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  Hemostatic compositions and devicesUSPTO Application #: 20060019868Title: Hemostatic compositions and devices Abstract: The present invention includes both sterilized and unsterilized hemostatic compositions that contain a continuous, biocompatible liquid phase having a solid phase of particles of a biocompatible polymer suitable for use in hemostasis and which is substantially insoluble in the liquid phase, and a discontinuous, biocompatible gaseous phase, each of which is substantially homogenously dispersed throughout the continuous liquid phase, methods for making such compositions, medical devices that contain sterilized hemostatic compositions disposed therein and methods of making such devices. (end of abstract) Agent: Philip S. Johnson Johnson & Johnson - New Brunswick, NJ, US Inventors: Sanyog M. Pendharkar, Anne J. Gorman, Thomas L. Craven USPTO Applicaton #: 20060019868 - Class: 514002000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai The Patent Description & Claims data below is from USPTO Patent Application 20060019868. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to hemostatic compositions suitable for use in hemostatic devices that in turn are suitable for applying flowable hemostatic compositions to a site requiring hemostasis, to such hemostatic devices containing such compositions disposed therein and to methods of making such hemostatic compositions and devices. BACKGROUND OF THE INVENTION [0002] Gelatin-based hemostats, both in solid sponge or powder form, are commercially available and are used in surgical procedures. Gelatin powder, when mixed with fluid, can form a paste or slurry that is useful as a flowable, extrudable and injectable hemostat for diffuse bleeding, particularly from uneven surfaces or hard to reach areas. The conventional slurry is prepared at the point of use by mechanical agitation and mixing of the powder and liquid to provide uniformity of the composition. The paste then is placed into a delivery means or applicator, e.g. a syringe, and applied to the wound. [0003] The main disadvantage of this approach is the need to mix the powder with the liquid, knead it into a paste and back-fill it into the delivery device of choice, all at the time of need and at the point of use. The manipulations are time consuming and potentially can compromise the sterility of the delivered product. Thus, a need exists for a sterile, flowable, moldable hemostatic composition that is ready to use at the point of use or can be prepared with minimal manipulation and without risk of compromising the sterility of the product. [0004] It would be desirable if a hemostatic device, e.g. a delivery means such as a syringe or other applicator, would be pre-filled with a hemostatic composition and instantly available to the surgeon at the point of use without need for further manipulation. The hemostatic composition pre-filled in the device or applicator should be sterile and flowable and should require minimum preparation time and minimal force when extruded or injected through the delivery means at the point of use. The compositions of the present invention provide such properties and pre-filled devices. SUMMARY OF THE INVENTION [0005] The present invention is directed to hemostatic compositions suitable for use in preparing hemostatic devices that in turn are suitable for use in applying flowable hemostatic compositions and comprising a substantially homogenous, sterilized hemostatic composition disposed therein, where the composition comprises a continuous, biocompatible liquid phase, a solid phase comprising porous or non-porous particles of a biocompatible polymer suitable for use in hemostasis and which are substantially insoluble in the liquid phase, and a discontinuous gaseous phase comprising a biocompatible gas. The continuous liquid phase comprises the solid particulate phase and the discontinuous gaseous phase substantially homogenously dispersed there through. The ratio of the liquid phase, the solid particulate phase and the discontinuous gaseous phase is effective to provide the composition with hemostatic properties, both prior to and after sterilization. Compositions of the present invention may be prepared well in advance of the time of use and need not be prepared at the point of use, yet they maintain physical properties effective to provide flowability, extrudability or injectability at the point and time of use. The present invention also includes methods of making the hemostatic compositions, medical devices containing the compositions disposed therein and methods of making such devices. DETAILED DESCRIPTION OF THE INVENTION [0006] Both sterilized and unsterilized compositions of the present invention contain solid, porous or non-porous particles of a biocompatible polymer suitable for use in hemostasis, a biocompatible liquid and a biocompatible gas as its three necessary components. The particles, liquid and gas are combined and mixed