Compositions containing oxidized cellulose

Abstract

Disclosed is a composition comprising oxidized cellulose (OC) in powder form, wherein the OC has a carboxyl content of about 9% to about 18% by weight. Optionally, the powder is in agglomerated form. Further disclosed is a use of the composition for preventing tissue adhesions in the presence of bleeding.

Description

[Technical Field]

[0001] The present invention relates, inter alia, to oxidized cellulose powder and the use of oxidized cellulose powder for preventing adhesions at bleeding sites. [Background technology]

[0002] In various situations during surgery, therapeutic agents are deployed within the human body to prevent bleeding or adhesions after surgery. Existing agents have drawbacks, such as difficulty in deploying sheets during minimally invasive surgeries (MIS).

[0003] Prevention of adhesions and control of bleeding are essential and important in surgical procedures to minimize blood loss, reduce postoperative complications, and shorten surgical time in the operating room.

[0004] Selection of an appropriate method or product for controlling bleeding and / or adhesions depends on many factors, including, but not limited to, the severity of the bleeding, the anatomical location of the bleeding source and the proximity of adjacent critical structures, whether the bleeding is from a discrete source or from a larger surface area, the visibility and precise identification of the bleeding source, and access to the bleeding source.

[0005] Several products are commercially available to prevent adhesion formation. Some adhesion barriers are based on oxidized cellulose (OC), such as oxidized regenerated cellulose (ORC), modified sugars, and modified starches.

[0006] In an effort to address the above-mentioned problems, materials have been developed for both adhesion prevention and excessive bleeding control. Topical absorbable hemostats (TAHs) are widely used in surgical applications. TAHs include products based on OC, gelatin, collagen, chitin, chitosan, etc. To improve hemostatic performance, scaffolds based on the above-mentioned materials can be combined with biologically derived clotting factors such as thrombin and fibrinogen.

[0007] Due to their biodegradability and their antiseptic and hemostatic properties, OC-based materials, such as ORC, have long been used as topical hemostatic agents. ORC-based products are used in a variety of surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, gynecological surgery, and skin and subcutaneous tissue procedures. Several methods are known for forming various types of hemostatic agents based on OC materials, whether they are made as powders, woven fabrics, nonwoven fabrics, knitted fabrics, and other forms. Currently utilized hemostatic agents include powders or fabrics containing ORC.

[0008] There is a need for improved forms and materials that facilitate ease of application, particularly at the site of bleeding and in hard-to-reach areas.

[0009] US Pat. No. 9,447,196 (B2) discloses a process for dissolving modified cellulose, comprising contacting a modified cellulose solution with at least one non-solvent to form a plurality of modified cellulose particles.

[0010] No. 9,572,907 describes an implantable medical device comprising a polymeric film layer containing glycerol and at least one biopolymer.

[0011] EP 3258974 describes a hemostatic composition comprising a moisture-retaining agent, a binder dust suppressant, an inorganic hemostatic agent and an organic hemostatic agent.

[0012] US Patent No. 6,627,749 discloses a controlled chemical method for producing oxidized cellulose in high yields (75-95%) and at different oxidation levels (carboxyl content <25.6%, w / w)), suitable for use as an immobilization matrix or carrier for drugs, chemicals, and biopolymers.

[0013] US Patent Application Publication No. 20060008505 discloses a hemostatic delivery system comprising a self-adhesive strip of a bioadhesive, specifically pectin, and a glycerol plasticizer.

[0014] WO2013049049 discloses an anti-adhesion fabric having a first absorbable oxidized regenerated cellulose nonwoven fabric and a second absorbable oxidized regenerated cellulose woven or knitted fabric, the anti-adhesion fabric being useful for preventing adhesions in the presence of blood.

[0015] INTERCEED (Johnson & Johnson Patient Care Inc., New Brunswick, NJ) is an absorbent fabric specifically designed to reduce postoperative adhesions (FERTILITY AND STERILITY Vol. 51, No. 6, June 1989 INTERCEED (TC7) Adhesion Barrier Study Group). Summary of the Invention [Means for solving the problem]

[0016] The present invention relates, inter alia, to a composition comprising oxidized cellulose (OC), e.g., oxidized regenerated cellulose (ORC) in powder form, wherein the carboxyl content of the OC ranges from about 9% to about 21% by weight, and to the use of the composition for preventing adhesions at bleeding sites.

[0017] The present invention is based, inter alia, on the unexpected discovery that oxidized OC, e.g., ORC in powder form, can be effective in preventing adhesions even in the presence of blood. The carboxyl content of the OC can be 21% by weight or less, e.g., up to 18% by weight. This finding is surprising because it has previously been reported that the effectiveness of INTERCEED in preventing adhesions is limited in the presence of bleeding.

[0018] In one aspect, a composition is provided comprising oxidized cellulose (OC) in powder form, the OC having a carboxyl content of about 9% to about 21% by weight. In some embodiments, the OC has a carboxyl content of 18% or less by weight. In some embodiments, the composition is for use as an adhesion barrier at a bleeding site. In some embodiments, the powder is in agglomerated form (i.e., in the form of one or more aggregates). In some embodiments, the powder comprises ground OC or ORC.

[0019] In some embodiments, the powder is in an agglomerated form, the OC comprises an ORC, and the OC or ORC has a carboxyl content of 18% or less by weight.

[0020] In some embodiments, the particle size of at least 90% of the powder is in the range of 10 to 2,000 μm, optionally 50 to 300 μm.

[0021] In some embodiments, the composition in any of its embodiments is characterized by an anti-adhesion efficacy of at least 120% compared to an OC fabric having or consisting of the same carboxyl content, hi some embodiments, the powder is subjected to gamma irradiation.

[0022] In some embodiments, the OC comprises ORC in the form of a compacted powder, optionally comprising particles having an average aspect ratio of about 1 to about 18.

[0023] In some embodiments, the powder has an average particle size of 1.75 micrometers to 116 micrometers, with a median diameter of about 36 micrometers. In some embodiments, the consolidated ORC powder is roller-compacted and / or hammer-milled ORC powder. In some embodiments, agglomerates of ORC (e.g., made by milling) are consolidated.

[0024] In some embodiments, the composition further comprises an additive, which may include carboxymethyl cellulose (CMC) or other polysaccharides, calcium salts, anti-infective agents, hemostatic promoters, gelatin, collagen, or combinations thereof.

[0025] In some embodiments, the composition is in the form of a particulate aggregate, and the OC, in the form of the aggregate, forms interconnected individual cellulosic fibrils having a sphericity of at least 0.6 and a dimension along its longest axis that is less than about 500 micrometers and greater than about 50 micrometers. In some embodiments, the aggregate has a size distribution profile with a D15 greater than about 80 micrometers, a D50 of about 140-250 micrometers, a D90 less than about 370 micrometers, a bulk density greater than 0.45 g / mL, and / or a sphericity (sh50) of 0.7 or greater.

[0026] In another aspect, a kit is provided that includes: a. a container containing a composition of the present invention in any of its embodiments; b. an applicator for applying the composition to tissue; and c. optionally, instructions for use.

[0027] In some embodiments, the container is included in an applicator.

[0028] In another aspect, a method for preventing tissue adhesions is provided, comprising applying a composition disclosed in any of the embodiments thereof into / onto bleeding tissue. In some embodiments of this aspect, the OC comprises an ORC.

[0029] By "preventing tissue adhesions" it is intended to include preventing tissue adhesions within the tissue (to which the composition is applied) or adjacent tissues, where blood is present in one or both of these tissues.

[0030] In some embodiments of any aspect, the carboxyl content of the ORC is 18% or less.

[0031] In some embodiments, the composition further comprises at least one biologically active agent. In some embodiments of any aspect, the at least one biologically active agent is or comprises calcium. In some embodiments of any aspect, the composition further comprises one or more excipients selected from the group consisting of sodium chloride, mannitol, albumin, and sodium acetate.

[0032] In some embodiments of any aspect, the OC powder comprises ORC powder.

[0033] Typically, a powder is a finely divided substance, such as a particulate material. A powder can be a loose collection or agglomerate of solid particles, typically, but not exclusively, smaller than 1000 micrometers.

[0034] Absorbable oxidized regenerated cellulose fabrics that can be used to prepare the powder are knitted and include, but are not limited to, INTERCEED available from Johnson & Johnson Wound Management, a division of Ethicon, Inc., (Somerville, NJ).

[0035] Absorbable oxidized regenerated cellulose nonwoven, woven, or knitted fabrics may also be used to prepare powders. Such fabrics are described, for example, in U.S. Patent Nos. 4,626,253, 5,002,551, and 5,007,916, the contents of which are incorporated herein by reference as if set forth in their entireties.

