WO2009012601A1 - Antigen-adjuvant compositions and methods - Google Patents
Antigen-adjuvant compositions and methods Download PDFInfo
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- WO2009012601A1 WO2009012601A1 PCT/CA2008/001386 CA2008001386W WO2009012601A1 WO 2009012601 A1 WO2009012601 A1 WO 2009012601A1 CA 2008001386 W CA2008001386 W CA 2008001386W WO 2009012601 A1 WO2009012601 A1 WO 2009012601A1
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- adjuvant
- antigen
- composition
- vitreous
- foam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/122—Foams; Dry foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/20—Surgical instruments, devices or methods, e.g. tourniquets for vaccinating or cleaning the skin previous to the vaccination
- A61B17/205—Vaccinating by means of needles or other puncturing devices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
Definitions
- Vaccine compositions generally include one or more antigens, but may also include one or more adjuvants, as well as various other components. Although vaccine compositions are frequently administered to individuals in liquid form, dried vaccine compositions are often preferred for storage and transportation purposes. Stability over time of the components of dried vaccine compositions may be enhanced relative to liquid compositions and the dried compositions may not require refrigeration. Dried compositions can then be reconstituted into a liquid formulation before administration to an individual. Methods for preparing dried vaccine compositions, however, can affect the immunogenicity of the compositions, possibly by altering the integrity of components that make up the compositions. For example, lyophilization or freeze drying of compositions containing aluminum salt adjuvants (e.g., aluminum phosphate adjuvant, aluminum hydroxide adjuvant, alum) may result in loss of immunogenic activity.
- aluminum salt adjuvants e.g., aluminum phosphate adjuvant, aluminum hydroxide adjuvant, alum
- the interactions between certain components within a vaccine composition can also affect immunogenicity of the composition.
- adsorption of antigens to aluminum salt adjuvants is believed to enhance immunogenicity of the antigens within a vaccine composition.
- a variety of factors may affect the ability of antigens to adsorb to the adjuvants in vaccine compositions, including for example, electronic charge of both antigen and adjuvant, pH, temperature, ionic strength, presence of excipients, and other factors.
- Methods for preparing vaccine compositions including methods for preparing dried compositions, will also generally affect the association between antigen and adjuvant.
- Vitreous compositions of antigens and adjuvants are disclosed.
- the vitreous compositions are in the form of a foam.
- the antigens are proteins or peptides.
- the adjuvants are aluminum salt adjuvants.
- the vitreous compositions contain polyols and/or synthetic polymers that can form a glass.
- Pharmaceutically acceptable formulations, as well as reconstituted liquid formulations of the vitreous compositions are also disclosed. Methods for preparing the vitreous compositions, as well as for administering and eliciting immune responses in mammals, are disclosed. Kits containing the vitreous compositions and microneedle arrays coated with the vitreous compositions are also disclosed.
- Figure 1 illustrates example results of a study examining the effects of foam drying on aluminum adjuvant stability in various preparations as described in more detail in Example 2 herein.
- the vertical axis is a measure of mean particle size in microns.
- Figure 2 illustrates example results of a study examining the effects of foam drying on aluminum adjuvant stability in various preparations as described in more detail in Example 3 herein.
- the vertical axis is a measure of mean particle size in microns.
- Figure 3 illustrates example results of a study examining the appearance of reconstituted foam dried samples containing aluminum phosphate adjuvant by transmission electron microscopy as described in more detail in Example 4 herein.
- the electron micrographs in panels (A) and (B) were directly magnified 150,000 times.
- the electron micrograph in panel (C) was directly magnified 100,000 times.
- Figure 4 illustrates example results of a study examining the appearance of reconstituted foam dried samples containing aluminum hydroxide adjuvant by transmission electron microscopy as described in more detail in Example 4 herein. The electron micrographs were directly magnified 100,000 times.
- Figure 5 illustrates example results of a study examining the effects of foam drying on aluminum adjuvant stability in preparations containing different concentrations of sucrose, as described in more detail in Example 5 herein.
- the vertical axis is a measure of percent of total volume.
- the horizontal axis is a measure of mean particle size in microns.
- Figure 6 illustrates example results of a study examining the effects of foam drying on adsorption of a protein antigen to an aluminum adjuvant, as described in more detail in Example 6 herein. Percent of protein antigen that was adsorbed to the adjuvant is shown on the y-axis. The experiment was done in duplicate (indicated as sample number 1 and 2 on the x- axis).
