Compositions and methods relating to fucans and modified fucans for the treatment of various medical conditions

Abstract

Compositions, systems, methods, etc., comprising medically-acceptable fucans configured to be effective for medical treatments, post-surgical treatments, disease inhibition, etc., wherein signaling protein activity contributes to the initiation, progression, severity, prognosis etc., of such medical conditions. In some embodiments, such treatments comprise the medically-acceptable fucans inhibiting or sequestering such signaling proteins. Signaling proteins include proteins such as cytokines and chemokines.

Description

COMPOSITIONS AND METHODS RELATING TO FUCANS AND MODIFIED FUCANS FOR THE TREATMENT OF VARIOUS MEDICAL CONDITIONSBACKGROUND

[0001] Fucans (including fucoidan) are sulfated polysaccharides. In general terms, this means that they are molecules made up of a number of sugar groups, and also have sulfur atoms attached to the sugar groups. The main sugar group is called "fucose", which is sugar that has 6 carbon atoms and has the chemical formula CeHnOs. "Fucoidan" (or fucoidin) indicates fucans derived from brown algae (seaweed). Fucans can exist alone, or in a mixture of other sugars, for example in a mixture of sugars such as xylose, galactose, glucose, glucuronic acid and / or mannose. These other sugars may be extracted from the seaweed or other source with the fucan. Although fucans are currently derived from natural sources such as the brown algae (seaweeds), sea cucumbers, etc., mentioned herein, "fucan" includes polymer molecules having the chemical and structural motifs of the fucans as discussed herein regardless of the ultimate source(s) of the fucans.

[0002] Fucoidan can be obtained from a variety of species of brown algae including but not limited to: Adenocystis ulricularis. Ascophyllum nodosum, Chorda fihim, Cystoseirabies marina, Durvillaea antarctica, Ecklonia kurome, Ecklonia maxima, Eisenia bicyclis, Fucus evanescens, Fucus vesiculosis, Hizikia fusiforme, Himanthalia Elongata, Kjellmaniella crassifolia, Laminaria brasiliensis, Laminaria cichorioides, Laminaria hyperborea, Laminaria japonica, Laminaria saccharina, Lessonia trabeculata, Macrocystis pyrifera, Pelvetia fastigiata, Pelvetia Canaliculata, Saccharina japonica, Saccharina latissima, Sargassum stenophylum, Sargassum thunbergii, Sargassum confusum, Sargassum fusiforme and Undaria pinnatifida. These exemplary species are all from the taxonomic class Phaeophyceae and the majority of these species fall into the families of Fucales and Laminariaceae .

[0003] Fucans including fucoidan have been shown to be efficacious in treating a variety of different medical conditions, including fibrous adhesions and rosacea. The current disclosure provides compositions and methods comprising fucans for the treatment of other medical conditions for which there has gone an unmet need for compounds, compositions, methods and the like (including delivery approaches) to treat these medical conditions, including providing a treatment with few side effects. The present systems and methods, etc., provide these and / or other advantages.INCORPORATION BY REFERENCE

[0004] The present application incorporates by reference in their entirety the following publications: PCT / CA2019 / 051025, filed July 24, 2019; PCT / CA2019 / 051026, filed July 24, 2019; PCT / CA2019 / 051027, filed July 24, 2019, PCT / CA2019 / 051030, filed July 24, 2019; PCT / CA2019 / 051028, filed July 24, 2019; PCT / CA2020 / 050294, filed March 5, 2020; PCT / CA2020 / 050295, filed March 5, 2020; and PCT / CA2019 / 051029, filed July 24, 2019.SUMMARY

[0005] Composition and methods herein comprise medically-acceptable fucans suitable for medical and surgical applications, including the treatment of diseases, infections, traumas, injuries, reactions, and other medical conditions, all of which are collectively referred to as “medical conditions” hereafter, in a patient, i.e., animal, including a human. The present compositions and methods can comprise medically-acceptable fucans in medically-acceptable compositions and can be effective for medical treatments, post-surgical treatments, disease inhibition etc. In some embodiments, the medically-acceptable fucan is fucoidan. The present medically-acceptable fucans can themselves be, or can be included on or in medical compositions including for example medically acceptable medical devices, biologies (including products that are derived from living sources such as animals including humans, and microorganisms, for example blood, vaccines, allergenics, tissues, cells, and cellular and gene therapies), drugs, combination products, pharmaceutical compositions, biopharmaceuticals and other medically acceptable, therapeutically and / or medically effective compositions, all of which are collectively referred to as “medical compositions” herein. Patients receive a medical composition comprising a medically-acceptable fucan as discussed herein to treat a medical condition as discussed herein. Treatment herein includes the inhibition, prevention, removal, reduction or other treatment of the medical condition being discussed. The compositions discussed herein can comprise medically-acceptable fucans with a suitably low endotoxin level for use in a medical and / or surgical setting. The compositions herein may further comprise medically-acceptable fucans having a desired molecular weight distribution and / or sulfate level. The treatment can comprise treating the medical condition at asuspected site, wherein suspected indicates that a practitioner believes the site is already affected by the medical condition or is at a heightened risk of contracting the medical condition.

[0006] The present systems, devices and methods, etc., provide methods of treating certain medical conditions, particularly medical conditions wherein signal activity such as cytokine or chemokine activity is a component of the condition. In some embodiments, the treating comprises inhibiting the presence or formation of such medical condition at a particular site in a patient, or systemically throughout a patient. The methods comprise administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the medical condition.

[0007] In some embodiments, the methods further comprise, before administering the medically acceptable fucan composition to the patient, identifying a need for the inhibiting of the identified medical condition in the patient and then selecting the medically acceptable fucan composition specifically for administering to the patient to effect the inhibiting or other treating. In some embodiments, the administering, treating and / or inhibiting includes rinsing a specific treatment site suspected of having the medical condition, or otherwise directly administering the medically acceptable fucan composition to the site having or suspected of having the medical condition.

[0008] As noted above, the medical conditions herein are each individually susceptible to the treatment methods and compositions herein; the recitation of multiple such medical conditions does not detract from the importance of each medical condition on its own. Specific medical conditions include bum scarring; acne; surgery-induced cancer metastasis; chronic obstructive lung disease (COLD); post-viral airway disease; chronic sinusitis; asthma; pulmonary fibrosis; osteoporotic fracture; and, liver fibrosis. Rinsing as the administration and / or treatment / inhibition modality can be particularly advantageously applied, for example, to surgery-induced cancer metastasis; burn scarring; acne; chronic sinusitis.

[0009] In some aspects of the present systems, devices and methods, etc., the administering comprises directly delivering the medically acceptable fucan composition to the site of the medical condition, for example via an instillate, rinse, gel or powder; such does not include systemic administration such as via an oral medication. The medically acceptable fucan composition can be substantially continuously administered to the site of the medical condition via controlled release from a polymeric or other acceptable controlled release dosage form. The medically acceptable fucan composition can be administered intravenously, intraarticularly, intralesionally,intravaginally, rectally, intramuscularly, intraperitoneally, subcutaneously, topically, intranasally, intraocularly or orally.

[0010] The medically acceptable fucan compositions can further comprise at least one medically acceptable excipient selected from the group consisting of gelatin, hypromellose, lactose, water for injection USP, sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffers, citrate buffers, phosphate-citrate buffers, pluronic, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, lactic acid, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan and lactated Ringer’s injection USP. The patient can be an animal including in some instances a human. The medically acceptable fucan composition can comprise fucoidan, and the embodiments, etc., herein include use of a medically acceptable fucan composition to treat, including inhibit, the medical conditions as discussed herein. Also included herein are compositions comprising a medically acceptable modified fucan for treating, including inhibiting, at least one of the medical conditions herein including, e.g., surgery-induced cancer metastasis, chronic obstructive lung disease, post viral airway disease, chronic sinusitis, asthma, pulmonary fibrosis, osteoporotic fracture, liver fibrosis, burn scarring and acne.