[0036] In some embodiments of any aspect, to achieve adhesion prevention, the OC has a carboxyl content of 18% or less, eg, according to United States Pharmacopeia (USP) 23-NF18.

[0037] Throughout this specification, the carboxyl content of OC is in wt %.

[0038] Prevention can be achieved by administering a compound to a subject prone to adhesions.

[0039] In some embodiments, the carboxyl content of the OC (or ORC) is greater than or equal to 9% and less than or equal to 18% or less than or equal to 21% according to United States Pharmacopeia (USP) 23-NF 18. In some embodiments, the carboxyl content of the OC (or ORC) is greater than or equal to 3% and less than or equal to 18% or less than or equal to 21% according to United States Pharmacopeia (USP) 23-NF 18.

[0040] In some embodiments of any aspect, the carboxyl content of the OC (or ORC) is greater than or equal to 9% and less than or equal to 18% according to United States Pharmacopeia (USP) 23-NF18.

[0041] In some embodiments of any aspect, the carboxyl content of the OC (or ORC) is greater than or equal to 12% and less than or equal to 18%, for example, according to United States Pharmacopeia (USP) 23-NF18.

[0042] Suitable ORC fabrics include, but are not limited to, absorbable adhesion barriers such as the INTERCEED absorbable adhesion barrier available from Ethicon, Inc. (Somerville, NJ).

[0043] In some embodiments of any aspect, the textile is a warp-knit tricot fabric composed of bright rayon yarn, which is subsequently oxidized to contain an effective amount of carboxyl or aldehyde moieties to render the textile biodegradable. The textile may be oxidized by reacting cellulose with a solution of nitrogen dioxide in a perfluorocarbon solvent, as described in U.S. Patent No. 5,180,398 to F. Boardman et al. In one embodiment, the carboxyl content ("oxidation degree") ranges from about 9% to about 21% (wt / wt). In another embodiment, the carboxyl content ranges from about 12% to about 18% (wt / wt). In yet another embodiment, the oxidized regenerated cellulose oxidation degree ranges from about 9.5% to about 10.5% (wt / wt). In some embodiments, the oxidation degree is about 9% to about 21% (wt / wt) according to United States Pharmacopeia (USP) 23-NF18. In some embodiments, the degree of oxidation is from about 9% to about 18% (wt / wt) according to United States Pharmacopeia (USP) 23-NF18.

[0044] In some embodiments of any aspect, the OC powder has a carboxyl content of 9% or greater according to United States Pharmacopeia (USP) 23-NF18. In some embodiments of any aspect, the OC powder has a carboxyl content of 9% or greater and 18% or less (wt / wt) according to United States Pharmacopeia (USP) 23-NF18. In some embodiments of any aspect, the OC powder has a carboxyl content of 12% or greater. In some embodiments of any aspect, the OC powder has a carboxyl content of 12% or greater and 18% or less (wt / wt) according to United States Pharmacopeia (USP) 23-NF18. In one embodiment, the carboxyl content (oxidation level) ranges from about 9% to about 21% (wt / wt). In another embodiment, the oxidation level ranges from about 12% to about 18% (wt / wt).

[0045] In yet another embodiment, the oxidized regenerated cellulose fabric has a degree of oxidation ranging from about 9.5% to about 10.5%. In some embodiments, the OC has a carboxyl content of about 9% to about 21% according to United States Pharmacopeia (USP) 23-NF18.

[0046] In some embodiments of any aspect, the OC has a carboxyl content of about 9% to about 21% according to United States Pharmacopoeia (USP) 23-NF 18. In some embodiments, the OC has a carboxyl content of about 18% to about 21%.

[0047] In some embodiments of any aspect, the composition is for use as an adhesion barrier.

[0048] In some embodiments of any aspect, the OC has a carboxyl content of about 18% to about 21%, for example, for use in preventing adhesions at bleeding sites in soft tissue. In some embodiments of any aspect, the OC has a carboxyl content of about 12% to about 18%, for example, for use in preventing adhesions at bleeding sites in soft tissue. Prevention of adhesions can be achieved by administering the composition in one embodiment into or near bleeding tissue, for example, in a wound.

[0049] In some embodiments of any aspect, the particle size of the OC powder is between 10 μm and 2,000 μm, optionally between 50 μm and 300 μm. In some embodiments, the carboxyl content of the OC in the powder is between about 12% and about 21%. In some embodiments, the carboxyl content of the OC in the powder is between about 18% and about 21%. In some embodiments, the carboxyl content of the OC in the powder is between about 12% and about 18%. In some embodiments, the carboxyl content of the OC is between about 12% and about 21%, and the composition is not flowable at one or more temperature values ​​selected from the group consisting of 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 37° C., and 40° C.

[0050] In some embodiments of any aspect, the total water content of the composition is less than about 8% w / w.

[0051] In some embodiments of any aspect, the compositions disclosed throughout are adhesion prevention powders for use at bleeding sites that include an OC having a carboxyl content equal to or below 18% (by weight) (e.g., 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%, including any values ​​and ranges between the recited values), characterized by at least 120%, or at least 150%, adhesion prevention efficacy compared to an OC fabric having or consisting of a similar carboxyl content. As used herein, similar means the same or ±10%. In some embodiments, the powder is a irradiated powder, e.g., a gamma-irradiated powder.

[0052] In one embodiment of any aspect, the adhesion prevention powder for use at a bleeding site comprises milled OC (e.g., ORC) in an agglomerated form. In some embodiments, the carboxyl content of the OC powder in the milled OC having an agglomerated form for use at a bleeding site is 9% or more and 18% or less (by weight) in accordance with United States Pharmacopeia (USP) 23-NF18. In some embodiments, the carboxyl content of the OC powder in the milled OC having an agglomerated form for use at a bleeding site is 9% or more and 18% or less (by weight) in accordance with United States Pharmacopeia (USP) 23-NF18. In some embodiments, the carboxyl content of the OC powder in the milled OC having an agglomerated form for use at a bleeding site is 12% or more and 18% or less (by weight) in accordance with United States Pharmacopeia (USP) 23-NF18.

[0053] The term "bleeding site" also encompasses situations in which bleeding does not necessarily originate at the site, but rather from other sites or sources, such as, for example, potentially adjacent tissue. Thus, the terms "at the bleeding site" and "in the presence of blood" are used interchangeably throughout this specification.

[0054] Absorbable oxidized regenerated cellulose nonwoven, woven or knitted fabrics may be used to prepare the powder.

[0055] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, representative methods and / or materials are described below. In case of conflict, the present patent specification, including definitions, will govern. It should be noted that the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting. [Brief explanation of the drawings]

[0056] Some embodiments of the present invention are herein described, by way of example only, with reference to the accompanying drawings. Referring now specifically to the drawings in detail, it is emphasized that the details shown are exemplary and are for the purpose of illustrating embodiments of the invention. In this regard, the description using the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Figure 1] 1 is a graph showing adhesion strength in a rat cecal abrasion model treated with a composition comprising INTERCEED® ORC and glycerol. Left to right: No treatment, INTERCEED®, INTERCEED® powder (milled / crushed ORC compressed into small granules), n=6. DETAILED DESCRIPTION OF THE INVENTION

[0057] It is an object of the present invention to provide compositions, e.g., comprising oxidized cellulose (OC), for use as adhesion barriers that can be easily applied to the site of bleeding, particularly in hard-to-reach areas of the body. A further advantage of the compositions of the present invention is that they are bioabsorbable and therefore can be left in place after surgery without causing side effects.

[0058] Thus, the present invention is based on the surprising discovery that OC powder in a specific range of oxidation degree can be applied to the required site to obtain biological activity such as adhesion prevention.

[0059] "Applied to the site in need" is meant to refer to local application of the composition at or adjacent to a site, such as a surgical site, where tissue is bleeding, to prevent adhesions.

[0060] Referring to Figure 1, there is shown a comparison of adhesion prevention tested in a rat cecal abrasion model using: 1 - INTERCEED® fabric; 2 - ground / milled INTERCEED compressed into small granules (INTERCEED powder). INTERCEED powder was found to exhibit superior or comparable adhesion prevention activity to INTERCEED sheet at the bleeding site. It is further noteworthy that gamma-irradiated INTERCEED agglomerated powder exhibited approximately 135% adhesion prevention efficacy compared to INTERCEED fabric.

[0061] INTERCEED powder in the form of an agglomerate is also referred to herein as milled / crushed INTERCEED in agglomerated form, milled / crushed INTERCEED compressed into small granules, compacted INTERCEED powder, and INTERCEED compacted in agglomerate form.

