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WO2009058146A1 - Dispositifs d'administration et de stockage de sang à revêtement de polyphosphazène spécifique, conçus pour une élution de vasodilatateur, et leurs procédés de fabrication et d'utilisation - Google Patents

Dispositifs d'administration et de stockage de sang à revêtement de polyphosphazène spécifique, conçus pour une élution de vasodilatateur, et leurs procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2009058146A1
WO2009058146A1 PCT/US2007/083209 US2007083209W WO2009058146A1 WO 2009058146 A1 WO2009058146 A1 WO 2009058146A1 US 2007083209 W US2007083209 W US 2007083209W WO 2009058146 A1 WO2009058146 A1 WO 2009058146A1
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Prior art keywords
och
blood
coating
polyphosphazene
chf
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Inventor
Olaf Fritz
Ulf Fritz
Roman Denk
Teresa Wilson
Ralph E. Gaskins, Jr.
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Celonova Bioscience Inc
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Celonova Bioscience Inc
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Priority to PCT/US2007/083209 priority Critical patent/WO2009058146A1/fr
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/14—Mechanical aspects of preservation; Apparatus or containers therefor
    • A01N1/146—Non-refrigerated containers specially adapted for transporting or storing living parts whilst preserving
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/08—Tubes; Storage means specially adapted therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers

Definitions

  • the present invention is directed to blood storage and handling products that comprise a specific polyphosphazene and a capability of releasing nitric oxide or other smooth muscle relaxant compounds in vivo or into stored blood to achieve vascular dilatation, reduce adverse reactions, reduce thrombosis, reduce the incidence of post-transfusion acute myocardial infarction, and improve blood storage capabilities.
  • Nitric oxide (NO) is one of the few gaseous biological signaling molecules known. It is a key biological messenger, playing a role in a variety of biological processes.
  • Nitric oxide also known as the 'endothelium-derived relaxing factor', or 'EDRF', is biosynthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by reduction of inorganic nitrate.
  • NOS nitric oxide synthase
  • the endothelial cells that line blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow.
  • the production of nitric oxide is elevated in populations living at high-altitudes, which helps these people avoid hypoxia. Effects include blood vessel dilatation, and neurotransmission.
  • Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body.
  • Phosphodiesterase type 5 inhibitors often shortened to PDE5 inhibitors. are a class of drugs used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining blood vessels. NO activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels. PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5 (PDE5).
  • Nitric oxide is also generated by macrophages and neutrophils as part of the human immune response. Nitric oxide is toxic to bacteria and other human pathogens. In response, however, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.
  • S-nitrosylation the conversion of thiol groups, including cysteine residues in proteins, to form S- nitrosothiols (RSNOs).
  • S-Nitrosylation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.
  • GTN Nitroglycerine or glyceryl trinitrate
  • NO nitric oxide
  • GTN is a pro-drug which must first be denitrated to produce the active metabolite NO.
  • Nitrates which undergo denitration within the body to produce NO are called nitrovasodilators and their denitration occurs via a variety of mechanisms. The mechanism by which nitrates produce NO is widely disputed.
  • nitrates produce NO by reacting with sulfhydryl groups, while others believe that enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation.
  • enzymes such as glutathione S-transferases, cytochrome P450 (CYP), and xanthine oxidoreductase are the primary source of GTN bioactivation.
  • CYP cytochrome P450
  • mtALDH mitochondrial aldehyde dehydrogenase
  • NO is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms; this activation results in cGMP formation from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • GTP is more useful in preventing angina attacks than reversing them once they have commenced.
  • Patches of glyceryl trinitrate with long activity duration are commercially available. It may also be given as a sublingual dose in the form of a tablet placed under the tongue or a spray into the mouth for the treatment of an angina attack.
  • Long acting Nitrates can be more useful as they are generally more effective and stable in the short term. GTP is also used to help provoke a vasovagal syncope attack while having a tilt table test which will then give more accurate results.