- Figure 7 illustrates example results of a study examining adsorption of a protein antigen to an aluminum adjuvant in a foam dried preparation over time, as described in more detail in Example 7 herein. Percent of protein antigen that was adsorbed to the adjuvant is shown on the y-axis. On the x-axis, the time in weeks at which the various samples were analyzed is shown.
- Figure 8 illustrates example results of a study examining adsorption of a protein antigen to an aluminum adjuvant in a foam dried preparation over time, as described in more detail in Example 8 herein. Percent of protein antigen that was adsorbed to the adjuvant is shown on the y-axis. On the x-axis, the time in weeks at which the various samples were analyzed is shown.
- Figure 9 illustrates example vials of foam dried formulations produced as described in Example 9 herein.
- Figure 10 illustrates example results of a study examining adsorption of a protein antigen to different adjuvants over time in dried foams where secondary drying was performed at 25°C, as described in more detail in Example 10 herein. Percent of protein adjuvant that was adsorbed to the adjuvant is shown on the y-axis. On the x-axis, the time in weeks at which the various samples were analyzed is shown.
- Figure 11 illustrates example results of a study examining adsorption of a protein antigen to different adjuvants over time in dried foams where secondary drying was performed at 37°C, as described in more detail in Example 10 herein. Percent of protein adjuvant that was adsorbed to the adjuvant is shown on the y-axis. On the x-axis, the time in weeks at which the various samples were analyzed is shown.
- this application describes solid vitreous compositions of antigens and adjuvants.
- the vitreous compositions are in the form of mechanically stable porous structures or foams.
- the antigens within the vitreous compositions are adsorbed to the adjuvants.
- Methods for making the vitreous compositions are disclosed.
- the vitreous composition is a foam
- a method for making the composition is disclosed and is called foam drying.
- pharmaceutically acceptable formulations of the vitreous compositions and methods for preparing these compositions Reconstituted liquid forms of a solid vitreous composition of an antigen and adjuvant are disclosed.
- kits containing the vitreous compositions and methods and devices for use in administering formulations of the vitreous compositions to mammals.
- Adjuvant refers to agents or substances that modulate the immunogenicity of an antigen.
- Modulate the immunogenicity includes enhancing the magnitude, duration and/or specificity of an immune response stimulated by an antigen.
- Amorphous solid refers to solids substantially lacking crystalline structure.
- Antigen refers to a substance capable of initiating and mediating an immune response. Antigens that stimulate or potentiate immune responses are said to be immunogenic and may be referred to as immunogens.
- Boiling refers to a phase transition that occurs when a liquid is vaporized.
- the "boiling point” is a property of a liquid at a given pressure and is defined as the temperature at which the vapor pressure of the liquid is equal to the external pressure to which the liquid is exposed. Boiling is generally visually observed as bubbling within the liquid.
- Foam refers to a type of amorphous solid that has a mechanically stable porous structure.
- a foam may also be referred to as a “foamed glass.”
- Foam drying refers to a process of forming a foam. Foam drying is a type of vitrification process.
- Glass refers to a type of substantially non-porous amorphous solid.
- Glass transition temperature refers to the temperature at which a vitreous solid is formed. Amorphous solids are in a glassy state below the glass transition temperature. The glass transition temperature may be abbreviated as “T g ".
- Polyol refers to polyalcohols, and more generally may refer to substances capable of forming glasses and/or foams.
- Vaccine refers to a pharmaceutically acceptable formulation of at least one antigen.
- Such pharmaceutical acceptable formulations of an antigen may also include adjuvants, excipients, diluents, etc. that enhance the activity, stability, etc. of a formulation or administration.
- Vacuum refers to a pressure less than 1 atm or 760 Torr.
- Viscos refers to the "thickness" of a liquid or its internal resistance to flow.
- a liquid that is referred to as viscous generally is a fluid that can be boiled under a vacuum, as is performed in the foam drying process as disclosed below. Viscous liquids may also be referred to as syrups.
- viscous liquids generally have a viscosity in the range of 10 6 -10 7 Pascal seconds.
- Vitreous composition refers to a type of amorphous solid that includes foams and glasses.
- Vitrification refers to a process for converting a material into a vitreous composition.
- Antigens are generally substances capable of stimulating immune responses (i.e., antigens are potentially immunogenic).
- the immune responses stimulated by antigens may be one or both of humoral or cellular, and generally are specific for the antigen.
- Antigens therefore, are substances that may be bound by antibody molecules or by T cell receptors.
- Many types of biological and other molecules can act as antigens.
- antigens may originate from molecules that include, but are not limited to, proteins, peptides, carbohydrates, polysaccharides, oligosaccharides, sugars, lipids, phospholipids, metabolites, hormones, nucleic acids, and other molecules, and fragments and/or combinations thereof.