[0062] INTERCEED powder in the form of an aggregate can be produced by the process described in the examples of U.S. Patent No. 9,539,358. Oxidized regenerated cellulose (ORC) is the base material in INTERCEED® sheets (Ethicon), which can be used in place of SURGICEL® sheets (Ethicon). INTERCEED powder in the form of an aggregate can be subjected to 20 to 45 kilograys of gamma radiation (e.g., by technology from Sorvan Radiation LTD) to provide sterility.

[0063] As used herein, unless otherwise specified, the terms "by weight," "w / w," "weight percent," or "wt %" may be used interchangeably herein to describe the concentration of a particular substance in the total weight of the corresponding mixture, solution, formulation, or composition.

[0064] As used herein, the term "hemorrhage" refers to the extravasation of blood from any component of the circulatory system. Thus, "hemorrhage" encompasses unwanted, uncontrolled, and often excessive bleeding associated with surgery, trauma, or other forms of tissue damage, as well as unwanted bleeding in patients with bleeding disorders.

[0065] As used herein, the term "adhesion" or "tissue adhesion" refers to the connection of tissues that are not normally connected. For example, adhesions can occur as a post-surgical complication.

[0066] As used herein, the terms "control," "prevent," or "reduce" may be used interchangeably herein in connection with tissue adhesions (including all grammatical inflections thereof) to indicate that the formation of tissue adhesions is completely or partially prevented, or the severity of the adhesions is reduced, for example, according to the adhesion rating scheme by Poehnert et al., 2015, International Journal of Medical Sciences 12(1):1-6, as described in the Examples section.

[0067] "At or near room temperature" is meant to refer to at least one temperature within the range of 10°C to 40°C, or 15°C to 37°C, for example, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 37°C, or 40°C (including any value therebetween).

[0068] Non-limiting exemplary powders include solid particles including ORC fibers and / or granules (also referred to as "granular ORC").

[0069] As used herein, "homogeneous" is meant to refer to uniform composition and texture throughout.

[0070] The term "oxidized cellulose" (or "OC") refers to a cellulose derivative in which at least a portion of the primary alcohol groups, e.g., the 6-carbon of the anhydroglucose units, have been oxidized to a carboxylic acid, and optionally functionalized.

[0071] OC can be produced by applying an oxidizing agent to cellulose. The oxidizing agent can be selected from, but is not limited to, chlorine, hydrogen peroxide, peracetic acid, chlorine dioxide, nitrogen dioxide, persulfates, permanganates, dichromate-sulfuric acid, hypochlorous acid, hypohalous acids, periodates, or any combination thereof, and / or various metal catalysts. Depending on the nature of the oxidizing agent and reaction conditions, the oxidized cellulose may contain carboxylic acid, aldehyde, and / or ketone groups in place of, or in addition to, the original hydroxyl groups of the starting cellulose.

[0072] The OC used in the compositions of the present invention is typically, but not limited to, in the form of a powder (also referred to as granular OC, milled / ground OC, or agglomerated milled / ground OC). Milled / ground OC can be prepared by various methods, including from existing products, and some non-limiting examples of such products are described below. Because some existing products are in the form of fabric, OC powders may be prepared by crushing or grinding the fabric to obtain a powder. For example, milled OC (or ORC) can be obtained by reducing the size of OC sheets, such as SURGICEL® or INTERCEED® sheets, by grinding as described in U.S. Pat. No. 9,539,358, which discloses the preparation of compacted powders, including ORC-ball-milled powders (BMP).

[0073] Thus, in a non-limiting exemplary embodiment, several pre-trimmed pieces of non-sterile INTERCEED fabric (ETHICON, Inc., lot number 7A8654) measuring 4 inches by 4 inches can be vacuum dried for 24 hours prior to milling. A 6-gram sample can be mixed with 12 high-density ZrO2 balls (20 mm diameter, Glen Mills Inc., Clifton, NJ, USA) and sealed in a 250 mL milling jar. The jar can be clamped into a latch bracket and then balanced in a mill (Planetary Ball Mill PM100; Retsch, Inc., Newtown, PA, USA). Milling can be carried out at 300 rpm for 10 minutes. The milled powder can then be dried at 65°C for 2.5 hours in a vacuum oven (Fisher Scientific Model 280A Isotemp Vacuum Oven) equipped with a vacuum pump (LabCare America Pump PV-35). The milled powder can finally be stored in a nitrogen box. Using a similar method as above, powders can be prepared using ORC-based SURGICEL® NU-KNIT® absorbent hemostat. Roller-compacted ORC powder can be prepared using ORC that has been shredded through a Fitz Mill equipped with sieve mesh sizes 1726-150. The shredded ORC powder can be fed into a roller compactor (WP 120x 40V, #900-0071 (Alexanderwerk, Inc., PA)) and compacted as described in U.S. Pat. No. 9,539,358.

[0074] Additionally or alternatively, the powder composition according to the invention, comprising fibers and optionally other compounds, is optionally compacted into an agglomerate form using a process of drying, grinding / milling and sieving, for example as described in U.S. Patent No. 10,034,957. The sieve used defines the particle size of the powder.

[0075] Thus, as described in U.S. Pat. No. 10,034,957, the grinding step can be preceded by a step of slitting and chopping the cellulosic raw material to form fragments. The grinding step can be a two-part process, with the second part being performed in an air classifier and the second part being repeated three times. The intermediate fine fibers produced by this process can have a size distribution with a D50 of less than about 100 micrometers and a D90 of less than about 180 micrometers. The intermediate fine fibers can be moistened to a moisture content of 11.0% to 20% by weight. The intermediate fine fibers can be roller-compacted material, then subjected to pre-crushing and then to a final grinding step. The intermediate fine fibers can be compressed with a roller pressure of at least 130 bar. The intermediate fine fibers can be compressed with a roller force of at least 26.0 kN / cm. The resulting material may be an aggregate fraction having a dimension along its longest axis of 75-300 μm by screen sieving. In some embodiments, the aggregate fraction is characterized by a size distribution in which D15 is greater than about 80 micrometers, D50 is about 140-250 micrometers, and D90 is less than about 370 micrometers. As described throughout this specification, the source material may be selected from ORC fabric, ORC nonwoven, shredded ORC material, or a combination thereof. The source material may further include, without limitation, an additive or active agent selected from carboxymethylcellulose, calcium salts, anti-infective agents, gelling agents, gelatin, collagen, or a combination thereof.

[0076] In some embodiments, one process for producing the hemostatic aggregates of the present invention comprises the steps of: a) cutting the cellulose raw material into strips; b) grinding the material resulting from step a); c) a second grinding step in an air classifier; d) moistening; e) roller compaction; f) sieving; g) dehumidifying or drying; h) optionally pouring into storage containers or delivery devices and primary and secondary packaging; and i) an optional sterilization step.

[0077] Slitting can be performed to slit the fabric into pieces of appropriate size, between about 1 inch by 3 inches or 2 inches by 3 inches, although smaller pieces can also be used. The primary operations performed for slitting are unwinding a roll of fabric material, slitting the fabric material into strips, cutting the strips to size, and feeding the cut pieces to the first grinding step. Many cutting and slitting machines are known and commercially available, such as, but not limited to, the AZCO Model FTW-1000 available from AZCO.

[0078] In some embodiments, in the first milling step, the treated cellulose fabric pieces are converted from the intermediate coarse fibers produced in the slitting step into a material having a D90 value of less than 452 μm and a D50 value of less than 218 μm, while minimizing the impact on the color index and water soluble content of the material. Numerous machines for milling are commercially available, including, but not limited to, models DASO6 and WJ-RS-D6A manufactured by Fitzpatrick, which are hammer mill-type mills equipped with a 497-micrometer round screen and a set of blades that break down the fabric until it passes through the screen to produce intermediate coarse cellulose fibers. In an exemplary processing run, the mill speed may be approximately 7000 RPM, the processing temperature may be less than 80°C, the screen size may be 1534-9004, the number of blades may be eight (two impellers each), the blade type may be 225 knives, the impact blades may be impact-type blades, and the blade orientation may be set as "impact." The intermediate coarse fibers from the first milling step may be fed at a controlled rate into a second mill and passed through two milling chambers separated by a milling screen. The material may be drawn from the milling chambers by a blower. The intermediate coarse fibers may be processed through an air classifier three times to obtain the desired size. At the end of the second milling step, the intermediate fine fibers may be collected.