  • Blood products can provide an excellent medium for bacteria! growth, and can become contaminated after collection while they are being stored.
  • the risk is highest with platelet transfusion, since platelets must be stored near room temperature and cannot be refrigerated.
  • the risk of severe bacterial infection and sepsis is estimated (as of 2001) at about 1 in 50,000 platelet transfusions, and 1 in 500,000 red blood cell transfusions.
  • Acute hemolytic reaction is a medical emergency resulting from rapid destruction (hemolysis) of the donor red blood cells by host antibodies. The most common cause is clerical error (i.e. the wrong unit of blood being given to the wrong patient).
  • the symptoms are fever and chills, sometimes with back pain and pink or red urine (hemoglobinuria).
  • An anaphylactic (or severe allergic) reaction can occur at a rate of 1 per 30,000-50,000 transfusions. These reactions are most common in people with selective IgA deficiency (although IgA deficiency is often asymptomatic, and people may not know they have it until an anaphylactic reaction occurs).
  • An anaphylactic reaction is a medical emergency, requiring prompt treatment, and may be life- threatening.
  • Transfusion-associated acute lung injury is a syndrome of acute respiratory distress, often associated with fever, non-cardiogenic pulmonary edema, and hypotension. It may occur as often as 1 in 2000 transfusions. Symptoms can range from mild to life-threatening, but most patients recover fully within 96 hours, and the mortality rate from this condition is less than 10%.
  • Patients with impaired cardiac function can become volume-overloaded as a result of blood transfusion, leading to edema, dyspnea (shortness of breath), and orthopnea (shortness of breath white lying flat). This is sometimes called TACO, or Transfusion Associated Circulatory Overload.
  • Each transfused unit of red blood cells contains approximately 250 mg of elemental iron. Since elimination pathways for iron are limited, a person receiving numerous red blood cell transfusions can develop iron overload, which can in turn damage the liver, heart, kidneys, and pancreas. The threshold at which iron overload becomes significant is somewhat unclear, but is likely around 12-20 units of red blood cells transfused.
  • Transfusion-associated graft-vs-host disease refers to an immune attack by transfused ceils against the recipient. This is a common complication of stem cell transplantation, but an exceedingly rare complication of blood transfusion. It occurs only in severely immunosuppressed patients, primarily those with congenital immune deficiencies or hematologic malignancies who are receiving intensive chemotherapy. When GVHD occurs in association with blood transfusion, it is almost uniformly fatal. Transfusion-associated GVHD can be prevented by irradiating the blood products prior to transfusion.
  • Blood banking containers and accessories used in the handling of blood are among the items that could benefit from an inherent ability to increase and maintain nitric oxide levels within the contained and processed blood and blood products.
  • Blood bags are commercially available for the collection, storage, and processing of blood and blood products, such as packed red cells, plasma, platelets, and cryoprecipitate.
  • PVC polyvinyl chloride
  • di-2-ethylhexylphthalate a plasticizer
  • Such a plasticizer is absolutely necessary for polyvinyl chloride formulations, since polyvinyl chloride itself is not a suitable, flexible plastic material for use in containers.
  • Such blood bags have served extremely well in the storage and processing of blood and blood components, exhibiting a high survival rate with low plasma hemoglobin content after, for example, 21 days of storage at about 4°C.
  • Plasticized PVC containers possess a number of advantages which makes it the material of choice for medical and more particularly for blood contact applications.
  • PVC containers' more important features include: ability to be welded together which enables the production of leak-free products and offers infinite design possibilities, steam sterilizability even at 12 TC, favorable cost/performance ratio, and low bulk density offering low storage and distribution costs.
  • the plasticizers used in the compounding of PVC are mainly responsible for achieving desirable characteristics for medical applications such as low toxicity, transparency, flexibility, strengths, elongation, stability at low and high temperatures, permeability to water, oxygen and carbon dioxide in the desired range. While a wide range of plasticizers are available for food contact and most medical applications, the choices for blood contact applications are very limited.