- Antigens of any of these origins and types, as well as others not listed, may be used in the vitreous compositions and processes described herein.
- Antigens may originate from innate sources (e.g., self antigens, autoantigens, tumor- associated antigens) or from sources extrinsic to a particular mammal or other animal (e.g., from infectious agents).
- Antigens may possess multiple antigenic determinants such that exposure of a mammal to an antigen may produce a plurality of corresponding antibodies or cellular immune responses with differing specificities.
- Antigens may be purposefully introduced into a mammal for purposes of eliciting an immune response (e.g., immunization) by a variety of routes, including but not limited to, ingestion, inhalation, skin contact, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, contact with mucosal surfaces and by other routes.
- routes including but not limited to, ingestion, inhalation, skin contact, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, contact with mucosal surfaces and by other routes.
- Antigens may include or be part of components larger than single molecules, such as all or parts of cells, bacteria, viruses, and other microorganisms, and part or combinations of these.
- Bacteria and viruses particularly those responsible for diseases in mammals, are sources of antigens that may be useful in the vitreous compositions and processes described herein.
- Bacterial antigens include proteins, polysaccharides and other molecules derived from the outer surfaces of the cell, from the cell interior, from the flagella, or from other components.
- Other antigens may be those secreted by an infected cell or released upon cell death or disruption. Examples of these antigens may include diphtheria, tetanus, and botulism toxins.
- antigens which may be used in the vitreous compositions described herein may include, but are not limited to, antigens from rotavirus, the agent for foot and mouth disease, influenza, parainfluenza, herpesvirus species (herpes simplex virus, Epstein Barr virus, chickenpox virus, pseudorabies, cytomegalovirus), rabies virus, polio virus, Hepatitis A, B, C and E, distemper, Venezuelan equine encephalomyelitis, feline leukemia virus, reovirus, respiratory syncytial virus, Lassa fever virus, polyoma virus, canine parvovirus, papilloma virus, tick borne encephalitis, Rinderpest, rhinoviruses, enteroviruses, Mengo virus, paramyxoviruses (mumps, measles, respiratory syncytial virus), avian infectious bronchitis virus, HTLV 1, HIV-I and -2, influenza virus A
- cholera V. parahaemolyticus
- Shigella Pseudomonas, Brucella species, Klebsiella, Mycobacteria species (tuberculosis, avium, BCG, leprosy), Pneumococci, Staphylococci, Enterobacter species, tetanus, anthrax, Streptococcus pneumoniae, meningococcus A, B, C, Y, W, W- 135, Helicobacter pylori, Rochalimaea henselae, Pasteurella (P. haemolytica, P. multocida), Chlamydia (C. trachomatis, C. psittaci, C.
- malariae malariae
- schistosomes trypanosomes
- leishmania filarial nematodes
- trichomoniasis sarcosporidiasis
- Taenia T saginata, T. solium
- Toxoplasma gondi Trichinosis (Trichinella spiralis)
- Coccidiosis Eimeria species
- fungi including Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus, Coccidioidomycosis, and others.
- the antigens employed in the disclosed vitreous compositions and processes may be the naturally occurring form of the antigen as derived from its natural source.
- the naturally occurring antigens may also be converted to other forms, including less toxic forms, which may be fragments or may contain other deletions, additions or modifications. These converted forms of antigens generally will retain immunogenicity.
- Diphtheria and tetanus toxoids are examples of detoxified forms of natural antigens, in this case produced by chemical (e.g., formaldehyde) treatment.
- Other means for eliminating toxicity of antigens are well known and include enzymatic digestion/fragmentation of protein antigens, denaturation (commonly through heat or chemical treatment), conjugation, chemical modification, and others.
- compositions of the present disclosure may similarly include multiple antigens.
- antigens which are combined include diphtheria, tetanus, pertussis and other antigens.
- Antigens may also be associated with a carrier protein that mediates the immunogenicity of the antigens. Examples of such conjugated antigens are well known in the art and commercially available in pharmaceutical formulations as vaccines. All of these example antigens, combination antigens, carrier-associated antigens, and others, may be incorporated into the vitreous compositions and processes described herein.
- the concentration of the antigen in the vitreous composition may be of any concentration, but generally is sufficient to stimulate an immune system when administered to an individual or mammal.
- the concentration of one or more antigens is 10 ⁇ g per ml.
- the concentration of one or more antigens may be 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 ⁇ g/ml.
- the concentration of antigen may be 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/ml or even more.
- the concentration of the one or more antigens may also be in a range between any two of the values listed above.