[0079] In an exemplary processing run, a Quadro air classifier F10 can be used in the second milling step with a milling speed of 8400 rpm, a blower speed of 1800 rpm, a 0.0018-inch round-hole screen, and three passes. ORC intermediate fine fibers can also be produced in one step by ball milling instead of the two-step milling process described above. In an alternative ball milling embodiment, 50 g of pre-cut ORC fabric (2 inches x 2 inches) is ball milled in 12-density zirconia (20 mm diameter zirconium dioxide, ZrO2; Glen Mills Inc., Clifton, NJ, USA) by placing the balls and sample in a 500 mL milling jar. The jar can be clamped into a latch bracket and then balanced in a planetary ball mill PM100 (Retsch, Inc., Newtown, PA, USA). Milling can then be carried out bidirectionally at 450 rpm for 20 minutes.

[0080] In some embodiments, after the milling process, the resulting cellulose intermediate fines are humidified to a moisture content of about 11% to about 18%, or 11% to about 16%, or about 12% to 16%, for subsequent processing, including roller compaction. A non-limiting humidity chamber suitable for the humidification step is commercially available from Thermal Product Solutions as Model CEO-916-4-B-WF4-QS. Humidification of the chamber air can be achieved by water vapor injection. A typical steady-state temperature of 25°C may be utilized, while humidity levels may be cycled between 75% and 85%, with an air humidity of 85% being the target. The humidification time or residence time of the material in the humidity chamber can range from several hours to several days, depending on the material and the amount of air recirculation. In a typical cycle, the material is placed in several trays and subjected to a relative humidity of 85% and a target moisture content of 12% for approximately 3,000 grams of cellulose intermediate fines, with a residence time of 12-13 hours. Cellulose intermediate fines with a moisture content of over 16% by weight, such as 20% by weight, may be used for the compaction process. The resulting ORC intermediate fines may solidify during compaction, exhibit very poor flowability, and interfere with the compactor. Therefore, high moisture content of the intermediate fines may not result in a suitable hemostatic aggregate material. Conversely, when the moisture content of the intermediate fine cellulose fibers is less than about 8%, the yield of hemostatic aggregate is extremely low, with the yield of the desired hemostatic aggregate being approximately 5%. The moistened intermediate fine ORC fibers are then compacted and sieved to obtain the hemostatic aggregate material. A roller compactor may compress the feed, which may then be subjected to pre-crushing, final grinding, and sieving in a screener to obtain the desired hemostatic aggregate size.

[0081] Compaction equipment is known and commercially available. Non-limiting exemplary compaction units are the Fitzpatrick Chilsonator IRR220-L1A equipped with a Retsch manual sieve AS200 screener and the Fitzpatrick Chilsonator CCS220 / M3B & RV-M5A equipped with a Sweco Vibro-energy unit integrated under the M5A screener. The compaction process can be carried out using two separate subsystems linked by a common electrical system. For example, the first subsystem (roller compactor: main unit) can be a Fitzpatrick Chilsonator CCS220 roller compactor and an M3B mill for pre-crushing the compacted material, while the second subsystem (roller compactor: secondary grinding unit) can be an M5A mill for final grinding with a Sweco or Retsch screener for separation to obtain aggregates of the desired size. The moistened intermediate-fine cellulose fibers may be fed into the hopper of a roller compactor unit, first passing through a main grinding unit and then through a secondary grinding unit. A container may be provided to capture the pre-ground cellulose material obtained from the main grinding unit. The pre-ground cellulose material fragments may then be fed into a secondary grinding unit, which performs final grinding and screening using a screen mesh. The resulting ground cellulose material may be separated into fine (<75 μm), target (75-300 μm), and oversized (>300 μm) fractions using a screen mesh, such as the Sweco or Retch screeners described herein.

[0082] Other methods besides ball milling can be used to produce high-density, low-aspect-ratio consolidated ORC powders. Rolling compaction refers to the continuous consolidation of powders by a roll mill. The powder can be delivered to the rolls by a feed screw and densified by pressure and shear forces. Roll compaction is a powder agglomeration process used in a variety of industries, including the pharmaceutical, mineral, and chemical industries. Roll compaction of a poorly flowing powder mixture can involve screw-feeding the powder between two counter-rotating rollers. These counter-rotating rollers can then draw the powder into a consolidation zone and apply high pressure to form a strip of consolidated powder. Powder compressed into such a strip or ribbon by the pressure between the two counter-rotating rollers can then be further milled into low-aspect-ratio fine particles. Woven or nonwoven ORC material, or chopped or ball-milled ORC material, can be further roller-compacted to achieve the desired low-aspect-ratio, high-density ORC particles.

[0083] Hammer mills are another method that can be used to produce ORC particles with sufficiently low aspect ratios and high tap densities. Hammer mills operate by impact action and pulverize most dry, free-flowing materials. Material can be fed into the hammer mill from the top and then dropped into the grinding chamber. This material can be contacted by a series of hardened steel hammers rotating at high speed. The material can be pulverized by repeated contact with the hammers, contact with the walls of the grinding chamber, and contact between particles. Material can remain in the hammer mill grinding chamber until it is small enough to escape by passing through a perforated screen that covers the bottom half of the grinding chamber.

[0084] A hammer mill is essentially a steel drum containing a vertical or horizontal rotating shaft or drum fitted with hammers. The hammers can be freely swinging at the ends of a cross or fixed to a central rotor. The rotor can rotate at high speed inside the drum while the material is fed into a feed hopper. The material can be impacted by the hammer bars, thereby shredding it and discharging it through a screen within the drum of a selected size. Hammer mills can be used as primary, secondary, or tertiary crushers; i.e., ORC can be hammer-milled from woven or nonwoven ORC sources, or from shredded or ball-milled ORC material. The primary difference between chopping (shredding) and ball milling and other compaction / grinding processes is the mechanical impact of crushing, without the sharp blades used in ball milling and other compaction processes. Due to the lack of sharp blades, the particles can acquire different properties in terms of particle shape, surface, tap density, etc., compared to shredded (i.e., blade-ground) particles.

[0085] In an exemplary embodiment, the OC is oxidized to contain carboxyl moieties in an amount effective to provide biodegradability.

[0086] U.S. Patent No. 3,364,200 discloses the preparation of carboxy-oxidized cellulose using an oxidizing agent such as nitrogen dioxide in a Freon medium. U.S. Patent No. 5,180,398 discloses the preparation of carboxy-oxidized cellulose using an oxidizing agent such as nitrogen dioxide in a perfluorocarbon solvent. After oxidation by either method, the fabric may be thoroughly washed with a solvent such as carbon tetrachloride, followed by a 50% aqueous solution of isopropyl alcohol (IPA), and finally 99% IPA. Prior to oxidation, the fabric may be constructed of any desired woven or nonwoven structure.

[0087] Typically, hemostatic agents compatible with acid-sensitive species include a fabric substrate prepared from a biocompatible, aldehyde-oxidized polysaccharide. In such exemplary hemostatic agents, the polysaccharide contains an effective amount of aldehyde moieties to render the modified polysaccharide biodegradable, meaning that the polysaccharide is capable of breaking down into components that can be reabsorbed by the body or easily passed through the body. More specifically, the biodegraded components do not induce a permanent, chronic foreign body reaction when absorbed into the body, such that substantially no permanent, minor component or component residue ultimately remains at the implantation site.

[0088] In certain embodiments of the present invention, the OC comprises particles prepared from biocompatible, biodegradable, aldehyde-oxidized regenerated cellulose. In some embodiments, the aldehyde-oxidized regenerated cellulose comprises repeating units of Structure II of U.S. Patent No. 8,709,463. In some embodiments, ORC is used to prepare adhesion barriers, particularly at bleeding sites in tissue. Typically, regenerated cellulose is preferred because it has a higher degree of homogeneity than unregenerated cellulose. Detailed descriptions of regenerated cellulose and methods for producing regenerated oxidized cellulose are found, for example, in U.S. Patent Nos. 3,364,200 and 5,180,398.

[0089] Thus, in some embodiments, the OC comprises an ORC. Examples of OC-based products that may be in an agglomerated form or crushed or ground and thus can be utilized to prepare particles of the composition include, but are not limited to, INTERCEED® absorbable adhesion barrier, SURGICEL® Original absorbable hemostat, SURGICEL® NU-KNIT® absorbable hemostat, SURGICEL® FIBRILLAR™ absorbable hemostat, SURGICEL® SNoW™ absorbable hemostat, and SURGICEL® powder absorbable hemostat, GelitaCel® absorbable cellulose coating (Gelita Medical BV, Amsterdam, The Netherlands).

[0090] In some embodiments, the OC is derived from a plant source. The usual source of OC is plant material, although it is understood that the OC can also be derived from a bacterial source.

[0091] In some embodiments, the cellulose for use in the present invention does not include carboxymethyl cellulose (CMC).