  • the principal plasticizer for blood containers and related applications used is di, (2-ethyl hexyl) phthalate (DEHP) which offers the benefits of overall performance, ready availability at high purity and cost effectiveness.
  • DEHP is not covalently bonded to PVC and so could migrate out of the plastic. This is particularly so in the presence of solubilizing lipids, lipoproteins and albumin.
  • Jaegar and Rubin (1970) reported the leaching of DEHP into stored human blood.
  • PVC materials plasticized with DEHP have been used in patient health care for over 50 years and there are over 3000 published papers discussing its potential toxicological hazards.
  • Platelets from 400 ml donor blood could be stored in DEHP plasticized bags meant for storage of platelets from 450 ml of blood without deterioration. Such platelets were not inferior to platelet concentrates stored for 5 days in PL 732 (Polyolefin) or PL 1240 (BTHC) containers.
  • PL 732 Polyolefin
  • BTHC PL 1240
  • BTHC n-butyrul, tr ⁇ n-hyxyl citrate
  • Modified poiyolefins are suitable for the storage of platelets for up to seven days because of their higher gas permeability. However, aberrant morphology has been observed after 2-3 days. Such modified polyolefms are reported to be free of plasticizers, but may contain antioxidants to prevent oxidative deterioration. Polyolefin materials have also been shown to give rise to leaching. Thus polypropylene releases many low molecular weight oligomers while polyethylene releases higher molecular weight oligomers. [0031] PVC blood bags are also available incorporating a less leachable phthalate ester - di, n-decyl phthalate (DnDP) which has better gas permeabilities.
  • DnDP n-decyl phthalate
  • the leachab ⁇ ity of this plasticizer into plasma is l/80th that of DEHP.
  • the LD50 values of DnDP is approximately ten times that of DEHP. This makes DnDP appear more than 800 times safer than DEHP.
  • the new bag has been shown to be suitable for the five day storage of platelet concentrates. [0032] Adverse transfusion reactions are encountered in 2%-10% of patients receiving transfusions; such reactions may range from infectious blood-borne diseases or allergic reactions to death in some individuals patients. Repeatedly, medical studies have been reported, showing disturbing increased rates in heart disease and death in patients who previously received transfusions. [0033] Therefore, it would be desirable to improve the risk of heart attack and death from transfusion by replacing nitric oxide in stored blood. [0034] It would also be desirable to therapeutically increase the nitrous oxide content in blood in vivo in anatomic areas for treatment for diseases or pathologic conditions in which localized or systemic vasodilatation is compromised.
  • polyvinyl chloride or other plastic blood bags, administration tubing, and other blood-handling or storage devices may be formulated to provide desirable physical characteristics, along with a coating capable of both reducing the plasma concentration of extractable plasticizer and eluting nitrous oxide to provide decreased transfusion-related morbidity and mortality.
  • the invention includes a coating for medical devices for use blood storage, handling, and administration in therapeutic settings where it is desirable to have such devices release nitric oxide or other smooth muscle relaxant drugs into blood.
  • the medical devices of the present invention further comprise poly[bis(trifluoroethoxy)phosphazene] and/or a derivative thereof and one or more smooth muscle relaxant active agents.
  • Poly[(bistrifluorethoxy)phosphazene] has antibacterial and anti-inflammatory properties and inhibits the accumulation of thrombocytes.
  • Further described herein is a method of delivering an active agent capable of eluting nitric oxide or other smooth muscle relaxants from within a specific polyphosphazene coating into an anatomic area or a container space is therapeutically desirable.
  • Fig. IA shows a surface of a film of the present invention.
  • Fig. IB shows a cross section of the film of the present invention from Fig.
  • Fig. 2A shows a blood bag assembly comprising a blood bag and blood administration tubing.
  • Fig. 2B shows a cross section of a biood administration tubing of the present invention.