- Adjuvants generally are substances that can enhance the immunogenicity of antigens. Adjuvants often are incorporated into vaccine compositions and function during and after the vaccine composition is administered to an individual or mammal. Adjuvants may play a role in both acquired and innate (e.g., toll-like receptors) immunity and may function in a variety of ways, not all of which are understood.
- adjuvants may include, but are not limited to, mineral salts, squalene mixtures, muramyl peptide, saponin derivatives, mycobacterium cell wall preparations, certain emulsions, monophosphoryl lipid A, mycolic acid derivatives, nonionic block copolymer surfactants, Quil A, cholera toxin B subunit, polyphosphazene and derivatives, immunostimulating complexes (ISCOMs), cytokine adjuvants, MF59 adjuvant, lipid adjuvants, mucosal adjuvants, certain bacterial exotoxins and other components, certain oligonucleotides, PLG, and others. These adjuvants may be used in the vitreous compositions and methods described herein.
- Aluminum salt adjuvants include aluminum hydroxide adjuvant (crystalline aluminum oxyhydroxide or AlOOH), aluminum phosphate adjuvant (amorphous aluminum hydroxyphosphate) and alum (potassium aluminum sulfate or A1K(SO 4 ) 2 ).
- the adjuvant employed in the composition is an aluminum salt adjuvant
- the compositions generally should not be exposed to extreme temperatures, i.e., below freezing (0°C) or extreme heat (e.g., 70°C), at least for long periods of time, as it is well known that exposure to extreme temperatures may affect both immunogenic activity of the aluminum adjuvant as well as the adsorbed antigen.
- antigens can adsorb to aluminum salt adjuvants. Electrostatic attraction, at least in part, may be responsible for adsorption of antigens to these adjuvants.
- the electrostatic interactions between antigen and adjuvant may be optimized by considering the isoelectric point (IEP) of antigens and surface charge (point of zero charge or PZC) of aluminum salt adjuvants.
- IEP isoelectric point
- PZC point of zero charge
- a protein antigen with an IEP ⁇ 7 will better adsorb to aluminum hydroxide adjuvant (PZC > 7) than to aluminum phosphate adjuvant (PZC ⁇ 7).
- PZC > 7 aluminum hydroxide adjuvant
- a protein antigen with an IEP > 7 will better adsorb to aluminum phosphate adjuvant than to aluminum hydroxide adjuvant.
- the foam drying procedures may partially overcome less than optimum electrostatic interactions between antigens and adjuvant to increase antigen adsorption to adjuvant. This is indicated by increased adsorption of antigen to aluminum salt adjuvants in foam dried preparations of antigen and adjuvant, as compared to adsorption of antigen to aluminum salt adjuvants in preparations that have not been foam dried.
- the foam drying method may provide for a composition of a protein antigen with an IEP ⁇ 7 that is adsorbed to aluminum phosphate adjuvant. In one example, the foam drying method may provide for a composition of a protein antigen with an IEP > 7 that is adsorbed to aluminum hydroxide adjuvant. Other compositions of antigen and adjuvant may also be produced. In one example, a composition of a protein antigen with an IEP ⁇ 7 that is adsorbed to aluminum hydroxide adjuvant is produced. In one example, a composition of a protein antigen with an IEP > 7 that is adsorbed to aluminum phosphate adjuvant is produced.
- the concentration of the adjuvant in the vitreous composition may be of any concentration, but generally is sufficient to enhance an antigen's ability to stimulate the immune system when administered to an individual or mammal.
- the concentration of one or more adjuvants is 0.1 mg/ml.
- the concentration of the one or more adjuvants is 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or even 10.0 mg/ml or even more.
- the concentration of the one or more adjuvants may also be in a range between any two of the values listed above.
- a composition that is to undergo a vitrification process generally will contain one or more substances capable of forming a vitreous composition, or facilitating formation of a vitreous composition, like a foamed glass.
- a liquid formulation containing these substances can be cooled to form a solid substantially free of crystalline structure, like a glass or foam.
- T g glass transition temperature
- these substances do not interfere with the activity of antigens or adjuvants within the vitreous compositions.
- These substances may also stabilize antigens and/or adjuvants and generally do not negatively affect the activity of biological components.
- These substances also may enhance or facilitate the ability of antigens and/or adjuvants to withstand the drying process and subsequent storage.
- a variety of substances capable of forming a glass or foam, or facilitating formation of a glass or foam can be used. Some of these substances include sugars, carbohydrates, polyols, polymers, proteins, peptides, amino acids (e.g., glycine, alanine, arginine, lysine, glutamine) and others. Combinations of these substances may be used. These substances may be referred to using a variety of names or labels. For example, some of these substances may be referred to as stabilizers, glass- or foam-forming agents, vitrifying enhancers, polyols, protectants, glass or foam matrix-forming materials, as well as other names. [0049] In one example, polyols can be used.