[0092] The compositions of the present invention may be non-aqueous compositions, meaning that the predominant liquid in the composition is not water, and the composition has very low water content or no water at all.

[0093] In some embodiments, the composition has a water content of less than about 8 wt%. In some embodiments, the composition has a water content of less than about 7 wt%. In some embodiments, the composition has a total water content of less than about 6 wt%, 5 wt%, 4 wt%, 3 wt%, 2 wt%, 1 wt%, 0.5 wt%, 0.1 wt%, or 0.01 wt%. In some embodiments, the composition is substantially free of water. In some embodiments, the composition contains no water.

[0094] In some embodiments, the composition does not further comprise a solvent. In some embodiments, the composition does not further comprise an organic solvent, such as, for example, ethanol.

[0095] In some embodiments, the compositions of the present invention include an OC in the form of a powder (e.g., a ground OC). As noted above, various cellulosic materials can be ground or milled to obtain powders that can be used to prepare the compositions of the present invention.

[0096] Cellulosic materials, such as cellulosic fabrics, may be milled to obtain fibers having a size distribution of D90 less than 350 μm and D50 less than 167 μm, as described above. If desired, the milling process can be repeated to obtain a size distribution of D90 less than 177 μm and D50 less than 95 μm.

[0097] As described herein, in one embodiment, fibers for making the composition are prepared by grinding cellulosic raw materials. The grinding step can be preceded by a step of slitting and cutting the cellulosic raw materials to form pieces. In this embodiment, the grinding step can be a two-stage process, with the second stage being carried out in an air classifier, and the second stage can be repeated three times. Thus, after the first pass through the air classifier, the resulting "long fibers" can have a size distribution with a D90 of less than 350 μm and a D50 of less than 167 μm. After three passes through the air classifier, the resulting fine ORC fibers can have a size distribution with a D90 of less than 177 μm and a D50 of less than 95 μm. Thus, in one embodiment, the "long fibers" have a size distribution with a D90 of less than 350 μm and a D50 of less than 167 μm.

[0098] In one embodiment of the present invention, the "fine" or "short" cellulosic fibers in the composition have a size distribution with a D90 of less than 177 μm and a D50 of less than 95 μm. The cellulosic material can be mixed or blended with compounds before, during, and / or after the milling process.

[0099] In some embodiments, the disclosed aggregates are composed of a plurality of interconnected individual cellulosic fibrils in the form of an aggregate having a sphericity of at least 0.5 and a diameter along its longest axis that is less than about 500 micrometers and greater than about 50 micrometers. The aggregates may alternatively be described as having a size distribution profile with a D15 greater than about 80 micrometers, a D50 between about 140 and 250 micrometers, a D90 less than about 370 micrometers, a bulk density greater than 0.45 g / mL, and / or a sphericity (sh50) of 0.70 or greater. The aggregates may be characterized as having substantially no or minimal size distribution change upon exposure to vibrational loads; for example, the size distribution profile of the hemostatic aggregate, as measured by D50, is not less than 100 micrometers. In one embodiment, the size distribution change is characterized by a QICPIC optical sensor at 0.2 bar. In yet a further embodiment, the size distribution change or minimal size distribution change is based on treatment at a 1.0 bar vacuum. In some embodiments, the aggregate is a cellulosic material that has been ground, moistened, roller-compacted, and dried.

[0100] The terms "D15," "D50," "D70," and "D90" refer to 15%, 50%, 70%, and 90% of the particles (by number or volume) having a size less than or equal to the corresponding value, respectively.

[0101] As provided herein, in some embodiments, the compositions of the present invention are prepared from OCs in the form of aggregates. The term "aggregates" describes particles formed from combined components.

[0102] As further provided herein, the agglomerates may optionally be made by one of the following steps: moistening the powder composition; compressing the powder, for example by rollers and / or pounding the powder to form agglomerates; dehumidifying; grinding; sieving the agglomerates; and optionally placing the resulting agglomerates into a storage container or delivery device.

[0103] In some embodiments, the particle size of the OC is 10 μm to 2,000 μm, 50 μm to 1,500 μm, 100 μm to 1,000 μm, 100 μm to 500 μm, 100 μm to 300 μm, 50 μm to 1,000 μm, 50 μm to 500 μm, or 50 μm to 300 μm.

[0104] As provided above, in some embodiments, the OC (e.g., ORC) powder is compacted. The compacted ORC powder can be roller-compacted ORC powder or hammer-milled ORC powder. The disclosed powders preferably have a density of at least 0.45 g / cm of hemostatic material. 3 and / or a flowability of at least 7.5 cm / s, and / or an average particle size of 1.75 micrometers to 116 micrometers, with a median diameter of 36 micrometers. In one embodiment, the disclosed powders have an average aspect ratio of about 1 to about 5, a mass fraction of at least 0.67 g / cm 3 and particles having a flowability of at least 70 cm / s.

[0105] In one embodiment, the particulates compacted into a high tap density powder have a density of about 0.35 to about 1 g / cm 3 , or 0.4 to 0.9 g / cm 3 , for example, 0.42 to 0.78 g / cm 3 The ORC particles have a tap density in the range of 0.01 to 0.05. The ORC particles having a specific aspect ratio can be made directly from an ORC material, such as an ORC fabric or nonwoven fabric, characterized above, using a ball milling process. As described herein, the particle size can have an overall size (largest dimension) of less than 500 micrometers, such as less than 300 micrometers, less than 200 micrometers, and less than 100 micrometers.

[0106] In another embodiment, the disclosed composition is in the form of a paste comprising the hemostatic material described above and saline solution, and the paste may have a viscosity of greater than 10,000 Pa·s at room temperature.

[0107] In another embodiment, the invention is a consolidated ORC-based material in the form of a powder having an aspect ratio of about 1 to about 18. The ORC-based material can be shredded ORC material. In one embodiment, the consolidation is carried out by ball milling, as described above. In another embodiment, the consolidation is carried out by roller compaction or by hammer milling, as described above.

[0108] In another embodiment, the present invention is directed to a method of preventing adhesions at a bleeding site by applying the composition disclosed in one embodiment thereof, e.g., in powder form as described above, to and / or within the bleeding site in the tissue of a subject.

[0109] Due to the high tap density and low aspect ratio of the powders of the present invention, the resulting ORC powders, whether in paste or powder form, can be utilized as adhesion prevention materials at bleeding sites due to their excellent hemostatic properties and good tissue compatibility and flowability. Additionally, these ORC materials can be physically blended with other drugs and biopolymers to improve anti-adhesion properties at bleeding sites.

[0110] Particles with low aspect ratios (1-20) may constitute the majority of the particles in the powder material, i.e., more than 50%, such as more than 80% or more than 90% of the particles. Particles having an overall size (largest dimension) of less than 500 micrometers, such as less than 300, 200 micrometers, and less than 100 micrometers, may constitute the majority of the particles in the powder material, i.e., more than 50%, such as more than 80% or more than 90% of the particles.

[0111] In another embodiment of the present invention, products resulting from a ball milling process containing low aspect ratio, high tap density ORC particles, as described above, have been shown to have effective anti-adhesion properties.

[0112] In this disclosure, the aspect ratio of a powder is defined as the average aspect ratio of the particles comprising the powder, where the aspect ratio of a particle is defined as the measurement of the particle's longest dimension (length) divided by its shortest dimension (width) when visible under an electron or optical microscope at appropriate magnification. A minimum aspect ratio (AR) of 1 corresponds to a round particle having its longest dimension equal to its shortest dimension. An aspect ratio of about 20 corresponds to a fibrous particle having a length 20 times its diameter. Exemplary aspect ratios, according to the present invention, are from 1 to 20, more specifically from about 1.5 to about 17.5.

[0113] In some embodiments, the disclosed compositions having an OC with a carboxyl content of about 12% to about 18% are useful as adhesion prevention compositions, for example, to prevent the formation of adhesions at a site of bleeding in tissue. In some embodiments, flowable or non-flowable compositions of the present invention, in which the OC has a carboxyl content of about 12% to about 18%, are used as adhesion preventatives to reduce or prevent adhesions at a site of bleeding in tissue.

[0114] In some embodiments, the disclosed compositions, wherein the carboxyl content of the OC is from about 12% to about 18%, are flowable at one or more temperature values ​​selected from the group consisting of 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 37°C, and 40°C.

[0115] Particle flowability is a parameter that influences the powder's deployment during a surgical procedure: a high degree of flowability may be preferred in a surgical environment to facilitate deployment.