[0011] In some embodiments, the compositions comprise a medically acceptable modified fucan with less than about 0.2 EU / mg, 0.1 EU / mg, 0.05 EU / mg, 0.02 EU / mg, 0.01 EU / mg, 0.005 EU / mg, 0.002 EU / mg. In further embodiments, the compositions can comprise less than about 0.40% w / w total nitrogen, less than about 0.20% w / w total nitrogen, less than about 0.15% w / w total nitrogen or less than about 0.10% w / w total nitrogen. The modified medically acceptable fucan can comprise between about 10% w / w and 60% w / w sulfate or between about 30% w / w and 60% w / w sulfate. The modified medically acceptable fucan can comprise a molar ratio of total sulfate to total fucose of between 0.5 and 3.0.

[0012] The modified medically acceptable fucan can comprise a molar ratio of total sulfate to total fucose of between 1.1 and 3.0. The modified medically acceptable fucan can comprise a molar ratio of total sulfate to total fucose and galactose of between about 0.5 and 3.0, or of between about 1.1 and 3.0. The modified medically acceptable fucan can comprise a total carbohydrate content of between about 27% w / w and 80% w / w, or between about 30% w / w and 70% w / w. The modified medically acceptable fucan can comprise a fucose content as a percentage of the total carbohydrate of more than about 30% w / w, 40% w / w, 50% w / w, 70% w / w, 80% w / w, or 90%w / w. The modified medically acceptable fucan can comprise a galactose content as a percentage of the total carbohydrate of less than about 60% w / w, 30% w / w, 20% w / w, or 10% w / w. The modified medically acceptable fucan can comprise a total glucuronic acid, mannose, rhamnose and xylose content as a percentage of the total carbohydrate content of less than about 30% w / w, 20% w / w, 10% w / w or 5% w / w.

[0013] These and other aspects, features and embodiments are set forth within this application, including the following Detailed Description. Unless expressly stated otherwise, all embodiments, aspects, features, etc., can be mixed and matched, combined and permuted in any desired manner.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows a side plan view of an example of a hemostatic agent in combination with a modified fucan within a surgical patch.

[0015] FIG. 2 shows a side plan view of the surgical patch of FIG. 1 applied to a surgical site comprising a bleeding site.

[0016] The drawings present exemplary embodiments of the present disclosure. Certain features may be exaggerated or otherwise represented in a manner to help illustrate and explain the present systems, methods, etc. Actual embodiments of the systems, methods, etc., herein may include further features or steps not shown in the drawings. The exemplifications set out herein illustrate embodiments of the systems, methods, etc., in one or more forms, and such exemplifications are not to be construed as limiting the scope of the disclosure in any manner. The embodiments herein are not exhaustive and do not limit the disclosure to the precise form disclosed, for example in the following detailed description.DETAILED DESCRIPTION

[0017] The current compositions, systems, methods, etc., discussed herein comprise medically- acceptable fucans configured to be effective for medical treatments, post-surgical treatments, disease inhibition, etc. In some embodiments, signaling protein activity contributes to the initiation, progression, severity, prognosis etc., of such medical conditions. In some embodiments, such treatments comprise the medically-acceptable fucans inhibiting or sequestering such signaling proteins. Signaling proteins include proteins such as cytokines and chemokines.

[0018] In some embodiments, the medically-acceptable fucan is fucoidan. The present medically-acceptable fucans can themselves be, or can be included on or in, medical devices, combination products, biologies or in pharmaceutically or medically acceptable, therapeutically and / or medically effective compositions. The compositions discussed herein can comprise medically-acceptable modified fucans with a desired, specific low endotoxin level for use in a medical and / or surgical setting. The compositions herein may further comprise medically- acceptable modified fucans having a desired, specific molecular weight distribution and / or sulfate level.

[0019] The following paragraphs turn to a brief discussion of some of the medical conditions that can be treated with the medically-acceptable fucans discussed herein.ConditionsSurgery-induced Cancer Metastasis

[0020] Cancer has been the second leading cause of death in the U.S. and accounts for over 20% of all mortalities. Cancer is a proliferative disease and is characterized by the uncontrolled division of certain cells, which may lead to the formation of one or more tumors. A number of methods are used to treat cancer, including surgery, radiation, chemotherapy and combinations thereof. Although surgery is a relatively common method used for some localized tumors, there is still a significant chance of tumor recurrence after tumor excision. In addition, there is potential for surgery-induced cancer metastasis, resulting from the spreading of tumor cells during the surgical procedure due to the generation of free / mobile tumor cells related to surgical techniques used to remove the rumors. A rinse solution can be used to limit the metastasis resulting from the surgery, however current rinse solutions can include harmful chemotherapeutic agents, or are not successful in limiting the spreading of the cancerous cells. Thus there has gone an unmet need for a safe and effective way to inhibit or prevent cancerous cells from spreading during surgical procedures involving tumor excision.

[0021] The present discussion includes use of medically-acceptable fucans in a rinse solution during surgical procedures involving the tumor excision, to treat surgery-induced cancer metastasis.Chronic Obstructive Lung Diseases and Post-Viral Airway Diseases

[0022] A chronic obstructive lung diseases (COLD) is a disorder that persistently obstructs bronchial airflow. These obstructions are generally permanent and progress over time. Chronic obstructive lung diseases (COLD), such as asthma, currently have no curative therapies. Respiratory viral infections such as post-viral airway diseases lead to the development and exacerbation of COLD. Respiratory paramyxoviral infection such as Sendai virus (SeV) has been shown to lead to long lasting COLD with airway hyperreactivity and mucous cell metaplasia.

[0023] This post viral airway disease has been shown to be dependent upon the production of the signaling protein chemokine CCL28 from lung dendritic cells. CCL28 serves as a chemoattractant to recruit IL- 13 producing Th2 cells to the lung to ultimately drive the development of airway hyper-responsiveness (AHR) and mucous cell metaplasia (MCM). The role of chemokine CCL28 elicits studies into the antagonism of CCL28 for the treatment of post viral airway diseases, however there is a lack of therapeutic options available for such treatments. The compositions herein may be used to treat COLD and post-viral airway diseases and / or provide a significant therapeutic effect in patients suffering from COLD and post-viral airway diseases.Chronic Sinusitis

[0024] Chronic sinusitis is a prevalent chronic illness, affecting persons of all age groups. If left untreated, it can reduce the quality of life and be a cause of morbidity. In chronic sinusitis, the sinus cavities are blocked and they become ideal breeding grounds for bacteria and viruses. The blockage of the sinus cavities results in difficulty in breathing, inflammation of the sinus cavities, loss or reduced sense of smell and / or taste, headaches and postnasal drip. The compositions herein can be used as a nasal spray and / or a nasal rinse solution that coats the sinus cavity walls, treating sinusitis related inflammation and preventing bacteria from sticking to the sinus cavity walls.

[0025] Minimally invasive sinus surgery is often required to alleviate the symptoms associated with chronic sinusitis, however this procedure leads to scarring and re-obstruction of sinus cavities. The compositions herein can be used to improve the outcome of sinus surgeries by limiting the post-operative scarring and keeping the nasal cavities open.Asthma

[0026] Asthma is a common inflammatory disease of the airway, characterized by wheezing and shortness of breath, often apparent at early childhood. Epithelial cells play an important role in the inflammation associated with asthma, releasing multiple signaling proteins, including cytokines and chemokines, for example, CCL17, CCL22 and thymic stomal lymphopoietin (TSLP), which is a cytokine belonging to the IL-7 family. TSLP plays a key role in the release of CCL17 and CCL22 which attract Th2 cells. Th2 cells are predominant in patients with asthma and orchestrate allergic inflammation through release of IL-4, IL-5, IL-9 and IL-13. Although there have been several attempts to inhibit specific signaling proteins involved with asthma, there are a lack of therapeutic options available that are effective in treating asthma. The compositions herein can be effective in the treatment of asthma.Pulmonary Fibrosis

[0027] Pulmonary fibrosis is a lung disease that occurs when lung tissue becomes damaged and scarred, resulting in the lungs not being able to function properly. In cases where no cause of the disease can be found, the medical condition is termed idiopathic lung fibrosis. As pulmonary fibrosis progresses, the patient experiences a worsening shortness of breath, significantly effecting quality of life.