- polyols may include simple sugars (e.g., glucose, maltose, sucrose, xylulose, robose, mannose, fructose, raffinose, trehalose and others) or carbohydrate sugars (e.g., mannitol, sorbitol, erythritol, xylitol, maltitol, siomalt, lactitol and others).
- simple sugars e.g., glucose, maltose, sucrose, xylulose, robose, mannose, fructose, raffinose, trehalose and others
- carbohydrate sugars e.g., mannitol, sorbitol, erythritol, xylitol, maltitol, siomalt, lactitol and others.
- stabilizing sugars e.g., glucose, maltose, sucrose, x
- methylated monosaccharides may include some arabino, galacto, gluco, manno or xylo pyranosides.
- polyol may be used to generally refer to substances capable of forming, or facilitating forming, glasses and/or foams.
- Monosaccharides, disaccharides, trisaccharides, oligosaccharides and their corresponding sugar alcohols may be used to form or facilitate forming of glasses or foams.
- Sugar alcohol glycosides may be used.
- Polyhydroxy compounds, like carbohydrate derivatives and chemically modified carbohydrates may be used.
- Palatinit a mixture of ⁇ -D- glucopyranosyl-l -> 6-sorbitol (GPS) and ⁇ -D-glucopyranosyl-l -> 6-mannitol (GPM)
- GPS ⁇ -D-glucopyranosyl-l -> 6-mannitol
- sucrose, methyl ⁇ -D- glucoside, 2-HP- ⁇ -cyclodextrin and arginine, alone or in various combinations, may be used.
- Polysaccharides may also be used.
- polymers may also be used in formation, or facilitating or enhancing formation, of the vitreous compositions disclosed herein.
- Some examples of polymers that may be used include polyethylene glycol, hydroxyethyl starch, polyvinyl pyrrolidone, polyacrylamide, polyethyleneimine, and others.
- Sugar copolymers, like Ficoll and dextrans, may also be used.
- the concentration of the polyol, or other foam- or glass-forming or facilitating substance, or combination of substances is generally sufficient to achieve a viscous liquid composition, or to achieve a viscous liquid composition after a process step designed to increase the viscosity of the liquid (see discussion of this step below).
- the total concentration of polyols, synthetic polymers and other glass- or foam-forming substances is 5%.
- the total concentration of polyols, synthetic polymers and other glass- or foam- forming substances is at least 5%.
- the total concentration of these substances is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or even higher.
- the concentration of the one or more glass- or foam-forming substances may also be in a range between any two of the values listed above.
- a liquid containing the antigens, adjuvants and glass-/foam-forming or facilitating substances are combined in a liquid, which is then subjected to the foam drying process as described below.
- these components can be combined in the liquid in various ways.
- the antigens and adjuvants are first combined in a liquid and the polyols are subsequently added.
- the antigens and adjuvants may be present together in a liquid for a period of time (e.g., 24-48 h) before the polyols are added.
- the antigen and adjuvant may be incubated at various temperatures (e.g., 2-8°C) before addition of the polyols. This may facilitate association between the antigen and adjuvant.
- the antigens, adjuvants and polyols are added to a liquid concurrently. Other combinations of adding the components are possible.
- the liquids containing the antigens, adjuvants and polyols generally are aqueous liquids, although organics may be present in at least some concentration if the organics are compatible with the antigens, adjuvants and polyols that are used.
- the liquids may be buffered.
- the buffering system used is compatible with the antigens, adjuvants and polyols that are used.
- Substances other than antigens, adjuvants and polyols may be incorporated into the vitreous compositions. Generally, these other substances would be added to the liquid containing the antigen/adjuvant/polyol that is to be used in the foam drying process.
- additional substances may include, for example, substances that aid in solubilizing antigens, adjuvants or polyols that are components of the liquid that is to be foam dried, substances that enhance glass or foam formation or stabilize glasses or foams, substances that affect the T g , substances that enhance drying of the glass or foam, substances that stabilize (e.g., prevent degradation (Maillard reaction) or aggregation) antigens and/or adjuvants in the glass or foam, and substances that perform other functions.
- Salts may also be added to the liquid to be foam dried and may be incorporated into the vitreous compositions.
- Other substances like biologicals, biological modifiers, pharmaceutical agents, and others, may also be added.
- Vitreous solid forms of antigen/adjuvant/polyol compositions are prepared through vitrification.