  • Fig. 2C shows a cross section of a wall of a blood bag of the present invention.
  • a or “an” can mean one or more, depending upon the context in which it is used.
  • Described herein are medical devices for the storage, handling, and administration of blood or blood products, said devices comprising poly[bis(trifluoroethoxy)phosphazene] and/or a derivative thereof and one or smooth muscle relaxant active agents capable of in vivo release into blood or blood products stored or administered using said devices.
  • medical devices for the storage, handling, and administration of blood or blood products are provided with a polymeric coating comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof releasably bonded to compounds capable of producing nitric oxide or other bioactive nitrogen compounds upon release from the polymer.
  • the present invention further includes methods for the manufacture and use of medical devices for the storage, handling, and administration of blood or blood products comprising a polymeric coating comprising poly[bis(trifluoroethoxy)phosphazene] and/or a derivative thereof releasably bonded to compounds capable of producing nitric oxide or other bioactive nitrogen compounds upon release from the polymer.
  • FIG. IA shows an exemplary surface view of a film surface of a medical device of the present invention.
  • a cross section through such a film surface is shown in FIG. IB, where a substrate medical device surface 205 is coated with the poly[bis(trifluoroethoxy)phosphazene] polymer represented by formula (I) in an exterior polymeric coat 215, with an intermediate smooth muscle relaxant coating 210 sandwiched between the substrate 205 and the polymeric coat 215.
  • the intermediate smooth muscle relaxant coating 210 as shown in FIG. IB may be any nitrogen compound capable of in vivo breakdown to nitric oxide or other vasoactive nitrite or nitrate compounds.
  • the intermediate smooth muscie relaxant coating 210 may be a non- nitrogen based smooth muscle relaxant agent.
  • the intermediate smooth muscle relaxant coating 210 is shown as a separate layer, adherent to the substrate 205 and covalently bonded or otherwise adherent to the exterior polymeric coat 215.
  • smooth muscle relaxant agent may be integrated into the exterior polymeric coat 215.
  • FIG. 2A shows an exemplary plastic blood bag assembly 300, comprising a blood bag 305 and a blood administration tubing 310.
  • Blood banks commonly use such blood bag assemblies 300 to collect, process, store, and administer blood or blood product transfusions.
  • a blood bag assembly 300 of the present invention externally may appear the same as a conventional product, but further comprises an inner polymeric coating comprising poly[bis(trifluoroethoxy)phosphazene] and/or a derivative thereof releasably bonded to compounds capable of producing nitric oxide or other bioactive nitrogen compounds upon release from the polymer.
  • An exemplary blood bag assembly 300 of the present invention provides a gradual release of nitric oxide into the blood or blood product(s) contained within said blood bag assembly 300, thus improving product shelf life and reducing the incidence and severity of transfusion reactions associated with the administration of transfusions of the contained blood or blood product(s) into patients,
  • FIG. 2B shows a cross-sectional view through a representative section of an exemplary blood administration tubing 310 of the present invention.
  • the blood administration tubing 310 comprises an outer tubing wall 315, an inner polymeric coating 325, and an intermediate nitric oxide eluting layer 320.
  • blood or blood products either contained within blood administration tubing 310 or transient therethrough receives nitric oxide, produced by gradual chemical breakdown of the an intermediate nitric oxide eluting layer 320.
  • the inner polymeric coating 325 comprising poly[bis(trifluoroethoxy)phosphazene] and/or a derivative thereof, imparts antithrombotic, anti-inflammatory, and lubricious qualities to the inner wall of the blood administration tubing 310, thus reducing blood cell or platelet injuries or clot formation during containment or administration.
  • the intermediate nitric oxide eluting layer 320 as shown in FlG.
  • nitric oxide-eluting compounds may be integrated into the inner polymeric coating 325,
  • FIG. 2C shows a cross-sectional view through a representative section of an exemplary blood bag 305 of the present invention, comprising an outer blood bag wall 330, an inner polymeric coating 340, and an intermediate nitric oxide eluting layer 335,
  • blood or blood products either contained within a blood bag 305 of the present invention receives nitric oxide, produced by gradual chemical breakdown of the an intermediate nitric oxide eluting layer 335.