[0028] It has been found that several signaling proteins, including cytokines, have been involved in the progression of pulmonary fibrosis, including TGFb, TNFa, PDGFs, fibroblast growth factors (FGFs), TGFa, IL-1, IL-4, IL-5, IL-10, IL-13, MCP-1 and MIP-1. Of these signaling proteins, TGFb is involved in the direct stimulation of lung matrix expression which results in pulmonary fibrosis. These signaling proteins are important in the pathogenesis of pulmonary fibrosis. Compositions for the treatment of pulmonary fibrosis that inhibit a portion of these signaling proteins can lead to potential treatment for pulmonary fibrosis, including idiopathic pulmonary fibrosis, however there are a lack of therapeutic options available for such treatments. The compositions herein can be used to treat pulmonary fibrosis, including idiopathic pulmonary fibrosis.Osteoporotic Fractures

[0029] Osteoporosis is a disease characterized by low bone mineral density, a loss of bone mass and a destruction of bone microarchitecture - resulting in an increased risk of bone fractures. It has been shown that there is a decrease in regeneration potential and prolonged healing time for osteoporotic fractures. Osteoporosis becomes more common with age. About 70% of those over 80 are affected, the disease is also more common in women than in men. In the developed world, between about 2 and 8% of males and between about 9 and 38% of females are affected dependent on the method of diagnosis.

[0030] Osteoporotic fractures are injuries that are a dangerous aspect of osteoporosis, leading to acute and chronic pain. Osteoporotic fractures often impair mobility and often require surgery, with fractures of the vertebrae and hip resulting in chronic pain, disability and even post-fracture mortality.

[0031] Most current available treatments involve drugs with moderate ability to increase bone density and lower fracture risk, however their use is associated with toxic side effects. One target signaling protein, Midkine (Mdk), has previously been shown to be involved in skeletal development and bone regeneration and is a potential target in the treatment of this delayed bone healing in osteoporotic fractures. Mdk deficient mice have been shown to have high bone mass due to an increase in bone formation rate or a higher osteoblast activity outlining the role of Mdk as an inhibitor of osteoblast function. The role of Mdk in osteoblast regulation elicits studies into the antagonism of Mdk for the treatment of osteoporotic fractures, however there is a lack of therapeutic options available for such treatments. The compositions herein may be used to treat osteoporotic fractures and / or provide a significant therapeutic effect in patients suffering from osteoporotic fractures.Liver Fibrosis

[0032] Liver fibrosis is the liver’s wound-healing response to injury and is a major cause of mortality and morbidity worldwide. Over time, the liver fibrosis can worsen and proceed to cirrhosis, which is considered to be an advanced stage of liver fibrosis. There are numerous different diseases that result in liver fibrosis, the most common of which are hepatitis B and C, non-alcoholic fatty liver disease and chronic alcohol abuse. One of the most dangerous aspects of liver fibrosis is that symptoms often do not present until the liver damage is extensive.

[0033] Liver fibrosis has long been considered a static process, only recent findings and studies indicating that liver fibrosis can be a reversible medical condition in some cases.

[0034] A crucial step in the development of liver fibrosis is the activation of hepatic stellate cells, which proliferate and accumulate in the injured liver and release large amounts of extracellular matrix proteins including signaling proteins, for example chemokine CCL2 (also known as MCP- 1), CCL3 (also known as MIP-la), CCL5 (also known as RANTES), CCL11 (also known as Eotaxin-1), CXCL8 (also known as IL-8), CXCL9 (also known as monokine induced gamma interferon or MIG) and CXCL10 (also known as IP-10). Chemokines, being an example of a class of signaling proteins, are key drivers of fibrogenesis and are therefore considered to be potential targets for the treatment and reversal of liver fibrosis. One such chemokine, CCL5 has been found to be strongly expressed in human and murine during liver injury with studies showing that increased receptors for CCL5 in mice promotes liver fibrosis. There is evidence to suggest that the inhibition or sequestration of CCL5 can lead to the treatment and reversal of liver fibrosis, however there is a lack of therapeutic options available for such treatments.

[0035] The compositions herein may be used to treat, or cause the regression of liver fibrosis and / or provide a significant therapeutic effect in patients suffering from liver fibrosis.Scarring in Burn Patients

[0036] Cutaneous scarring results from damage to the skin as a result of trauma or surgery. They are the result of a wound healing by resolution rather than regeneration. A scar forms and matures over the course of on average one year, and the resulting scar tissue surrounding the scar consists mainly of collagenous extracellular matrix, due to a local concentration of signaling protein transforming growth factor-P (TGFb). As repair of the wound and scar formation continues, wound contraction is further facilitated by platelet derived growth factors.

[0037] Hypertrophic scars are those characterized by excessive fibrosis and extracellular matrix deposition. Burn patients who develop hypertrophic scars have higher IL- 10, TGFb serum levels and elevated numbers of IL-4 positive Th2 cells early after trauma compared to normal scarring.

[0038] There is a lack of safe and non-invasive therapeutic options available for the treatment of scarring in burn patients, including a lack of rinsing agents capable of providing a therapeutic effect to the afflicted site. The compositions herein may be used to treat scarring in burn patients and / or provide a significant therapeutic effect in patients suffering from scarring due to burns.Acne

[0039] Acne is a common disease affecting almost 80 percent of adolescents and young adults. Acne can have a significant impact on a patient's physical and physiological well-being. Upregulation of signaling proteins, for example E-selectin, vascular cell adhesion molecule (VCAM) 1, interleukin (IL) 1 and integrin, are thought to be involved in increasing the severity of acne. Propionibacterium acnes and Staphylococcus epidermidis can also increase the severity of acne. This can be due to the activation of toll-like receptor (TLR) 2, resulting in the production of cytokines IL-12 and IL-8. P. acnes and S. epidermidis can also contribute to the severity of acne by inducing monocytes to secrete signaling proteins TNFa and IL-lb. There is evidence that IL-1 expression can be increased in the presence of acne.

[0040] The inhibition or sequestration of the signaling proteins involved in acne can lead to the treatment of acne, however there are a lack of safe and non-invasive therapeutic options available for the treatment of acne, including a lack of rinsing agents capable of providing a therapeutic effect to the afflicted site.

[0041] The compositions herein may be used to treat acne and / or provide a significant therapeutic effect in patients suffering from acne.Anaphylaxis

[0042] Anaphylaxis is a life-threatening reaction resulting from IgE-mediated release of vasoactive and inflammatory mediators from mast cells and basophils. These mediators include numerous signaling proteins, including cytokines and chemokines, for example TNFa, IL-1, IL-4, IL-5, IL-6, IL-8, IL-9, IL-13, CCL-7 (also known as MCP-3) and CCL-1. Due to the acute, lifethreatening and unexpected nature of anaphylaxis, mediators of anaphylaxis have been difficult to define. Treatments for anaphylaxis include epinephrine, antihistamines and glucocorticoids, of which epinephrine offers the best outcomes. There has gone an unmet need for safer alternative medicines for use in the treatment of anaphylaxis. The compositions herein may be used to treat anaphylaxis.Hemostasis

[0043] Surgery generally requires at least some form of hemostasis, which is vital in achieving positive patient outcome. Hemostasis is the process of limiting blood loss from an injured bloodvessel. There are four major physiological events that participate in a biological hemostatic process: vascular constriction, platelet plug formation, fibrin formation and fibrinolysis. A hemostatic agent is a substance, material or composition that induces, promotes or initiates hemostasis (or in other words, that inhibits or prevents blood loss from an injured blood vessel). In other words, a hemostatic agent acts to reduce or arrest bleeding or hemorrhage. The following presents an example of a hemostatic agent in combination with a modified fucan as discussed herein.