- Vitrification is a process of converting a material into a glass-like amorphous solid which is substantially free from crystalline structure.
- Vitrification also refers to converting a material into a foam.
- Solidification of the vitreous solid occurs at the glass transition temperature (T g ), which is a property of the material, and occurs during cooling of the material. Glass transition temperature is usually applicable to wholly or partially amorphous phases such as glasses and plastics. At or below the glass transition temperature, the physical properties of amorphous materials are converted to a vitreous amorphous solid.
- the vitreous solid forms disclosed herein may be foams.
- Foams generally are stable porous structures with high surface areas. Foams can be of different thicknesses and generally are less dense than non-foamed forms of similar composition (e.g., true glasses).
- the foams as disclosed herein have also been termed foamed glasses, foamed glass matrices, dried foams and stabilized foams.
- Foam drying procedures and equipment to perform the processes and procedures have been disclosed (see e.g., U.S. Pat. Nos., 5,766,520, 6,509,146 and 6,964,771, the entire teachings of which are incorporated by reference).
- Foam drying processes are generally distinguished from other vitrification protocols by the formation of the foams.
- Foams can be prepared from a variety of liquids, dispersions, suspensions, emulsions, mixtures and solutions. Generally, at least in the example where the liquids contain antigens, the prepared liquids are compatible with biologicals.
- the foam drying process uses boiling of a liquid in a vacuum to cause evaporation of liquid from the sample and formation of the foam.
- the boiling is performed under a vacuum so that the sample is not subjected to the higher temperatures that would be needed to boil the liquid at atmospheric pressure (i.e., no vacuum present).
- the vacuum under which the liquid is boiled is a relatively high vacuum.
- the pressure is ⁇ 25 Torr (less than about 0.033 atm). In other examples, the pressure is ⁇ 10 Torr (less than about 0.013 atm), ⁇ 8 Torr (less than about 0.010 atm) or ⁇ 5 Torr (less than about 0.007 atm).
- the vacuum is maintained until a foam is formed, although the vacuum can be maintained for a time after a foam is formed. Continued application of the vacuum may result in decreasing the residual moisture content of the foam that has formed.
- the vacuum may be maintained for approximately 4 h, but the duration of the vacuum may be more or less than this. In other examples, the vacuum may be maintained for 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24 or even 48 h.
- the evaporation of liquid that occurs during the boiling process generally has a cooling effect on the sample and the sample temperature decreases during boiling.
- the evaporation of liquid also generally has the effect of increasing the glass transition temperature (Tg) of the sample and the sample T g increases during boiling.
- Tg glass transition temperature
- the sample temperature and the T g coincide and are the same.
- a vitreous solid is formed.
- the vitreous solid is a foam.
- the temperature of the samples may fluctuate, but generally is kept within a range such that desired properties (e.g., immunogenicity) of the biological materials within the samples are retained.
- temperatures during the boiling process may be below 100 0 C and may be above 0 0 C.
- the temperature of the sample remains below 70 0 C and above 0 0 C.
- Other temperature ranges are possible.
- at least parts of the sample may, at least briefly, go below 0 0 C. It may be that a slurry is formed.
- the equipment used to perform this boiling step, to obtain a foam generally has the ability to control both vacuum and temperature of the samples during the process. In some cases, conventional freeze-drying machines or modified freeze-drying machines may be used.
- a process step may be performed that is designed to increase the viscosity of the liquids, dispersions, suspensions, emulsions, mixtures or solutions that are to be subjected boiling step of the foam drying process. In some cases, this step may be optional.
- This "viscosity-increasing" step can be performed by a variety of methods. In one method, liquid samples can be subjected to a relatively low vacuum (e.g., a pressure in the range of about 0.9 to 0.1 atm). In one example, a pressure of about about 0.2 atm or 152 Torr may be used. Other pressures can be used.
- the pressure may be ⁇ 1 atm, ⁇ 0.9 atm, ⁇ 0.8 atm, ⁇ 0.7 atm, ⁇ 0.6 atm, ⁇ 0.5 atm, ⁇ 0.4 atm, ⁇ 0.3 atm, ⁇ 0.2 atm, or even ⁇ 0.1 atm.
- the relatively low vacuum can be applied at room temperature or at other temperatures.
- the liquid may be vaporized by boiling under a vacuum. This step may be separate from or continuous with the boiling step of the foam drying process already described. This latter method can be performed under similar conditions as is the previously described boiling step, although the vacuum and the duration in which the vacuum is applied may be different.
- this higher viscosity liquid may be called a syrup.