under conditions effective to provide a substantially homogeneous hemostatic composition comprising a continuous liquid phase having the solid polymer particles and a discontinuous gas phase homogenously dispersed there through. The amount and average diameter of particles contained in the composition and the relative amounts of the solid, liquid and gaseous phases is effective to provide the composition with hemostatic and physical properties, as described herein below. [0007] The hemostatic composition so formed is a hemostatic paste, or slurry, that exhibits improved properties of flowability, extrudability and/or injectability when compared to flowable hemostatic compositions of similar liquid/particle composition but that do not contain a gaseous phase. Compositions of the present invention may be prepared, filled into a medical device, such as a syringe or other known applicators used to dispense flowable hemostatic compositions, and sterilized by ionizing irradiation, well in advance of the time of their intended use. The compositions further may include additives to facilitate the preparation of the composition, enhance physical and mechanical properties, enhance the hemostatic properties of the composition or provide antimicrobial properties. [0008] As used herein, "continuous" and "discontinuous" are used in the ordinary meaning of those words in the context of standard nomenclature used to define and describe dispersions. For example, when combined and mixed with the continuous liquid phase, the volume of biocompatible gas added to the liquid phase is disrupted by mixing so as to form the discontinuous, i.e. dispersed, gaseous phase comprising pockets or isolated bodies of gas. [0009] As used herein, "substantially homogenous" denotes that physical state of the compositions or pastes where the solid and/or gaseous phases are uniformly dispersed throughout the continuous liquid phase such that the ratio of solid:gas:liquid and the density of any portion or cross-section of the composition or paste are substantially the same. [0010] As used herein, "sterile" means substantially free of living germs and/or microorganisms and as further recognized and described by governmental standards pertaining to compositions and medical devices described and claimed herein. [0011] As used herein, "hemostatic", or "hemostatic properties", means the ability to stop or minimize bleeding, as one skilled in the art of hemostasis would understand those terms to mean, as further exemplified in the examples of the specification. [0012] As used herein, "Peak Expression Force" is the peak force value required to extrude compositions from a pre-filled 10 cc Becton Dickinson (BD) luer syringe fitted with a 14 gauge angiocatheter tip, as described in the examples of the specification. [0013] A variety of biocompatible natural, semi-synthetic or synthetic polymers may be used to prepare the solid particles used in compositions of the present invention. The polymer selected must be substantially insoluble in the liquid chosen for the particular composition. Preferably, water-insoluble biodegradable polymers that provide mechanical, chemical and/or biological hemostatic activity are used. Polymers that may be used include, without limitation, proteins and polysaccharides. Polysaccharides that may be used include oxidized cellulose, chitosan, chitin, alginate, oxidized alginate and oxidized starch. The biocompatible polymer used to prepare the particles preferably is a cross-linked or denatured protein, such as gelatin, collagen, fibrinogen or fibronectin. A preferred gelatin powder is Surgifoam.RTM. hemostatic gelatin powder, available from Johnson & Johnson Wound Management, a division of Ethicon, Inc. Surgifoam.RTM. powder is a partially cross-linked gelatin powder prepared by milling gelatin sponge into particles having an average diameter of from about 40 microns to about 1200 microns, more preferably from about 100 microns to about 1000 microns, as determined by laser diffraction. [0014] Compositions of the present invention comprise a continuous liquid phase in which the solid particles and gaseous phase are dispersed. Depending upon the particular medical device and use thereof, the liquid may be aqueous or non-aqueous. Preferably, the liquid phase is aqueous. Aqueous liquids may include, without limitation, biocompatible aqueous solutions, such as calcium chloride and saline. More preferably, the liquid phase comprises saline. The liquid phase and solid particulate phase are present in relative amounts effective to provide a paste, or slurry, suitable for use in providing hemostasis. Excessive dilution of the solid particulate phase, although beneficial to further reduce the peak expression force, will detrimentally affect the hemostatic properties of the material and therefore is not desired. The weight ratio of solid particles to liquid generally is from about 1:2 to about 1:12. A preferred weight ratio of the solid gelatin particles to saline