  • the inner polymeric coating 340 again comprising poly[bis(trifiuoroethoxy)phosphazene] and/or a derivative thereof, imparts antithrombotic, anti-inflammatory, and lubricious qualities to the inner wall of the blood bag 305, thus reducing blood cell or platelet injuries or clot formation during containment or administration.
  • the intermediate nitric oxide eluting layer 335 as shown in FIG. 2C may be any nitrogen compound capable of breakdown to nitric oxide or other nitrite or nitrate compounds.
  • the intermediate nitric oxide eluting layer 335 is shown as a separate layer, adherent to the inner layer of the blood bag wall 330 and covalently bonded or otherwise adherent to the inner polymeric coating 340.
  • nitric oxide-eluting compounds may be integrated into the inner polymeric coating 340.
  • the intermediate nitric oxide eluting layer 335 may further be releasable from its chemical bond to the inner polymeric coating 340 or the inner layer of the blood bag wall 330 in a time release manner, and/or such release may be accelerated or activated by the administration of releasing agents such as pH-altering agents, or by the administration of energy in the forms of thermal or electromagnetic radiation energy at desired times.
  • the polymer poly[bis(2,2,2- trifluoroethoxy)phosphazene] or derivatives thereof have chemical and biological qualities that distinguish this polymer from other know polymers in general, and from other know polyphosphazenes in particular.
  • the polyphosphazene is poly[bis(2,2,2-trif!uoroethoxy) phosphazene] or derivatives thereof, such as other alkoxide, halogenated alkoxide, or fluorinated alkoxide substituted analogs thereof.
  • the preferred poly[bis(trifluoroethoxy)phosphazene] polymer is made up of repeating monomers represented by the formula (I) shown below:
  • R 1 to R 5 are all trifluoroethoxy (OCH 2 CF3) groups, and wherein n may vary from at least about 40 to about 100,000, as disclosed herein.
  • n may vary from at least about 40 to about 100,000, as disclosed herein.
  • derivatives or “derivatives” is meant to refer to polymers made up of monomers having the structure of formula I but where one or more of the R !
  • R 6 functional group(s) is replaced by a different functional group(s), such as an unsubstituted alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R 1 to R 6 is replaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially altered.
  • a different functional group(s) such as an unsubstituted alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R 1 to R 6 is replaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially altered.
  • At least one of the substituents R ! to R 6 can be an unsubstituted alkoxy substituent, such as methoxy (OCH 3 ), ethoxy (OCH 2 CH 3 ) or n-propoxy (OCH 2 CH 2 CH 3 ).
  • at least one of the substituents R 1 to R 6 is an alkoxy group substituted with at least one fluorine atom.
  • R L to R 6 examples include, but are not limited to OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 , OCH(CF 3 ) 2 , OCCH 3 (CFa) 2 , OCH 2 CF 2 CF 2 CF 3 , OCH 2 (CFs) 3 CF 3 , OCH 2 (CF 2 ) 4 CF 3 , OCH 2 (CF 2 ) 5 CF 3!
  • trifluoroethoxy (OCH 2 CF 3 ) groups are preferred, these further exemplary functional groups also may be used alone, in combination with trifluoroethoxy, or in combination with each other.
  • examples of especially useful fluorinated alkoxide functional groups include, but are not limited to, 2,2,3,3,3-pentafiuoropropyloxy (OCH 2 CF 2 CF 3 ), 2,2,2,2',2',2'-hexafiuoroisopropyioxy (OCH(CF 3 ) 2 ), 2,2,3,3,4,4,4- heptafluorobutyloxy (OCH 2 CF 2 CF 2 CF 3 ), 3,3,4,4,5,5,6,6,7,7,8,8,8- tri decaf] uorooctyloxy (OCH 2 (CFs) 7 CF 3 ), 2,2,3,3,-tetrafluoropropyloxy
  • 1% or less of the R 1 to R 6 groups may be alkenoxy groups, a feature that may assist in crossiinking to provide a more eiastomeric phosphazene polymer
  • the residues R 1 to R 6 are each independently variable and therefore can be the same or different.