[0044] Hemostatic agents can include without limitation mucoadhesive agents, factor concentrators and procoagulant suppiementors. Mucoadhesive agents are substances, materials or compositions that adhere to mucosal surfaces, for example the interior of a damaged portion of a blood vessel. Mucoadhesive agents work by adhering to damaged tissues and physically sealing bleeding wounds. Suitable mucoadhesive agents include without limitation mucoadhesive chitosan granules, mucoadhesive chitosan granules with added silica and / or polyethylene, regenerated cellulose, oxidized regenerated cellulose, trilysine-PEG hydrogels, hydrogels, alum, aluminum sulfate, Veriset™, HemCon®, ChitoGauze®, ChitoFlex®, Celox®, Surgicel® and Avitene™. Factor concentrators rapidly absorb water from the blood, concentrating platelets, cellular and protein components of the blood, promoting clot formation. Suitable factor concentrators include without limitation granular mineral zeolites, chemically modified zeolites, superabsorbent polymers, binders, microporous polysaccharide particulates, microporous polysaccharide hemospheres, microfibrillar collagen, clay minerals, TraumaDEX™, QuickClot® and WoundStat™. Procoagulant suppiementors are compositions, substances, materials, devices, drugs or combination products capable of delivering procoagulant clotting factors to a wound site to activate the clotting cascade, increasing the rate of blood clot formation. These procoagulant clotting factors can include human clotting factors, bovine clotting factors, kaolin, kaolinite, hemostatin, propyl gallate, and Combat Gauze™. Hemostatic agents can function via more than one of the discussed hemostatic agent mechanisms, for example, a hemostatic agent can promote hemostasis by being both a factor concentrator and a procoagulant, or by being all three of a mucoadhesive agent, a factor concentrator, and a procoagulant. Example hemostatic agents that function via more than one hemostatic agent mechanism include without limitation, poly-N-acetyl glucosamine, RDH® and mRDH®.

[0045] During surgery, it is desirable to inhibit, prevent, remove, reduce or otherwise treat post-surgical fibrous adhesions. Fucans have been shown to be effective in the treatment of post- surgical adhesions, however based on some of the proposed mechanisms by which fucans inhibit the formation of fibrous adhesions, it may be anticipated that the presence of fucans would not be conducive to hemostasis and may hinder hemostasis. The compositions herein include compositions comprising hemostatic agents and fucans and may be used to address circumstances wherein there is a requirement for both hemostasis and the treatment of fibrous adhesions.

[0046] In one embodiment, the composition can be a hemostatic patch such as HemCon®, ChitoGauze®, ChitoFlex®, Celox ™, QuikClot Combat Gauze®, mRDH®, RDH®, Avitene™, Surgicel® further comprising fucans on the non-hemostatic side of the patch to inhibit the formation of post-surgical adhesions. In another embodiment, the composition can be a surface composed of a bioresorbable material wherein one side of the surface comprises a hemostatic agent and the other side of the surface comprises a fucan with anti -adhesive properties. Suitable surfaces include bioresorbable surfaces comprising, for example, at least one of polylactic acid, polylactic acid derivatives, polyglycolic acid, polyglycolide, cellulose, chitin, chitosan, alginates, hyaluron, dextran and pullulan.

[0047] FIG.l shows from a side-view an example of a hemostatic agent in combination with a modified fucan as discussed herein in a surgical patch 100 comprising: a) an absorbable tamponade portion 110 comprising a bioabsorbable material, for example, cellulose; b) A hemostatic layer 120 situated on a first surface of the tamponade portion 110, such first surface configured to contact tissue of a patient; and, c) an absorbable surgical adhesion-inhibiting layer 130 comprising, for example, an adhesion inhibiting fucan. Such absorbable surgical adhesion-inhibiting layer 130 can be located on a second surface of the tamponade portion 110 as in Figure 1, or it can either or also be combined within either of tamponade portion 110 or hemostatic layer 120.

[0048] The hemostatic layer 120 can be made of, for example, mucoadhesive chitosan granules, mucoadhesive chitosan granules with added silica and / or polyethylene, regenerated cellulose, oxidized regenerated cellulose, trilysine-PEG hydrogels, hydrogels, alum, aluminum sulfate, granular mineral zeolites, chemically modified zeolites, superabsorbent polymers, binders, microporous polysaccharide particulates, microporous polysaccharide hemospheres, microfibrillar collagen, clay minerals, human clotting factors, bovine clotting factors, kaolin, kaolinite, hemostatin, propyl gallate and poly-N-acetyl glucosamine.

[0049] FIG. 2 shows the surgical patch 100 of FIG.l applied to a surgical site 140 comprising a bleeding site 150. In this embodiment, the surgical patch 100 is applied with its hemostatic layer 120 facing, in contact with, and extending over the bleeding site 150. The surgical patch 100 adheres to the bleeding site 150. By the action of hemostatic agents in the hemostatic layer 120, hemostatis is induced, promoted, or initiated, and stops the bleeding at the bleeding site 150. Pressure may be applied to the surgical patch 100 for a short period, for example, 1 to 2 minutes, to aid the attainment of hemostasis. The surgical adhesion inhibiting layer 130 is, in the embodiment shown, the outward facing layer of the patch 100. The surgical adhesion inhibiting layer 130 prevents or inhibits organs or other portions of the body from adhering via surgical or fibrous adhesions to the area of the surgical site 140 covered by the surgical patch 100. The anti- surgical adhesion agent, such as the modified fucans herein, can also exude from the surgical patch 100 and inhibit surgical adhesions in other, non-covered locations within the surgical site.

[0050] In certain embodiments, the surgical adhesion inhibiting layer may comprise pastes, gels, films, lotions, creams, solids, implants, microspheres, powders or particulates comprising adhesion inhibiting fucans.

[0051] In some embodiments, the surgical adhesion inhibiting layer 130 on the surgical patch 100 may be washed or otherwise treated so as to distribute its anti-adhesion agents throughout the surgical site 140. For example, the surgical patch 100 may be washed with a sterile solution, for example normal saline, lactated Ringer’s solution or isotonic dextran, in order to spread the adhesion inhibiting fucan throughout the surgical site 140 and throughout the surgical cavity in order to prevent surgical adhesions throughout the entire surgical cavity. Surgical patch 100 is then absorbed over an extended period of time of the order of four weeks.

[0052] In yet other embodiments, the surgical patch composition comprising both hemostatic agents and fucans can be in the form of a paste, gel, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, microsphere or powder comprising at least one hemostatic agent and at least one adhesion inhibiting fucan. The surgical patch composition comprising both a hemostatic agent and an adhesion inhibiting fucan can be administered to a surgical site requiring both hemostasis and the inhibition of surgical adhesions.Medical Device, Combination, and Pharmaceutical Products

[0053] The discussion herein also provides medical devices, combination, and pharmaceutical products, comprising compositions as discussed herein in a medical device, combination product or pharmaceutically acceptable container. The products can also include a notice associated with the container, typically in a form prescribed by a governing agency regulating the manufacture, use, or sale of medical devices, combination, and pharmaceuticals or biopharmaceuticals, whereby the notice is reflective of approval by the agency of the compositions, such as a notice that the medically-acceptable fucan has been approved for human or veterinary administration to treat, for example, the medical conditions discussed herein. Instructions for the use of the fucan herein may also be included. Such instructions may include information relating to the dosing of a patient and the mode of administration.

[0054] The present application is further directed to methods of making the various elements of the medically-acceptable fucans, systems etc., discussed herein, including making the medically-acceptable medical compositions themselves, as well as to methods of using the same, including for example treatment of the medical conditions, diseases, etc., herein.Fucans

[0055] The medically-acceptable fucan compositions discussed herein may be modified to obtain medically-acceptable modified fucan compositions having low endotoxin levels. The medically- acceptable modified fucan compositions discussed herein may have an endotoxin level of less than about 0.2, 0.18, 0.12, 0.1, 0.09, 0.02, 0.01, 0.007, 0.005, 0.002 or 0.001 endotoxin units (EU) per milligram (mg) of the fucan (EU / mg).