- the higher viscosity liquid can be subjected to the boiling step to obtain a foam, as described above.
- the foam may be subjected to a vacuum (vacuum drying).
- vacuum drying the pressure may be ⁇ 5 Torr (less than about 0.007 atm).
- the pressure may be ⁇ 1 Torr (less than about 0.0013 atm).
- Other pressures may be used in the vacuum drying step.
- the foam may be stored in the presence of a desicant, such as DRIERITETM .
- the foam may be vacuum dried in the presence of a desicant.
- This "secondary drying" step may be performed at various temperatures and for various durations.
- the secondary drying may be performed at 25, 37, 40, 55°C, or at other temperatures.
- the secondary drying may be carried out over a period of hours, days, weeks or months.
- the secondary drying procedure will proceed for extended periods of time, depending on sample size, initial water concentration, etc.
- the procedure is carried out for a period in excess of 12 h and generally more than 24 or 48 h.
- the concentration of water in the sample may be determined by various sensor systems so that the secondary drying step can be stopped with the desired residual moisture content of the sample is reached.
- the residual moisture content of the samples is less than the residual moisture content of the sample before undergoing the secondary drying step.
- the samples that have completed the secondary drying process may have a residual moisture content of less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or even lower.
- Moisture content may be measured using different methods.
- the Karl Fisher Technique is used to measure the residual moisture content of the vitreous solid. Decreasing the moisture content of the foam, as is accomplished by this step, is facilitated by an increased surface area of the foam, as compared to vitreous compositions that are not foams.
- T g glass transition temperature
- the vitreous state is formed during the boiling step as the sample cools below the T g .
- a subsequent secondary drying step generally causes an additional reduction in moisture content and an increase in T g of the vitreous sample. Heating or storing a vitreous sample at or above its T g can cause changes in the vitreous sample that may not be advantageous to long-term stability of the components of the sample. Therefore, the vitreous samples generally are stored below their T g .
- the sample By reducing moisture content, and thereby raising the Tg, the sample may be stored at higher temperatures (and possibly decrease the need for a cold chain or temperature-controlled chain) without affecting stability of the sample or its components.
- samples may be cooled to a temperature below the T g at the conclusion of or after the secondary drying step, in order that the sample remains in a stable form during storage, until the sample is reconstituted as a liquid and administered to an individual.
- vitreous solid forms of the antigen/adjuvant/polyol compositions are prepared using a foam drying process as set forth below:
- a feature of the vitreous compositions is that both antigens and adjuvants of the compositions retain their integrity (i.e., they do not significantly degrade or aggregate).
- antigens in a vitreous composition are found to lack significant degradation.
- the integrity of the antigens is substantially maintained even when the vitreous compositions containing the antigens are stored over a period of time.
- protein antigens in a foam dried preparation lack substantial degradation and retain purity after storage at 25, 37 or 55 0 C for 52 weeks.
- the integrity of adjuvants is also maintained in the vitreous compositions.
- aluminum salt adjuvants that have been foam dried do not aggregate or degrade as measured by light scattering and as observed by transmission electron microscopy.
- a feature of the vitreous compositions is adsorption of the antigens to the adjuvants. Adsorption of antigens to adjuvants may also be referred to herein as binding of antigens to adjuvants, or association between antigen and adjuvant.
- a feature of the glasses and foamed preparations is that, generally, more antigen is adsorbed to adjuvant in those preparations as compared to liquid preparations of antigen and adjuvant that have not undergone the vitrification process. In one example, adsorption of antigen to adjuvant in the foam dried preparations is measured after the foam dried preparations are reconstituted into a liquid form.
- the adjuvants in these reconstituted preparations can be sedimented by centrifugation and separated from the liquid.
- the amount of antigen associated with or adsorbed to the adjuvant can then be determined.
- at least 10% of the antigen in a vitreous composition is adsorbed to the adjuvant.
- at least 20% of the antigen in a vitreous composition is adsorbed to the adjuvant.
- at least 30% of the antigen in a vitreous composition is adsorbed to adjuvant.
- at least 40%, 50%, 60%, 70%, 80%, 90% or even 100% of the antigens in a vitreous composition is adsorbed to the adjuvants in the composition.
- antigen is shown to be adsorbed to adjuvant after the vitreous compositions are stored at 25, 37 or 55°C for 52 weeks. Other storage temperatures may be used.
- the antigens in the solid vitreous compositions, and in the reconstituted liquid formulations of the vitreous compositions retain their immunogenic activity or their ability to stimulate an immune response in an individual or mammal to which the composition is administered.