is from about 1:3 to about 1:6. A more preferred weight ratio of the solid gelatin particles to saline is about 1:5. [0015] Any biocompatible gas may be used to prepare compositions of the present invention including, but not limited to, air, carbon dioxide, nitrogen, xenon or argon. Preferably an inert gas such as argon or nitrogen is used. Air, nitrogen and argon are sensitive to ultrasound and may provide a means to locate the composition once injected in the body. Similarly, as xenon is radio-opaque, using xenon also may provide a means to locate the composition once placed in the body. In addition, as carbon dioxide lowers pH, selection of carbon dioxide may enhance antimicrobial properties of the compositions. The gas must be combined and mixed with the continuous liquid phase until it is uniformly dispersed throughout the liquid phase so as to form a discontinuous, gaseous phase substantially homogenously dispersed in the continuous liquid phase. The homogenous dispersion of the gas phase in the liquid phase provides the composition with improved physical properties relating to flowability, extrudability and injectability, as described herein. Such improved properties are characterized by way of physical measurements of the compositions, including density and peak expression force, both prior to and after irradiation of the compositions during sterilization. [0016] The relative concentration of the three major components of the compositions of the present invention and the substantially homogenous nature of such compositions are key in providing both hemostatic and physical properties to the compositions. The solid particles, liquid phase and gaseous phase generally will be present in compositions of the present invention at a ratio of from about 1:2:1 to about 1:12:13, based on weight:volume:volume (g:ml:ml). Preferably the ratio will be from about 1:4:1 to about 1:8:9. More preferably the ratio will be about 1:5:3. The density of compositions of the present invention will be from about 0.9 g/ml to about 0.3 g/ml, more preferably from about 0.8 g/ml to about 0.6 g/ml. [0017] Compositions of the present invention include compositions described herein that are sterile, in that they have been irradiated with a level of, e.g. ionizing irradiation. Such irradiation may include e-beam or gamma irradiation. The level of irradiation and conditions of sterilization, including the time that the compositions are irradiated, are those that provide sterile compositions, as defined herein. Once having the benefit of this disclosure, one skilled in the art will be able to readily determine the level of irradiation necessary to provide sterile compositions. [0018] The hemostatic compositions may further comprise effective amounts of one or more additives or compounds including, but not limited to, antimicrobial agents, foaming agents, foam stabilizers, surfactants, antioxidants, humectants, wetting agents, lubricants, thickeners, diluents, irradiation stabilizers, e.g. radical scavengers, plasticizers, and stabilizers. For example, glycerol may be added to enhance the extrudability or injectability of the composition. When utilized, glycerol may be present in the compositions at from about 0% to about 20% by weight, based on the weight of the liquid phase. Preferably, the composition may comprise from about 1% to about 10% by weight of glycerol, based on the weight of the liquid phase. More preferably, the compositions may comprise from about 1% to about 5% by weight of glycerol, based on the weight of the liquid phase. [0019] In addition, quaternary amines may be used to provide enhanced properties to the compositions. For example, benzalkonium chloride, Polybrene or Onamer M may be used at levels up to about 1 percent by weight, based on the weight of the liquid phase. Preferably, benzalkonium chloride is used at levels of from about 0.001% to about 0.01% by weight, based on the weight of the liquid phase. More preferably, the compositions may comprise from about 0.002 to about 0.006% by weight benzalkonium chloride, based on the weight of the liquid phase. It is believed that the quaternary amines may serve multiple functions, acting as an antimicrobial agent, a foaming agent, a radical scavenger and as a heparin neutralizer. [0020] Such hemostatic compositions may further comprise heparin neutralizers, procoagulants or hemostatic agents, such as thrombin, fibrinogen, fibrin, Factor Xa, or Factor VIIa. By "effective amount", it is meant that amount necessary to provide to the compositions those properties for which the additive is being added. The effective amount also is limited by the maximum amount that may be added without causing detrimental biological affects. Continue reading... Full patent description for Hemostatic compositions and devices Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Hemostatic compositions and devices patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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