[0056] The medically-acceptable fucans discussed herein may be modified to obtain medically- acceptable modified fucans having low total nitrogen levels by removing nitrogen containing compounds that may be attached to the medically-acceptable fucan. The medically-acceptable modified fucans, and compositions comprising the medically-acceptable modified fucans discussed herein may have a total nitrogen level of less than 0.2, 0.1, 0.08, 0.05, 0.03 or 0.02 % w / w.

[0057] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may be incorporated in compositions further comprising any number of pharmaceutically acceptable excipients, for example, gelatin, hypromellose, lactose, water for injection USP, sodiumchloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffers, citrate buffers, phosphate-citrate buffers, pluronic, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, lactic acid, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan, injectable excipients and lactated Ringer’s injection USP.

[0058] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may be administered in a composition comprising at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, microsphere, powder or other desired form. The medically-acceptable fucans and medically-acceptable modified fucans may be administered via intravenous, intraarticular, intralesional, intravaginal, rectal, intramuscular, intraperitoneal, subcutaneous, topical, intranasal, intraocular or oral administration routes. The medically-acceptable fucans and medically-acceptable modified fucans may be directly delivered to the site of the medical condition. The medically-acceptable fucans and medically-acceptable modified fucans may be continuously released to the site of the medical condition via controlled release from a polymeric or other acceptable controlled release dosage form. A solution or spray comprising the medically-acceptable fucans and / or medically-acceptable modified fucans herein may be used to irrigate, rinse, flush or wash the site of the medical condition.

[0059] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may be administered as a component of a pharmaceutical or biologic or combination product or medical composition comprising the medically-acceptable fucan / medically-acceptable modified fucan and at least one other drug. The drug may be at least one of paclitaxel, doxorubicin, camptothecin, etoposide, mitoxantrone, methotrexate, menadione, plumbagin, juglone, beta- laperchone cyclosporin, sulfasalazine, steroid, rapamycin, retinoid, docetaxel, colchicine, antisense oligonucleotide, ribozyme and vaccine.

[0060] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may be administered as a component of a pharmaceutical or biologic or combination product or medical composition comprising the medically-acceptable fucan / medically-acceptable modified fucan and at least one hemostatic agent. Suitable hemostatic agents include without limitation, mucoadhesive chitosan granules, mucoadhesive chitosan granules with added silica and / or polyethylene, regenerated cellulose, oxidized regenerated cellulose, trilysine-PEG hydrogels, hydrogels, alum, aluminum sulfate, Veriset™, HemCon®, ChitoGauze®, ChitoFlex®, Celox®, Surgicel®, Avitene™, granular mineral zeolites, chemically modified zeolites,superabsorbent polymers, binders, microporous polysaccharide particulates, microporous polysaccharide hemospheres, microfibrillar collagen, clay minerals, TraumaDEX™, QuickClot®, WoundStat™, human clotting factors, bovine clotting factors, kaolin, kaolinite, hemostatin, propyl gallate, Combat Gauze™, poly-N-acetyl glucosamine, RDH® and mRDH®.

[0061] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may be administered as a component of a pharmaceutical or biologic or combination product or medical composition comprising the medically-acceptable fucan / medically-acceptable modified fucan and at least one binder, adjuvant, excipient, etc.

[0062] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a sulfation level of between about 10% w / w and 60% w / w, between about 20% w / w and 55% w / w, between about 30% w / w and 50% w / w, or between about 40% w / w and 45% w / w.

[0063] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a molar ratio of total fucose:total sulfate of between 1 :0.5 and 1 :4, between about 1 :0.8 and 1 :3.5, between about 1: 1 and 1 :2.5, between about 1 : 1.2 and 1 :2.0, or between about 1 : 1.5 and 1 :3.

[0064] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a molar ratio of total fucose and galactose:total sulfate of between about 1 :0.5 and 1 :4, between about 1 :0.8 and 1 :3.5, between about 1 :1 and 1 :2.5, between about 1 : 1.2 and 1 :2.0, or between about 1 : 1.5 and 1 :3.

[0065] The medically-acceptable fucans discussed herein may be modified to obtain medically- acceptable modified fucans having increased or decreased weight average molecular weight, number average molecular weight and / or peak molecular weight. The medically-acceptable fucans, having broad molecular weight distributions, discussed herein may be modified to obtain medically-acceptable modified fucans having a molecular weight distribution wherein a portion of the fucan at the low molecular weight end or at the high molecular weight end of the broad molecular weight distribution has been reduced or eliminated.

[0066] The molecular weight distribution of the medically-acceptable modified fucans may be measured using any desired, appropriate measurement system. Different systems can yield different readings or results from different compositions having essentially the same make-up, or even from the same batch when measured differently. One suitable measurement system is anaqueous gel permeation chromatography set up consisting essentially of one 300 mm analytical gel permeation chromatography column with a 7.8 mm inner diameter packed with hydroxylated polymethacrylate-based gel, having an effective molecular weight range of between about 50 kDa and about 5,000 kDa, one 300 mm analytical gel permeation chromatography column with a 7.8 mm inner diameter packed with hydroxylated polymethacrylate-based gel, having an effective molecular weight range of between about 1 kDa and about 6,000 kDa and one 40 mm guard column with a 6 mm inner diameter packed with hydroxylated polymethacrylate-based gel, the two analytical gel permeation chromatography columns and the one guard column contained in a column compartment at about 30 °C, a refractive index detector at about 30 °C, 0. IM sodium nitrate mobile phase run at 0.6 mL / min, and quantification against a peak molecular weight standard curve consisting essentially of a first dextran standard with a peak molecular weight of about 2,200 kDa, a second dextran standard with a peak molecular weight of between about 720 kDa and about 760 kDa, a third dextran standard with a peak molecular weight between about 470 kDa and about 510 kDa, a fourth dextran standard with a peak molecular weight between about 370 kDa and about 410 kDa, a fifth dextran standard with a peak molecular weight between about 180 kDa and about 220 kDa, and a sixth dextran standard with a peak molecular weight between about 40 kDa and 55 kDa. The peak molecular weight standard curve may further comprise a dextran standard with a peak molecular weight between 3 kDa and 5 kDa.

[0067] The medically-acceptable modified fucans discussed herein may have a weight average molecular weight greater than 300 kDa, for example between about 300 kDa and 2000 kDa, between about 350 kDa and 1500 kDa or between about 375 kDa and 1300 kDa.

[0068] The medically-acceptable modified fucans discussed herein may have a number average molecular weight greater than 100 kDa, for example between about 100 kDa and 800 kDa, between about 150 kDa and about 800 kDa or between about 170 kDa and 700 kDa.

[0069] The medically-acceptable modified fucans discussed herein may have a peak molecular weight greater than 200 kDa, for example between about 200 kDa and 800 kDa, between about 250 kDa and 750 kDa or between about 300 kDa and 700 kDa.

[0070] The medically-acceptable modified fucans discussed herein can have a molecular weight distribution wherein at least about 80% w / w or 90% w / w of the distribution is above 100 kDa. The medically-acceptable modified fucans discussed herein can have a molecular weight distribution wherein at least about 60% w / w, 70% w / w, 80% w / w or 90% w / w of the distribution is above 200kDa. The medically-acceptable modified fucans discussed herein can have a molecular weight distribution wherein at least 20%, 40%, 50% or 70% of the distribution is above 500 kDa.

[0071] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a total carbohydrate content of between 27% w / w and 80% w / w, between about 30% w / w and 70% w / w, between about 40% w / w and 90% w / w, or between about 50% w / w and 100% w / w.

[0072] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a fucose content as a percentage of total carbohydrate of about 30% w / w and 100% w / w, between about 40% w / w and 95% w / w, or between about 50% w / w and 90% w / w.

[0073] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a galactose content as a percentage of total carbohydrate of about 0% w / w and 60% w / w, between about 3% w / w and 30% w / w, or between about 0% w / w and 10% w / w.