[0116] Bulk density is the ratio of the mass of an untapped powder sample to the volume of that powder sample, including the contribution of the void volume between particles. Tap density is a measurement of the increased bulk density of a powder obtained by mechanically tapping a container of powder. Tap density appears to correlate with flowability. A high tap density may be preferred for ease of spreading and mixing. For purposes of this application, tap density may be measured using a modified USP 616 method, in which 1 gram of powder is introduced into a dry 10 mL graduated cylinder and tapped manually 100 times for approximately 2 minutes.

[0117] Additionally, the force of compression of a powder is an important parameter related to the deployment of a powder or paste during a surgical procedure. The effort required to expel a liquid from a syringe and to draw a liquid into a syringe is known as compression force and aspiration force, respectively. However, the measurement of compression force is more important for dual syringe mixing devices. In some embodiments, the composition can be passed through an applicator.

[0118] Dual syringe mixing devices produce a substantially homogenous paste mixture by mixing initially separate liquid and solid carriers and then pumping the combined contents back and forth between two connected syringes via interconnected outlets. Therefore, a low pressure force to dispense the paste from the syringes may be preferred for ease of mixing and ultimately for developing the resulting paste. The desired pressure force may be less than 1.51 lbf.

[0119] As described herein, in some embodiments, the composition may further comprise at least one biologically active agent, non-limiting examples of which include calcium, and therapeutic agents such as antibiotics, anti-inflammatory agents, growth factors, or clotting factors. For example, the composition may further comprise fibrinogen or thrombin.

[0120] In some embodiments, the composition may further comprise thrombin.

[0121] In some embodiments, the composition may further comprise calcium, a key component in the coagulation cascade that is required to activate factor XIII to factor XIIIa, which crosslinks and stabilizes fibrin to form an insoluble clot.

[0122] The calcium used in the present invention may be in the form of calcium chloride. Alternatively, other salts such as calcium acetate and / or calcium citrate may be used. In some embodiments, the calcium source is calcium chloride, for example, in the range of 40-60 mM.

[0123] In some embodiments, the composition may include two or more biologically active agents, for example, calcium and thrombin.

[0124] As used herein, "thrombin" refers to the activated enzyme resulting from the proteolytic cleavage of prothrombin (factor II). Thrombin may be produced by a variety of production methods known in the art, including, but not limited to, recombinant thrombin and plasma-derived thrombin.

[0125] Human thrombin is a 295 amino acid protein composed of two polypeptide chains joined by disulfide bonds. Both human and non-human (e.g., bovine) thrombin can be used within the scope of the present disclosure.

[0126] The composition may further comprise one or more of the following excipients selected from, but not limited to, albumin, sugars, sugar derivatives, polyols, acetates, citrates, amino acids, polyethylene glycol, and sodium chloride.

[0127] Albumin may be in the range of 0.05 to 1% (w / v), or in the range of 0.5 to 1% (w / w). The sugar source may be sucrose, for example, at a concentration of about 5 g / L.

[0128] In some embodiments, the saccharide derivative source comprises gluconic acid. In some embodiments, the polyol source comprises mannitol, for example, at a concentration of about 2% (w / v). In some embodiments, the acetate source is sodium acetate. In some embodiments, the citrate source can be sodium citrate. In some embodiments, the amino acid comprises histidine. In some embodiments, the polyethylene glycol (PEG) source is PEG-3350, and can be present, for example, at a concentration of about 0.03% by weight.

[0129] "PEG3350" refers to a PEG compound with an average molecular weight of 3350 daltons.

[0130] Thus, in some embodiments, the compositions of the present invention further comprise one or more excipients selected from the group consisting of sodium chloride, mannitol, albumin, and sodium acetate.

[0131] In some embodiments, the composition is non-flowable at at least one temperature near room temperature, such as one or more temperature values ​​selected from the group consisting of 10° C., 15° C., 20° C., 25° C., 30° C., 35° C., 37° C., and 40° C. This composition is hereinafter referred to as a "non-flowable" or "non-flowable" composition.

[0132] As mentioned above, the degree of oxidation of OC can be important for its functional properties, such as biocompatibility and bioresorbability. Products exist that contain varying degrees of oxidation of OC, such as surgical hemostats in which carboxylic acid groups are present at concentrations of 18–21% (by weight) of the oxidized cellulose. On the other hand, OCs with lower concentrations of carboxylic acid groups (e.g., 12–18%) may have superior adhesion prevention properties.

[0133] As used herein with reference to OC, the terms "oxidation level," "degree of oxidation," "carboxyl content," and "carboxylation level" are interchangeable and may be determined in accordance with United States Pharmacopeia (USP) 23-NF18.

[0134] Thus, in some embodiments, the carboxyl content of the OC is about 12%-24% (w / w). In some embodiments, the carboxyl content of the OC is 12-23% (w / w). In some embodiments, the carboxyl content of the OC is 12-22% (w / w). In some embodiments, the carboxyl content of the OC is about 12% to about 21% (w / w).

[0135] In some embodiments, the OC has a carboxyl content of 16-24% (w / w), and the composition may function as a hemostatic agent. In some embodiments, the OC has a carboxyl content of 17-23%. In some embodiments, the OC has a carboxyl content of 18-22% (w / w). In some embodiments, the OC has a carboxyl content of about 18% to about 21% (w / w).

[0136] In some embodiments, the OC has a carboxyl content of about 12% to about 18% (w / w). In some embodiments, the carboxyl content of the OC is 12-17% (w / w). In some embodiments, the carboxyl content of the OC is 12-16% (w / w).

[0137] In some embodiments, the carboxyl content of the OC is about 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, or 24% (w / w) (including any value and range therebetween).

[0138] Compositions of the present invention having an OC with a carboxyl content of about 12% to about 18% are useful as anti-adhesion compositions for preventing the formation of adhesions, for example, at sites of tissue bleeding. In some embodiments, the fabric for preparing the powder is a warp-knit tricot fabric composed of bright rayon yarn, which is subsequently oxidized to contain an effective amount of carboxyl or aldehyde moieties to render the fabric biodegradable. As noted above, the fabric can be oxidized by reacting cellulose with a solution of nitrogen dioxide in a perfluorocarbon solvent, as described in U.S. Patent No. 5,180,398 to F. Boardman et al.

[0139] In one embodiment, a method for preventing adhesions at a bleeding site uses an OC / ORC powder having a carboxyl content (oxidation level) ranging from about 9% to about 21%. In another embodiment, a method for preventing adhesions at a bleeding site uses an OC / ORC powder having a carboxyl content (oxidation level) ranging from about 12% to about 18%. In yet another embodiment, a method for preventing adhesions at a bleeding site uses an oxidized regenerated cellulose having a carboxyl content (oxidation level) ranging from about 9.5% to about 10.5%.

[0140] In some embodiments, the compositions of the present invention are further processed to reduce bioburden by any method known in the art, such as heat treatment, radiation treatment, filtration, or chemical treatment, e.g., gamma radiation, filtration using pore sizes of 0.22 μm or less, heat sterilization, and sterile field.

[0141] In some embodiments, the method further comprises adding calcium to the composition. In some embodiments, the method further comprises adding at least one biologically active agent to the composition. In some embodiments, the method further comprises adding one or more excipients selected from sodium chloride, mannitol, albumin, and sodium acetate to the composition.

[0142] Furthermore, in one aspect of the present invention, there is provided a method for reducing adhesions at a bleeding site in tissue, for example, in a patient undergoing surgery, comprising contacting the bleeding site with the composition disclosed in the above embodiment. Thus, in one embodiment, there is provided a method for preventing tissue adhesions, comprising applying the disclosed composition or ORC powder into / onto bleeding tissue. The tissue may be soft tissue or, for example, bone tissue.

[0143] The term "soft tissue," as used herein, refers to bodily tissue that is not solidified or calcified. This term refers to soft tissue that is vascularized and therefore may be a source of bleeding. Examples of such tissue include, but are not limited to, connective tissue (such as tendons, ligaments, fascia, skin, fibrous tissue, fat, and synovium), muscle, and internal organs. Generally, soft tissue is meant to exclude bone tissue.

[0144] In some embodiments of the method, the carboxyl content of the OC is at least 9% by weight or more, e.g., about 9% to about 21% by weight, or about 12% to about 21% by weight. In some embodiments of the method, the carboxyl content of the OC is about 18% by weight or less, e.g., about 18% by weight. In some embodiments of the method, the carboxyl content of the OC is about 9% to about 18% by weight, or 12% to about 18% by weight. In some embodiments of the method, the carboxyl content of the OC is about 9% to about 21% by weight, or 12% to about 21% by weight. In some embodiments of the method or composition, the carboxyl content of the OC is up to about 21% by weight.

