylamines, fatty acids, triglycerides, diglycerides, and waxes.

38. The drug delivering surgical implant, dressing or suture of claim 37, wherein said carrier is a porous matrix with said fibers being covalently cross-linked.

39. The drug delivering surgical implant, dressing or suture of claim 37, wherein said pharmaceutical is selected from the group consisting of antiseptics, antibiotics, antiinflammatories, local anesthetics, tissue growth promotors, tissue destruction inhibitors, and combinations thereof.

40. The drug delivering surgical implant, dressing, or suture of claim 37, further comprising a preservative.

41. The drug delivering surgical implant, dressing or suture of claim 37 wherein said coating substance is lecithin.

42. The drug delivering surgical implant, dressing or suture of claim 30 wherein said coating substance is lecithin.

43. A drug delivering surgical implant, dressing, or suture comprising:
a carrier comprising a pharmaceutically acceptable fibrous matrix;
a pharmaceutical comprising microparticles of between about 20 nanometers to about 20 micrometers, releasably bound to said fibers;
said fibers and said microparticles are each coated with an adjuvant selected from the group consisting of collagen, gelatin, carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, benzalkonium chloride, benzethonium chloride, long-chain alkylamines, cholesterol, fatty acids and their salts, triglycerides, diglycerides and waxes.

44. The drug delivering surgical implant, dressing or suture of claim 43 wherein said fibrous matrix comprises fibers having diameters of between about 0.1 to about 100 micrometers.

45. The drug delivering surgical implant, dressing or suture of claim 43, wherein said pharmaceutical is selected from the group consisting of antiseptics, antibiotics, antiinflammatories, local anesthetics, tissue growth promotors, tissue destruction inhibitors, and combinations thereof.

46. The drug delivering surgical implant, dressing, or suture of claim 43, further comprising a preservative.

47. The drug delivering surgical implant, dressing or suture of claim 46, wherein said preservative is taken from the group consisting of benzalkonium chloride, benzethonium chloride, propylparaben, butylparaben, chlorobutanol, benzyl alcohol, phenol, sodium benzoate, and EDTA.

48. The surgical implant, dressing or suture of claim 43, wherein said pharmaceutical microparticles are less than 10 microns.

49. The drug delivering surgical implant, dressing or suture of claim 43, wherein said carrier retains up to about 4 grams of pharmaceutical per gram of carrier.

50. The drug delivering surgical implant, dressing or suture of claim 43, wherein said fatty acid salt is selected from the group consisting of calcium stearate, magnesium stearate, sodium stearate, and glycerol monostearate.

51. The drug delivering surgical implant, dressing or suture of claim 43, wherein said adjuvant further includes an ionic surfactant comprising sodium lauryl sulfate to aid pharmaceutical loading and release.

52. The drug delivering surgical implant, dressing or suture of claim 43, wherein said adjuvant further includes a non-ionic surfactant selected from the group consisting of polyoxamers, polyoxyl stearates, polysorbates, polypropylene glycol, and sorbitan fatty esters.

53. The drug delivering surgical implant, dressing or suture of claim 43, wherein said fibrous matrix is selected from the group consisting of cross-linked collagen or gelatin, cellulose and derivatives thereof, pyrrolidone, acrylates, polybutyrates, polyvalerates, polyglycolic acid, polyglactin and poly-D1L-lactate.

54. The drug delivering surgical implant, dressing or suture of claim 43, wherein said fibrous matrix is an absorbable gelatin sponge.