[0074] The medically-acceptable fucans and medically-acceptable modified fucans discussed herein may have a total glucuronic acid, mannose, rhamnose and xylose content as a percentage of the total carbohydrate content of less than about 30% w / w.EXAMPLESExamples of methods that can be used to modify fucans and fucan compositions to obtain medically-acceptable modified fucans and medically-acceptable modified fucan compositions are discussed in the following patents: PCT / CA2019 / 051025, filed July 24, 2019; PCT / CA2019 / 051026, filed July 24, 2019; PCT / CA2019 / 051027, filed July 24, 2019,PCT / CA2019 / 051030, filed July 24, 2019; PCT / CA2019 / 051028, filed July 24, 2019;PCT / CA2020 / 050294, filed March 5, 2020; PCT / CA2020 / 050295, filed March 5, 2020; and PCT / CA2019 / 051029, filed July 24, 2019.

[0075] These methods can be applied, for example, to obtain medically-acceptable modified fucan compositions having low endotoxin levels. More particularly, the medically-acceptable modified fucan compositions had low levels of nitrogen-containing compounds, which could have interfered with the immunoassays discussed herein.Example 1: Analysis Of The Sulfate, Fucose, Galactose, Total Nitrogen Content And Molecular Weight Distribution Of Three Medically- Acceptable Modified Fucans

[0076] The three medically-acceptable modified fucans in the medically-acceptable modified fucan compositions used in the examples below were analyzed by the following methods to determine their physiochemical properties.

[0077] The three medically-acceptable modified fucans, hereafter referred to as Modified fucan 1, Modified fucan 2 and Modified fucan 3, were dissolved in 72% w / w sulfuric acid at 40 mg / mL and incubated at 45 °C in a water bath for 30 minutes. The resulting acid hydrolysates were then diluted to 4% w / w sulfuric acid in a high-pressure tube and incubated at 120 °C for 60 minutes. The resulting second acid hydrolysates were diluted to a 1 / 333 concentration with distilled water and run on a high performance anionic exchange column chromatography set up with pulsed amperometry detection (HPAE-P D). Separation of analytes was accomplished by running 10 mM NaOH eluent at 1.0 mL / minute using an isocratic pump.

[0078] The fucose contents of the three medically-acceptable modified fucans were determined by interpolation on a standard curve for fucose. The galactose contents of the three medically- acceptable modified fucans were determined by the standard addition.

[0079] The medically-acceptable modified fucans were dissolved in deionized water, hydrolyzed under acidic conditions and analyzed by ICP-MS for % w / w total sulfur content. The sulfur content was converted to sulfate content by multiplying the sulfur content by the molar ratio of sulfate to sulfur to obtain % w / w sulfate content in the modified fucans.

[0080] The three medically acceptable modified fucans were analyzed for total nitrogen by igniting samples in a combustion analyzer and analyzing for nitrogen in the nitrous oxide gas produced using a thermal conductivity detector.

[0081] Gel permeation chromatography was used to evaluate the molecular weight distributions obtained for the three medically-acceptable modified fucans. There are a large number of different parameters, columns and standards available for use in gel permeation chromatography (GPC), resulting in a variety of instrumentation set-ups available for the analysis of molecular weight. For molecular weight determinations herein, the GPC were conducted using the following parameters: The mobile phase was 0.1M sodium nitrate run at 0.6 mL / min. The column compartment and detector were at 30 °C. A Waters 2414 refractive index detector was used for detection.

[0082] Suitable GPC columns include GPC columns compatible with aqueous solvents, for example, columns packed with at least one of sulfonated styrene-divinylbenzene, NH- functionalized acrylate copolymer network, modified silica and hydroxylated polymethacrylate- based gel. For the analyses herein, three columns were used in series, comprising one 40 mm long guard column with an inner diameter (ID) of 6 mm packed with 6 pm particle size hydroxylated polymethacrylate-based gel, followed by a first 300 mm analytical GPC column with a 7.8 mm ID packed with 12 pm particle size hydroxylated polymethacrylate-based gel that has an exclusion limit of about 7,000 kDa and an effective molecular weight range of between about 50 kDa and about 5,000 kDa, followed by a second 300 mm analytical GPC column with a 7.8 mm ID packed with 10 pm particle size hydroxylated polymethacrylate-based gel that has an exclusion limit of about 7,000 kDa and an effective molecular weight range of between about 1 kDa and about 6,000 kDa. The total effective molecular weight range of the column set up was between about 1 kDa and about 6,000 kDa. An example of this column set up can be Ultrahydrogel® guard- Ultrahydrogel® 2000-Ultrahydrogel® Linear columns connected in series.

[0083] The samples of the three medically-acceptable modified fucans that were run were quantified against a standard curve containing traceable standards from the American Polymer Standards Corporation: DXT3755K (peak molecular weight=2164 kDa), DXT820K (peak molecular weight=745 kDa), DXT760K (peak molecular weight=621 kDa), DXT670K (peak molecular weight=401 kDa), DXT530K (peak molecular weight=490 kDa), DXT500K (peak molecular weight=390 kDa), DXT270K (peak molecular weight=196 kDa), DXT225K (peak molecular weight=213 kDa), DXT150K (peak molecular weight=124 kDa), DXT55K (peak molecular weight=50 kDa), DXT50K (peak molecular weight=44 kDa) and DXT5K (peak molecular weight=4 kDa), the peak molecular weights of these standards being between about 4 kDa and about 2,200 kDa. The standard curve used may, for example, include Dextran 3755 kDa, at least one of Dextran 50 kDa and Dextran 55 kDa, and between 3 to 6 additional traceable standards discussed herein, the calibration points being the peak molecular weights of the calibrants used. An example calibration curve may consist of DXT3755K, DXT 820K, DXT530K, DXT500K, DXT225K and DXT55K. The columns used herein had a total effective molecular weight range that encompassed and extended beyond the peak molecular weight range of the standards used for quantification of the three medically-acceptable modified fucans.

[0084] As is known, the identification of a molecular weight for a polymer including fucan / fucoidan, typically has a distribution of individual molecules having a variety of molecular weights. For a specified molecular weight identified within the distribution: there is a distribution of individual molecules of higher and lower molecular weights. The amount or percentage of individual polymers of a particular molecular weight increases or decreases as the molecular weight increases or decreases away from the specified molecular weight. The distribution may, but is not required to, have a generally Gaussian or distorted Gaussian shape.

[0085] The results for the total fucose, total galactose, total sulfate and molecular weight distribution of Modified fucan 1, Modified fucan 2 and Modified fucan 3 are presented in Table 1 below.

[0086] Results in the table below contain abbreviations used for certain characteristics of a molecular weight distribution. Peak molecular weight is denoted by PMW, weight average molecular weight is denoted by "WAMW", number average molecular weight is denoted by "NAMW", percentage distribution is denoted by "% dist".Table 1 - Physiochemical properties of 3 different modified fucansExample 2: Endotoxin measurement of Modified fucan 1

[0087] Modified fucan 1 was tested for endotoxins using Associates of Cape Cod Pyrotell®-T lysate in accordance with the manufacturer’s instructions. Turbidity measurements were taken using a Biotek Synergy® HTX incubating plate reader. Results were quantified against manufacturer CSE (control standard endotoxin) calibration curves. Modified fucan 1 was determined to have about 0.001 EU / mg.Example 3: In vitro immunoassay of fucan binding to signaling proteins

[0088] The binding of the three medically-acceptable modified fucans: Modified fucan 1, Modified fucan 2 and Modified fucan 3, to a variety of signaling proteins, including cytokines and chemokines, were studied herein via in vitro immunoassays to demonstrate the potential of fucans in inhibiting or sequestering these signaling proteins and consequently treating medical conditions associated with the respective signaling proteins.

[0089] The following human antibody array immunoassay procedure was performed:

[0090] The three different medically-acceptable modified fucans discussed in Table 1 were dissolved in deionized water at 100 mg / mL, 10 mg / mL, 1 mg / mL and 0.1 mg / mL to provide fucan stock solutions. Each individual fucan stock solution was diluted 1 : 1 with Quantibody® Sample Diluent (RayBiotech QA-SDB, RayBiotech, Georgia, USA). The fucan solution-diluent mixture was incubated at room temperature for about 1 hour. Each individual fucan solution-diluent mixture was then filtered through a 0.22 pm PVDF filter to obtain 50 mg / mL, 5 mg / mL, 0.5 mg / mL and 0.05 mg / mL fucan solution-diluent mixtures for each individual fucan.