[0145] In some embodiments, the composition is flowable at one or more temperature values ​​selected from the group consisting of 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 37°C, and 40°C.

[0146] In some embodiments, the composition is not flowable at one or more temperature values ​​selected from the group consisting of 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 37°C, and 40°C.

[0147] In some embodiments of the method, the composition is treated to reduce bioburden by methods known in the art, such as heat treatment, radiation treatment, filtration, or chemical treatment, e.g., gamma radiation, filtration using pore sizes of 0.22 μm or less, heat sterilization, and sterile fields.

[0148] In some embodiments of any of the aspects of the method, the composition further comprises one or more excipients selected from the group consisting of sodium chloride, mannitol, albumin, and sodium acetate.

[0149] Additionally, in one aspect of the present invention, there is provided a method of reducing adhesion formation in tissues and / or organs, for example, in a patient undergoing surgery, comprising applying or contacting at least the surgical site and / or proximate thereto a composition disclosed in the above embodiments.

[0150] In a further aspect, the present invention provides a kit comprising: a) a container containing the composition of the present invention described above; b) an applicator for applying the composition to tissue; and c) optionally, instructions for use.

[0151] In some embodiments, the contained is part of the applicator.

[0152] It is understood that the consistency of the composition is such that it can be applied, for example, by spreading or depositing the composition directly onto the bleeding site. Thus, the composition does not need to be further spread or applied onto a solid surface, object, or other solid medium, such as a strip or film, to be in a suitable form for application to the bleeding site. Nevertheless, a suitable applicator, such as a syringe, may be used to apply, spread, or deposit the composition onto the bleeding site for easy access and handling.

[0153] The terms "comprises," "comprising," "includes," "including," "having," and combinations thereof, mean "including but not limited to." The term "consisting of" means "including and limited to." The term "consisting essentially of" means that a composition, method, or composition may include additional components, steps, and / or parts, but only if the additional components, steps, and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method, or composition.

[0154] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0155] As used herein, the word "optionally" means "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the present invention may include multiple "optional" features unless such features are inconsistent.

[0156] As used herein, the singular forms "a," "an," and "the" are intended to include plural referents unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" may include multiple compounds, including mixtures thereof.

[0157] Throughout this application, various embodiments of the present invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the broadness of the range.

[0158] Whenever a numerical range is given herein, it is meant to include any recited number (fractional or integer) within the given range. The terms "ranging / ranges between" a first and second designator number and "ranging / ranges from" a first designator number to a second designator number are used interchangeably herein and are meant to include the first and second designator numbers and all fractional and integer numbers therebetween.

[0159] As used herein, the term "method" means methods, means, techniques, and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques, and procedures that are either known or readily developed as well-known methods, means, techniques, and procedures by practitioners in the chemical, pharmacological, biological, biochemical, and medical arts.

[0160] As used herein, the term "treating" includes arresting, substantially inhibiting, slowing, or reversing the progression of the condition, substantially ameliorating the clinical or cosmetic symptoms of the condition, or substantially preventing the appearance of the clinical or cosmetic symptoms of the condition.

[0161] When notation similar to "at least one of A, B, and C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand the notation (e.g., "a composition having at least one of A, B, and C" includes, but is not limited to, compositions having only A, only B, only C, both A and B, both A and C, both B and C, and / or all of A, B, and C, etc.). Those of ordinary skill in the art will further understand that whether in the specification, claims, or drawings, virtually all disjunctive words and / or phrases presenting two or more alternative terms should be understood to consider the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" would be understood to include the possibilities of "A" or "B" or "A and B."

[0162] Although certain features of the invention are described, for clarity, in the context of separate embodiments, it is understood that they may also be provided in combination in a single embodiment. Conversely, various features of the invention, while for brevity described in the context of a single embodiment, may also be suitably provided separately or in any suitable subcombination, or in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be construed as essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0163] Unless otherwise indicated, all numbers, such as those expressing ratios, weights, mole / mole, amounts, viscosities, temperatures, etc., are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in this description and appended claims are approximations that may vary by up to ±10% depending upon the desired properties sought to be obtained by the present invention.

[0164] Various embodiments and aspects of the present invention, as delineated hereinabove and as claimed in the claims section below, find experimental support in the following examples. [Example]

[0165] Reference is made to the following examples, which, together with the above description, illustrate some embodiments of the invention in a non-limiting fashion.

[0166] Example 1: Effectiveness of anti-adhesion treatment at the bleeding site in a rat cecal abrasion model Adhesion is a serious medical problem that can cause chronic pain, infertility, and is associated with intestinal obstruction, which can lead to death. Many of these adhesions result from surgical trauma to the peritoneum. To examine the ability of the composition of the present invention to reduce adhesions at bleeding sites, the composition was tested in an animal model. The selected modal was a rat model containing a cecal abrasion and an abdominal sidewall defect. The model was reviewed in Poehnert et al., 2015, International Journal of Medical Sciences 12(1):1-6, with minor modifications.

[0167] Materials and Methods Study Group: 1. No treatment (control); 2. INTERCEED group: commercially available INTERCEED® sheet (Ethicon) was cut to size to be applied to cover the cecum; 3. The INTERCEED® family of powders are in the form of agglomerates and were produced by the process described in Example 1 of U.S. Patent No. 10,034,957, except that the base material used was INTERCEED® sheet (Ethicon) rather than SURGICEL® sheet (Ethicon). INTERCEED powder in the form of agglomerates is also referred to throughout this specification as milled / crushed INTERCEED in agglomerated form, milled / crushed INTERCEED compressed into small granules, compacted INTERCEED powder, and INTERCEED compacted in agglomerate form.

[0168] Briefly, INTERCEED® was cut into 1- to 2-inch-wide sections before the material was fed into a blade that cut the fabric into smaller pieces. The cut ORC fabric pieces were then pulverized into intermediate ORC fine fibers through two sequential grinding processes (hammer milling and air-classified grinding). The resulting intermediate ORC fine fibers were then humidified to about 11% to about 16% as measured by an Ohaus halogen hygrometer and then roller-compacted into larger aggregates. The hygrometer operated on a thermogravimetric principle, where the hygrometer measured the weight of the sample, which was then rapidly heated by an integrated halogen dryer unit to evaporate the moisture. During the drying operation, the instrument continuously measured the weight of the sample and displayed the result.

[0169] Once drying is complete, the tabulated results are displayed as percent moisture, percent solids, weight, or percent recovery. Specifically, the analyzer tested 0.5 to 1 gram aggregates with a 4 minute ramp, a maximum temperature of 90°C, and the following settings: Test ID - LOD; Profile - Standard; Drying Temperature - 90°C; Switch Off - A60; Results - Moisture %; Custom - Off; Target Weight - None.

[0170] Sieving was performed to separate target particles with sizes between 75 and 300 micrometers, as determined by screen sieving. Excess moisture introduced for compaction purposes was removed by a dehumidification or drying process after the compaction and sieving steps for subsequent injection into the applicator device. The sample was then subjected to device packaging and sterilization. The storage moisture before injection into the applicator was approximately less than 2% at the end of drying to achieve a moisture content of less than 6% in a controlled environment for injection into the applicator (a moisture gain rate of 0.3-0.6% per hour per 500 g sample depending on relative humidity, typically 25-55%).

[0171] In summary, one process for producing the hemostatic aggregates of the present invention included the steps of: a) slitting and cutting the cellulose raw material; b) grinding the material resulting from step a); c) a second grinding step in an air classifier; d) moistening; e) roller compaction; f) sieving; g) dehumidifying or drying; h) optionally pouring into storage containers or into delivery devices and primary and secondary packaging; and i) an optional sterilization step.

[0172] Test articles were applied (repeated six times) to a rat cecal abrasion model as described herein.

[0173] In vivo rat cecal abrasion model for testing anti-adhesion activity: Briefly, animals were anesthetized using a single intramuscular injection of a mixture of ketamine HCl 80 mg / kg (Fort Dodge Pty. Ltd., Australia) and xylazine HCl 10 mg / kg (VMD, Belgium; because the surgical procedure was performed on the abdominal cavity, anesthesia was administered intramuscularly rather than intraperitoneally).