  • n can be as large as ⁇ in formula I, it is intended to specify values of n that encompass polyphosphazene polymers that can have an average molecular weight of up to about 75 million Daitons. For example, in one aspect, n can vary from at least about 40 to about 100,000. In another aspect, by indicating that n can be as large as ⁇ in formula I, it is intended to specify values of n from about 4,000 to about 50,000, more preferably, n is about 7,000 to about 40,000 and most preferably n is about 13,000 to about 30,000.
  • the polymer used to prepare the polymers disclosed herein has a molecular weight based on the above formula, which can be a molecular weight of at least about 70,000 g/mol, more preferably at least about 1,000,000 g/mol, and still more preferably a molecular weight of at least about 3x10 6 g/moi to about 2OxIO 6 g/mol. Most preferred are polymers having molecular weights of at least about 10,000,000 g/mol.
  • n is 2 to ⁇
  • R 1 to R 6 are groups which are each selected independently from alkyl, aminoalkyl, haloalkyl, thioalkyl, thioaryl, alkoxy, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyi, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, or a combination thereof, or heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, or a combination thereof.
  • R 1 to R 6 are each independently variable and therefore can be the same or different. Further, R 1 to R 6 can be substituted or unsubstituted.
  • the aikyl groups or moieties within the alkoxy, alkylsulphonyi, diaikylamino, and other alkyl-containing groups can be, for example, straight or branched chain alkyl groups having from 1 to 20 carbon atoms, typically from 1 to 12 carbon atoms, it being possible for the alkyl groups to be further substituted, for example, by at least one halogen atom, such as a fluorine atom or other functional group such as those noted for the R 1 to R 6 groups above.
  • alkyl groups such as propyl or butyl, it is intended to encompass any isomer of the particular alkyl group.
  • examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups, and the like, which can also be further substituted.
  • the alkoxy group can be substituted by at least one fluorine atom, with 2,2,2-trifluoroethoxy constituting a useful alkoxy group.
  • one or more of the alkoxy groups contains at least one fluorine atom.
  • the alkoxy group can contain at least two fluorine atoms or the alkoxy group can contain three fluorine atoms.
  • the polyphosphazene that is combined with the silicone can be poly[bis(2,2,2-trifluoroethoxy)phosphazene].
  • Alkoxy groups of the polymer can also be combinations of the aforementioned embodiments wherein one or more fluorine atoms are present on the polyphosphazene in combination with other groups or atoms.
  • alkylsulphonyl substituents include, but are not limited to, methy (sulphonyl, ethyl sulphonyl, propyisulphonyl, and butylsulphonyl groups.
  • dialkylamino substituents include, but are not limited to, dimethyl-, diethyl-, dipropyl-, and dibutylamino groups. Again, by specifying alkyl groups such as propyl or butyl, it is intended to encompass any isomer of the particular alkyi group.
  • Exemplary aryloxy groups include, for example, compounds having one or more aromatic ring systems having at least one oxygen atom, non-oxygenated atom, and/or rings having alkoxy substituents, it being possible for the aryl group to be substituted for example by at least one alkyl or alkoxy substituent defined above.
  • Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy groups, and derivatives thereof including, for example, substituted phenoxy and naphthoxy groups.
  • the heterocycloalkyl group can be, for example, a ring system which contains from 3 to 10 atoms, at least one ring atom being a nitrogen, oxygen, sulfur, phosphorus, or any combination of these heteroatoms.
  • the hetereocycloalkyl group can be substituted, for example, by at least one alkyl or alkoxy substituent as defined above.
  • Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, and morpholinyl groups, and substituted analogs thereof.
  • the heteroaryl group can be, for example, a compound having one or more aromatic ring systems, at least one ring atom being a nitrogen, an oxygen, a sulfur, a phosphorus, or any combination of these heteroatoms.
  • the heteroaryl group can be substituted for example by at least one alkyl or alkoxy substituent defined above.
  • heteroaryl groups include, but are not limited to, imidazolyl, thiophene, furane, oxazolyl, pyrrolyl, pyridinyl, pyridinolyl, isoquinolinyl, and quinolinyl groups, and derivatives thereof, such as substituted groups.
  • smooth muscle relaxant active agents or compounds capable of producing nitric oxide or other bioactive nitrogen compounds upon release of the present invention further comprise diazeniumdiolates, sodium nitroprusside, molsidomine, nitrate esters, the S-nitrosothiol family, L-arginine, nitric oxide- nucleophile complexes, glyceryl trinitrate, nitric oxide-primary amine complexes, and related compounds, esters, amines, or other compositions thereof.
  • Smooth muscle relaxant active agents or compounds capable of producing nitric oxide or other bioactive nitrogen compounds upon release of the present invention may further comprise any other inorganic or organic composition capable of forming nitric oxide upon chemical degradation.
  • diazeniumdiolates are incorporated into blood-insoluble polyphosphazene polymers that generate molecular NO at their surfaces.
  • diazeniumdiolates may be applied to a substrate surface of a medical device as an intermediate coating, which is then coated with the preferred poly[bis(trifluoroethoxy)phosphazene] polymer of the present invention.
  • a substrate inner surface of a blood storage or handling device may receive a first coating with the preferred poty[bis(trifluoroethoxy)phosphazene] polymer of the present invention, followed by an intermediate coating of diazeniumdiolates, followed by a second coating of the poly[bis(trifluoroethoxy)phosphazene] polymer as described herein.
  • the first and second coatings may each be bioabsorbable or non- bioabsorbable.
  • Diazeniumdiolates are now available with a range of half-lives for spontaneous NO release.
  • the ability of the diazeniumdiolates to generate copious NO at rates that vary widely is largely independent of metabolic or medium effects.
  • nitric ox ⁇ de-eluting or other smooth muscle relaxant compounds including, but not limited to sodium nitroprusside, molsidomine, nitrate esters, the iS-nitrosothiol family, L- arginine, nitric oxide-nucleophiie complexes, glyceryl trinitrate, nitric oxide-primary amine complexes, and related compounds.
  • the nitric oxide-eluting or other smooth muscle relaxant compounds may be incorporated into non-bioabsorbable polyphosphazene polymers that generate molecular NO at their surfaces.
  • nitric oxide-eluting or other smooth muscle relaxant compounds may be applied to a substrate inner surface of a blood storage or handling device as an intermediate coating, which is then coated with the preferred poly[bis(trifluoroethoxy)phosphazene] polymer of the present invention
  • a substrate surface of a medical device may receive a first coating with the preferred poly[bis(trifluoroethoxy)phosphazene] polymer of the present invention, followed by an intermediate coating of nitric oxide-eluting or other smooth muscle relaxant compounds, followed by a second coating of the poly[bis(trifluoroethoxy)phosphazene] polymer as described herein.
  • the first and second coatings may each be bioabsorbable or non- bioabsorbable.
  • the medical devices disclosed herein may comprise the poly[bis(trifluoroethoxy)phosphazene] polymer represented by formula (I) in various forms: as a coating, as a film, or as a solid structural component.
  • the po!y[bis(trifluoroethoxy)phosphazene] polymer may be provided in varying degrees of porosity, or as a solid surface.
  • Such coatings may be achieved by spin coating, spray coating, meniscus coating, roller curtain and extrusion coating techniques, in addition to plasma deposition and etectrophoretic photoresistance methods.