[0091] A signaling protein standard mix containing numerous signaling protein standards was diluted in series to obtain a concentration series of signaling protein standards.

[0092] Each fucan solution-diluent mixture was further diluted 1 : 1 with the most concentrated signaling protein standard. A 1 : 1 mixture of deionized water and the most concentrated signaling protein standard was used as a blank. Each resulting fucan solution-diluent-signaling protein standard mixture was incubated for 1 hour at room temperature.

[0093] A plurality of slides (Human Kiloplex Quantitative Proteomics Array, RayBiotech®, QAH-CAA-X00-1), each containing 40 different antibodies in wells ordered into microarrays, each antibody specific for one signaling protein in the signaling protein standard, were provided. The antibodies were blocked with Quantibody® Sample Diluent (RayBiotech®, QA-SDB) by incubation for 30 minutes followed by decanting. 95 pL of each fucan solution-diluent-signaling protein standard mixture was then added to each of the wells. The mixtures were allowed to incubate in the wells for 2.5 hours. The same blocking and incubation procedures were followed for the concentration series of signaling protein standards. Post incubation, all samples and signaling protein standards were decanted from each well. The wells were washed with 150 pL IX Wash Buffer 1, diluted from 20X Wash Buffer 1 (RayBiotech®, AA-WB1-30ML) 5 times at room temperature, removing the wash solution from the wells after each wash. The wells werethen washed with 150 pL IX Wash Buffer 2, diluted from 20X Wash Buffer 2 (RayBiotech®, AA- WB2-30ML) 2 times at room temperature, removing the wash solution from the wells after each wash.

[0094] 80 pL of Quantibody® Sample Diluent (RayBiotech®, QA-SDB) containing a plurality of biotinylated antibodies, each specific for a signaling protein in the signaling protein standard, was added to each well and was left to incubate for between 1 and 2 hours. The solution was decanted from the wells and the wells again washed with IX Wash Buffer 1 and IX Wash Buffer 2 in the same manner.

[0095] 80 pL of Quantibody® Sample Diluent (RayBiotech®, QA-SDB) containing Cy3 equivalent dye-conjugated streptavidin was added to each well and was left to incubate for about 1 hour in a dark room. The diluent solution was decanted from the wells and the wells were again washed with 150 pL IX Wash Buffer 1 a total of 5 times, removing the wash solution from the wells after each wash.

[0096] The slide was further washed on a slide washer / dryer with 30 mL IX Wash Buffer 1, then 30mL IX Wash Buffer 2, decanting the wash solution after each wash. Residual droplets were removed by drying with a N2 stream.

[0097] The slide was then imaged through the use of a laser scanner with a Cy3 wavelength. Results were obtained and transformed into signal reduction relative to the blank sample.

[0098] Table 2 below shows the immunoassay results, reported in percentage signal reduction compared to the blank for respective signaling proteins in the presence of the medically-acceptable modified fucans.:Table 2 - Immunoassay results for the 3 different medically-acceptable modified fucans presented in Table 1.*ND indicates that no data was obtained due to an instrument malfunction during the reading by the laser scanner.

[0099] The results in Table 2 demonstrate that the medically-acceptable modified fucans discussed herein inhibit a wide variety of signaling proteins, typically by significant and even highly significant amounts.[000100] For certain signaling proteins, the medically-acceptable modified fucans discussed herein were able to inhibit or sequester at least about 50% of the signaling protein activity. For other signaling proteins, the medically-acceptable modified fucans were able to inhibit or sequester at least about 60% of the signaling protein activity. For yet other signaling proteins, the medically- acceptable modified fucans were able to inhibit at least about 70% of the signaling protein activity. For yet other signaling proteins, the medically-acceptable modified fucans were able to inhibit at least about 80% of the signaling proteins activity. For yet other signaling proteins, the medically- acceptable modified fucans were able to inhibit at least about 90% of the signaling protein activity.For yet other signaling proteins, the medically-acceptable modified fucans were able to inhibit at least about 95% of the signaling protein activity. For yet other signaling proteins, the medically- acceptable modified fucans were able to inhibit at least about 98% of the signaling protein activity. [000101] The results in Table 2 also indicate that medically-acceptable modified fucans discussed herein, including the medically-acceptable modified fucans shown in Table 2, can inhibit or sequester a wide variety of signaling proteins at a target site in vivo, and therefore can be efficacious in the inhibition or treatment of the various medical conditions discussed herein.[000102] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester at least 98% of CCL28 activity. This indicates inhibition or sequestration of chemokines involved in aggravation of COLD and post-viral airway diseases by the medically-acceptable modified fucans discussed herein.[000103] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester at least 84% of IL-7 activity, between 22 and 88% of IL-4 activity, between 53 and 74% of IL-9 activity and between 27 and 61% of IL-13 activity. This indicates inhibition or sequestration of chemokines involved in aggravation of asthma by the medically acceptable modified fucans discussed herein.[000104] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester between 64 and 84% TGFbl activity, between 38 and 87% TGFb2 activity, between 1 and 53% TNFa activity, between 65 and 91% PDGF-AA activity, at least 92% PDGF-AB activity, between 69 and 93% PDGF-BB activity, between 66 and 99% PDGF-CC activity, between 36 and 78% FGF-12 activity, between 66 and 88% FGF-16 activity, at least 85% FGF-19 activity, between 37 and 84% FGF-23 activity, between 5 and 98% FGF-3 activity, between 70 and 85% FGF-6 activity, between 56 and 89% FGF-9 activity, between 72 and 86% IL-1 F7 activity, between 62 and 92% IL-1 R6 activity, between 22 and 88% of IL-4 activity, up to 89% IL-10 activity, between 27 and 61% of IL-13 activity, between 57 and 92% MCP-1 activity, up to 57% MIP-la activity and between 32 and 97% MIP-lb activity. This indicates inhibition or sequestration of chemokines involved in aggravation of pulmonary fibrosis by the medically acceptable modified fucans discussed herein.[000105] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester at least 92% Midkine activity. This indicates inhibition or sequestration of chemokinesinvolved in increasing the risk of osteoporotic fractures by the medically acceptable modified fucans discussed herein.[000106] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester between 57 and 92% MCP-1 activity, up to 57% MIP-la activity, between 76 and 99% RANTES activity, at least 85% Eotaxin 1 activity, up to 81% IL-8 activity, up to 69% MIG activity and at least 85% IP- 10 activity. This indicates inhibition or sequestration of chemokines involved in aggravation of liver fibrosis by the medically acceptable modified fucans discussed herein.[000107] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester between 64 and 87% TGFbl activity, between 38 and 87% TGFb2 activity, up to 89% IL- 10 activity and between 22 and 88% IL-4 activity. This indicates inhibition or sequestration of chemokines involved in increasing the prominence of hypertrophic scars in burn patients by the medically acceptable modified fucans discussed herein.[000108] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester up to 61% VCAM-1 activity, between 72 and 86% IL-1 F7 activity, between 62 and 92% IL-1 R6 activity, at least 88% TLR2 activity, between 8 and 74% IL- lb activity, between 1 and 53% TNFa activity, between 28 and 87% IL-12p40 activity, between 55 and 85% IL-12p70 activity and up to 81% IL-8 activity. This indicates inhibition or sequestration of chemokines involved in aggravation of acne by the medically acceptable modified fucans discussed herein.[000109] Modified fucan 1, Modified fucan 2 and Modified fucan 3 were all able to inhibit or sequester between 1 and 53% TNFa activity, between 72 and 86% IL-1 F7 activity, between 62 and 92% IL-1 R6 activity, up to 81% IL-8 activity, between 58 and 74% IL-9 activity, between 27 and 61% of IL-13 activity and at least 90% MCP-3 activity. This indicates inhibition or sequestration of chemokines involved in the occurrence of anaphylaxis by the medically acceptable modified fucans discussed herein.[000110] All terms used herein are used in accordance with their ordinary meanings unless the context or definition clearly indicates otherwise. Also unless expressly indicated otherwise, in this disclosure the use of "or" includes "and" and vice-versa. Non-limiting terms are not to be construed as limiting unless expressly stated, or the context clearly indicates, otherwise (for example, "including," "having," and "comprising" typically indicate "including withoutlimitation"). Singular forms, including in the claims, such as "a," "an," and "the" include the plural reference unless expressly stated, or the context clearly indicates otherwise.[000111] Unless otherwise stated, adjectives herein such as “substantially” and “about” that modify a condition or relationship characteristic of a feature or features of an embodiment, indicate that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended.[000112] The scope of the present methods, compositions, systems, etc., includes both means plus function and step plus function concepts. However, the claims are not to be interpreted as indicating a "means plus function" relationship unless the word "means" is specifically recited in a claim, and are to be interpreted as indicating a "means plus function" relationship where the word "means" is specifically recited in a claim. Similarly, the claims are not to be interpreted as indicating a "step plus function" relationship unless the word "step" is specifically recited in a claim, and are to be interpreted as indicating a "step plus function" relationship where the word "step" is specifically recited in a claim.[000113] From the foregoing, it will be appreciated that, although specific embodiments have been discussed herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the discussion herein. Accordingly, the systems and methods, etc., include such modifications as well as all permutations and combinations of the subject matter set forth herein and are not limited except as by the appended claims or other claim having adequate support in the discussion and figures herein.