[0174] A 6-cm incision was made on the skin overlying the ventral midline line. The abdominal skin was shaved, prepped with iodophor solution, and incised. The skin was retracted and subcutaneously peeled to facilitate suturing at the end of the procedure. With the muscle wall exposed, a 5-cm incision was made through the peritoneal cavity and along that line in the muscle. The right abdominal wall was reflected. A 1 × 2 cm section of peritoneum and muscle was removed. The medial edge of the defect was positioned 1 cm lateral to and parallel to the midline incision. The abdominal wall defect was monitored for bleeding. A corresponding defect was made in the cecum by scraping with a scalpel to form a uniform surface of punctate hemorrhage over a 1 × 2 cm area. The cecum was elevated before abrasion and positioned so that it would contact the abdominal wall defect during closure, inducing local adhesions. The two surfaces were allowed to air dry for 10 minutes. For each test article, a certain amount was spread onto the cecum to completely cover it with a thin layer of the test article. The "no treatment" group was left as is. After group assignment and application, the cecum and abdominal wall defect were held together for 1 minute before closing. The organs were returned to their anatomical positions, and two sutures were placed at each end of the defect to maintain the organs in proximity. The animals were carefully observed during the procedure, and any animals with an unexpected response to the anesthetic treatment were excluded.

[0175] Following the procedure, animals received a single dose of butorphanol tartrate (torbugestic) at 0.5–2.0 mg / kg body weight to alleviate pain. Animals were monitored daily, and if clinical signs or behavioral changes were observed, butorphanol was administered subcutaneously at 0.5–2.0 mg / kg body weight every 4 hours as needed to control pain, depending on the animal's behavior. Fourteen days after surgery, animals were euthanized by CO2 asphyxiation. The abdomen was opened, and the surgical site was inspected. Adhesion formation was graded by a blinded observer.

[0176] Adhesion strength to various abdominal organs was assessed according to the following scheme (Poehnert et al., 2015, International Journal of Medical Sciences 12(1):1-6): Grade 0 - no adhesions; Grade 1 - thin film adhesions, easy to separate; Grade 2 - releasable with blunt dissection; Grade 3 - sharp dissection required; Grade 4 - difficult to distinguish between different tissue edges, very difficult to separate. In addition to adhesion strength, adhesion extent was measured with a ruler. Adhesion strength was calculated as adhesion strength × adhesion extent (mm).

[0177] As seen in Figure 1, INTERCEED powder ORC (Group 3) demonstrated approximately 135% anti-adhesion efficacy compared to ORC fabric (Group 2).

[0178] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0179] [Embodiment] (1) A composition comprising oxidized cellulose (OC) in powder form, wherein the OC has a carboxyl content of about 9% to about 21% by weight. (2) The composition of embodiment 1, wherein the OC comprises oxidized regenerated cellulose (ORC). (3) The composition according to any one of the preceding claims for use as an anti-adhesion agent in the presence of blood. (4) The composition of any one of the preceding claims, wherein the powder is in an agglomerated form. (5) The composition of any one of claims 1 to 4, wherein the powder comprises ground OC.

[0180] (6) The composition of any one of the preceding claims, wherein at least 90% of the powder has a particle size in the range of 10 to 2,000 μm. (7) The composition of embodiment 6, wherein at least 90% of the powder has a particle size in the range of 50 to 300 μm. (8) The composition of any one of the preceding claims, wherein the powder has been gamma irradiated. (9) The composition of any one of embodiments 1 to 8, characterized by an anti-adhesion efficacy of at least 120% compared to an OC fabric having the same carboxyl content. (10) The composition of any one of the preceding claims, wherein the OC comprises ORC in the form of a compacted powder.

[0181] 11. The composition of claim 10, wherein the ORC powder comprises roller-compacted ORC powder and / or hammer-milled ORC powder. (12) The composition according to any one of the preceding embodiments, wherein the powder has an average particle size of 1.75 micrometers to 116 micrometers and a median diameter of 36 micrometers. (13) The composition according to any one of the preceding embodiments, further comprising an additive, the additive comprising one or more components selected from CMC or other polysaccharides, calcium salts, anti-infective agents, hemostatic promoters, gelatin, and collagen. (14) The composition of any one of the preceding claims, wherein the powder is in the form of particulate agglomerates having a size distribution profile in which D15 is greater than about 80 micrometers, D50 is about 140-250 micrometers, and D90 is less than about 370 micrometers. (15) The composition of any one of the preceding claims, wherein the powder has a bulk density greater than 0.45 g / mL.

[0182] (16) The composition according to any one of the preceding embodiments, wherein the powder has a sphericity (sh50) of 0.7 or more. (17) The composition of embodiment 16, wherein the OC, in the form of the aggregates, forms interconnected individual cellulosic fibrils having a sphericity of at least 0.6 and a dimension along the longest axis of less than about 500 micrometers and greater than about 50 micrometers. (18) The composition according to any one of the preceding embodiments, wherein the carboxyl content of the OC is 18% or less. (19) The composition of any one of embodiments 1 to 18, wherein the carboxyl content of the OC is at least 12%. (20) A kit comprising: a. a container containing the composition of any one of embodiments 1-19; b. an applicator for applying the composition to tissue; c. Optionally, instructions for use.

[0183] (21) The kit of embodiment 20, wherein the container is included in the applicator. (22) A method for preventing tissue adhesions, comprising applying a composition comprising oxidized cellulose (OC) in powder form into / onto tissue in the presence of blood, wherein the OC has a carboxyl content of about 9% to about 21% by weight. (23) The method of embodiment 22, wherein the OC comprises an ORC. (24) The method of any one of claims 22 to 23, wherein the carboxyl content of the OC is 18% or less.

Claims

1. 1. A composition for use as an adhesion preventative in the presence of blood, comprising oxidized cellulose (OC) in powder form, wherein the OC has a carboxyl content of 9% to 18% by weight.

2. The composition described in claim 1, wherein the carboxyl content of the OC is 12% by weight to 18% by weight.

3. The composition of claim 1 or 2, wherein the OC comprises oxidized regenerated cellulose (ORC).

4. The composition of any one of claims 1 to 3, wherein the powder is in agglomerated form.

5. The composition of any one of claims 1 to 4, wherein the powder comprises ground OC.

6. 6. The composition of claim 1, wherein the particle size of at least 90% of the powder is in the range of 10 to 2,000 μm.

7. 7. The composition of claim 6, wherein the particle size of at least 90% of the powder is in the range of 50 to 300 μm.

8. The composition of any one of claims 1 to 7, wherein the powder has been gamma irradiated.

9. The composition of any one of claims 1 to 8, characterized by an anti-adhesion efficacy of at least 120% compared to OC fabric having the same carboxyl content.

10. The composition of any one of claims 1 to 9, wherein the OC comprises ORC in the form of a compacted powder.

11. 11. The composition of claim 10, wherein the ORC powder comprises roller-compacted ORC powder and / or hammer-milled ORC powder.

12. 12. The composition of any one of claims 1 to 11, wherein the powder has an average particle size of 1.75 micrometers to 116 micrometers, with a median size of 36 micrometers.

13. 13. The composition of any one of claims 1 to 12, further comprising an additive, wherein the additive comprises one or more components selected from CMC or other polysaccharides, calcium salts, anti-infective agents, hemostasis-promoting agents, gelatin, and collagen.

14. 14. The composition of any one of claims 1 to 13, wherein the powder is in the form of particulate agglomerates having a size distribution profile with a D15 greater than about 80 micrometers, a D50 of about 140-250 micrometers, and a D90 less than about 370 micrometers.

15. The composition of any one of claims 1 to 14, wherein the powder has a bulk density greater than 0.45 g / mL.

16. The composition according to any one of claims 1 to 15, wherein the powder has a sphericity (sh50) of 0.7 or more.

17. The powder is in the form of particulate agglomerates having a size distribution profile in which D15 is greater than about 80 micrometers, D50 is about 140-250 micrometers, and D90 is less than about 370 micrometers; 17. The composition of claim 16, wherein the OC, in the form of the particulate agglomerates, forms interconnected individual cellulosic fibrils having a sphericity of at least 0.6 and a dimension along its longest axis of less than about 500 micrometers and greater than about 50 micrometers.

18. The composition of any one of claims 1 to 17, wherein the carboxyl content of the OC is 18% or less.

19. The composition of any one of claims 1 to 18, wherein the carboxyl content of the OC is at least 12%.

20. A kit comprising: a. a container containing the composition of any one of claims 1 to 19; b. an applicator for applying the composition to tissue; c. Optionally, instructions for use.

21. 21. The kit of claim 20, wherein the container is included in the applicator.

22. A composition for use in a method for preventing tissue adhesions in the presence of blood, said composition comprising oxidized cellulose (OC) in powder form, said method comprising applying said composition into and / or onto tissue in the presence of said blood, and wherein the carboxyl content of the OC in said composition is 9% to 18% by weight.

23. 23. The composition of claim 22, wherein the OC comprises an ORC.

24. 24. The composition of claim 22 or 23, wherein the carboxyl content of the OC is 12% to 18% by weight.

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