  • the poly[bis(trifluoroethoxy)phosphazene] polymer may be provided as either a bioabsorbable or non-b ⁇ oabsorbable form as most appropriate in various embodiments of the present invention.
  • two or more coatings of the poly[bis(trifluoroethoxy)phosphazene] polymer may be applied to the surface of a medical device, and the two or more coatings of the poly[bis(trifluoroethoxy)phosphazene] polymer may be independently provided as bioabsorbable or non-bioabsorbable.
  • an adhesion promoter may be provided in a layer between the surface of the substrate and the polymeric coating.
  • the adhesion promoter is an organosilicon compound, preferably an amino-terminated silane or a compound based on an aminosilane, or an alkylphosphonic acid.
  • Aminopropyltrimethoxysilane is a preferred adhesion promoter according to the present invention.
  • the adhesion promoter particularly improves the adhesion of the coating to the surface of the implant material through coupling of the adhesion promoter to the surface of the implant material, through, for instance, ionic and/or covalent bonds, and through further coupling of the adhesion promoter to reactive components, particularly to the antithrombogenic polymer of the coating, through, for instance, ionic and/or covalent bonds.

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Abstract

L'invention concerne des dispositifs médicaux comprenant des produits de stockage et de manipulation de sang, qui contiennent un polyphosphazène spécifique. Ces dispositifs peuvent libérer de l'oxyde nitrique ou d'autres composés relaxant les muscles lisses in vivo, ou dans du sang stocké ou s'écoulant temporairement dans un tubage, pour obtenir une dilatation vasculaire, des effets indésirables réduits, une thrombose réduite, des risques réduits d'infarctus aigu du myocarde post-transfusion, et/ou pour accroître les capacités de stockage de sang.
PCT/US2007/083209 2007-10-31 2007-10-31 Dispositifs d'administration et de stockage de sang à revêtement de polyphosphazène spécifique, conçus pour une élution de vasodilatateur, et leurs procédés de fabrication et d'utilisation Ceased WO2009058146A1 (fr)

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US11965175B2 (en) 2016-05-25 2024-04-23 Terumo Bct, Inc. Cell expansion
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US12077739B2 (en) 2016-06-07 2024-09-03 Terumo Bct, Inc. Coating a bioreactor in a cell expansion system
US11634677B2 (en) 2016-06-07 2023-04-25 Terumo Bct, Inc. Coating a bioreactor in a cell expansion system
US11999929B2 (en) 2016-06-07 2024-06-04 Terumo Bct, Inc. Methods and systems for coating a cell growth surface
US11629332B2 (en) 2017-03-31 2023-04-18 Terumo Bct, Inc. Cell expansion
US11624046B2 (en) 2017-03-31 2023-04-11 Terumo Bct, Inc. Cell expansion
US11702634B2 (en) 2017-03-31 2023-07-18 Terumo Bct, Inc. Expanding cells in a bioreactor
US12234441B2 (en) 2017-03-31 2025-02-25 Terumo Bct, Inc. Cell expansion
US12359170B2 (en) 2017-03-31 2025-07-15 Terumo Bct, Inc. Expanding cells in a bioreactor
US12043823B2 (en) 2021-03-23 2024-07-23 Terumo Bct, Inc. Cell capture and expansion
BE1029476B1 (nl) * 2021-06-09 2023-01-16 Ignore The Box Steriliseerbare slang voor een bloedzakset of dergelijke en een afsluitmechanisme daarvoor, evenals een bloedzakset daarmee uitgerust
US12152699B2 (en) 2022-02-28 2024-11-26 Terumo Bct, Inc. Multiple-tube pinch valve assembly
US12209689B2 (en) 2022-02-28 2025-01-28 Terumo Kabushiki Kaisha Multiple-tube pinch valve assembly
USD1099116S1 (en) 2022-09-01 2025-10-21 Terumo Bct, Inc. Display screen or portion thereof with a graphical user interface for displaying cell culture process steps and measurements of an associated bioreactor device

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