Claims

What is claimed is:

1. A method of treating a medical condition comprising bum scarring in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the bum scarring.

2. A method of treating a medical condition comprising acne in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the acne.

3. A method of treating a medical condition comprising surgery-induced cancer metastasis in a body of a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site in the body of the patient suspected of having the surgery-induced cancer metastasis.

4. A method of treating a medical condition comprising chronic obstructive lung disease in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the chronic obstructive lung disease.

5. A method of treating a medical condition comprising post-viral airway disease in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the post-viral airway disease.

6. A method of treating a medical condition comprising chronic sinusitis in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the chronic sinusitis.

7. A method of treating a medical condition comprising asthma in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the asthma.

8. A method of treating a medical condition comprising pulmonary fibrosis in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the pulmonary fibrosis.

9. A method of treating a medical condition comprising an osteoporotic fracture in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the osteoporotic fracture.

10. A method of treating a medical condition comprising liver fibrosis in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the liver fibrosis.

11. A method of treating a medical condition comprising anaphylaxis in a patient, comprising administering a therapeutically effective amount of a medically acceptable fucan composition to a site of the medical condition in the patient suspected of having the anaphylaxis.

12. A method of treating a medical condition comprising blood loss from, and fibrous adhesions in a patient, the method comprising administering a medically acceptable composition comprising a medically acceptable modified fucan and a hemostatic agent to a site of the medical condition in the patient suspected of having the blood loss.

13. The method of claim 12 wherein the hemostatic agent comprises at least one of a mucoadhesive agent, a factor concentrator and a procoagulant suppiementor.

14. The method of any of claims 1 to 3 the method further comprising, before administering the medically acceptable fucan composition to the patient, identifying a need for the treating of the medical condition identified in any one of claims 1 to 3, respectively, in the patient and then selecting the medically acceptable fucan composition for the administering of the medically acceptable fucan composition to the patient to effect the treating.

15. The method of any of claims 1 to 14 wherein the treating comprises inhibiting.

16. The method of any one of claims 1 to 15 wherein the administering comprises directly delivering the medically acceptable fucan composition to a site of the medical condition identified in any of claims 1 to 15.

17. The method of any one of claims 1 to 15 wherein the administering comprises rinsing the suspected site of the medical condition in the patient with the therapeutically effective amount of the medically acceptable fucan composition.

18. The method of any one of claims 1 to 15 wherein the medically acceptable fucan composition is substantially continuously administered to the site of the medical condition via controlled release from a polymeric dosage form.

19. The method of any one of claims 1 to 15 wherein the medically acceptable fucan composition is administered intravenously, intraarticularly, intralesionally, intravaginally, rectally, intramuscularly, intraperitoneally, subcutaneously, topically, intranasally, intraocularly or orally.

20. The method of any one of claims 1 to 11 wherein the medically acceptable fucan composition comprises at least one of a paste, gel, patch, film, spray, liquid, lotion, cream, solution, suspension, solid, implant, powder and microsphere.

21. The method of any one of claims 1 to 20 wherein the medically acceptable fucan composition further comprises at least one medically acceptable excipient selected from the group consisting of gelatin, hypromellose, lactose, water for injection USP, sodium chloride, sodium phosphate, sodium citrate, sodium ascorbate, phosphate buffers, citrate buffers, phosphate-citrate buffers, pluronic, cellulose, alginate, acrylate, hyaluronic acid, polyethylene glycol, lactic acid, carrageenan, polyurethane, polyethylene, polypropylene, polytetrafluoroethylene, chitosan and lactated Ringer’s injection USP.

22. The method of any one of claims 1 to 21 wherein the patient is an animal.

23. The method of any one of claims 1 to 22 wherein the medically acceptable fucan composition comprises fucoidan.

24. Use of a medically acceptable fucan composition to treat surgery-induced cancer metastasis.

25. Use of a medically acceptable fucan composition to treat chronic obstructive lung disease.

26. Use of a medically acceptable fucan composition to treat post viral airway disease.

27. Use of a medically acceptable fucan composition to treat chronic sinusitis.

28. Use of a medically acceptable fucan composition to treat asthma.

29. Use of a medically acceptable fucan composition to treat pulmonary fibrosis.

30. Use of a medically acceptable fucan composition to treat osteoporotic fracture.

31. Use of a medically acceptable fucan composition to treat liver fibrosis.

32. Use of a medically acceptable fucan composition to treat a burn scar.

33. Use of a medically acceptable fucan composition to treat acne.

34. Use of a medically acceptable composition comprising a pharmaceutically effective amount of a hemostatic agent to inhibit blood loss and a pharmaceutically effective amount of a medically acceptable modified fucan to inhibit fibrous adhesions.

35. Use of a medically acceptable medical device comprising a pharmaceutically effective amount of a hemostatic agent to inhibit blood loss and a pharmaceutically effective amount of a medically acceptable modified fucan to inhibit fibrous adhesions.

36. A composition for treating blood loss and fibrous adhesions, comprising a pharmaceutically effective amount of a hemostatic agent and a and a pharmaceutically effective amount of a medically acceptable modified fucan.

37. The composition of claim 36, the composition comprising less than about 200 Endotoxin Units (EU).

38. The composition of claim 36, the composition comprising less than about 100 Endotoxin Units (EU).

39. The composition of claim 36, the composition comprising less than about 50 Endotoxin Units (EU).

40. The composition of claim 36, the composition comprising less than about 20 Endotoxin Units (EU).

41. The composition of claim 36, the composition comprising less than about 10 Endotoxin Units (EU).

42. The composition of claim 36, the composition comprising less than about 5 Endotoxin Units (EU).

43. The composition of claim 36, the composition comprising less than about 2 Endotoxin Units (EU).

44. A medical device configured for treating blood loss and fibrous adhesions, comprising a pharmaceutically effective amount of a hemostatic agent and a pharmaceutically effective amount of a medically acceptable modified fucan, wherein each of the hemostatic agent and the modified fucan are exposed on different surfaces of the medical device.

45. The medical device of claim 44, the device comprising less than about 20 Endotoxin Units (EU).

46. The medical device of claim 44, the device comprising less than about 10 Endotoxin Units (EU).

47. The medical device of claim 44, the device comprising less than about 5 Endotoxin Units (EU).

48. The medical device of claim 44, the device comprising less than about 2 Endotoxin Units (EU).

Images