- the adjuvants in the solid vitreous compositions, and in the reconstituted liquid forms of the vitreous compositions retain their ability to enhance the immunogenicity of the antigens of the compositions.
- the vitreous solid form of the antigen/adjuvant/polyol composition may be useful in the preparation of a vaccine.
- the vaccine is a pharmaceutically acceptable formulation of the antigen/adjuvant/polyol vitreous composition.
- the vaccine compositions may include one or more excipients that may include stabilizers, emulsifiers, preservatives, carriers as well as substances that affect pH and/or isotonicity. Other substances, including other therapeutic agents, may be included. These substances may be part of the vitreous composition or may be added to a reconstituted liquid formulation of the vitreous composition. These substances may perform a variety of functions, including enhancing stability, improving pharmaceutical acceptability, delivery and others.
- compositions may also include diluents and other excipients.
- diluents may include binder, disintegrants, or dispersants such as starch, cellulose derivatives, phenol, polyethylene glycol, propylene glycol or glycerin.
- Additional excipients may include polysorbate (Tween) 80 and others.
- the vitreous solid form of the antigen/adjuvant/polyol composition may be presented in a kit form comprising the vitreous solid form of the antigen/adjuvant/polyol composition and a reconstitution solution comprising one or more pharmaceutically acceptable diluents to facilitate reconstitution of the vitreous solid for administration to a mammal using conventional or other devices.
- a kit would optionally include the device for administration of the liquid form of the composition (e.g. hypodermic syringe, microneedle array) and/or instructions for use.
- the present disclosure also provides methods of eliciting an immune response in a mammal by administering the vitreous vaccine compositions, or formulations thereof, to individuals or other mammals. This may be achieved by the administration of a pharmaceutically acceptable formulation of the compositions to the mammal to effect exposure of the antigen/adjuvant to the immune system of the mammal.
- the administrations may occur once or may occur multiple times. In one example, the one or more administrations may occur as part of a so-called "prime-boost" protocol.
- Other administration systems may include time- release, delayed release or sustained release delivery systems.
- Acceptable routes of administration include intradermal administration (by syringe or microneedle array systems), oral administration, rectal administration, topical administration, nasal administration, mucosal administration, intramuscular, intravenous, subcutaneous, or other parenteral routes of administration.
- Exposure of the mammal to the compositions disclosed herein may result in establishment of a temporary or permanent immune response in the mammal.
- the immune response may protect the mammal from subsequent exposure to the antigen, often by subsequent exposure to an infectious agent from which the antigen was derived. Therapeutic effects may also be possible.
- compositions and vaccines disclosed herein may also be incorporated into various delivery systems.
- the compositions may be applied to a "microneedle array” or "microneedle patch” delivery system for administration.
- These microneedle arrays or patches generally comprise a plurality of needle-like projections attached to a backing material and coated with a dried form of a vaccine.
- the needle- like projections When applied to the skin of a mammal, the needle- like projections pierce the skin and achieve delivery of the vaccine, effecting immunization of the subject mammal.
- a solution comprising the antigen/adjuvant/polyol composition is applied to the microneedle array prior to the foam drying process and the coated microarray is then exposed to the foam drying process.
- the viscous solution prepared in the initial step of the foam drying process i.e., before the boiling process step
- the remainder of the foam drying procedure is applied to the viscous solution coated microneedle array.
- a microneedle array coated with a vitreous composition comprising at least one antigen and at least one adjuvant results.
- Such arrays may be used to administer antigens, as well as antigens and adjuvants, to mammals to achieve an immune response to the antigen and vaccination of the mammal.
- a mixture was prepared containing 3 mg of alum or aluminum phosphate adjuvant per ml, 200 ⁇ g of a protein antigen from Streptococcus pneumoniae termed PhtD (Adamou et al., Infect. Immun. 69:949-958, 2001) per ml, and 40% sucrose in sodium phosphate buffer (pH 7.2).
- PhtD protein antigen from Streptococcus pneumoniae
- the PhtD protein used in these studies had a predicted isoelectric point of 5.1.
- Control samples were prepared in accordance with the foregoing containing the PhtD protein and sucrose but devoid of aluminum adjuvant.
- This mixture was stored at 2-8 0 C prior to drying to minimize the potential for protein degradation and to facilitate the association of antigen and adjuvant (e.g., 24-48 h).
- a phosphate buffered solution of the aluminum phosphate and PhtD protein were incubated alone, and sucrose was added later, before the drying process.
- the samples were then boiled for 4 h under a high vacuum (P ⁇ 0.01 atm). During this latter step, a stable dry foam was formed in the individual containers.
- the samples were then stored for 8 days over DRIERITETM (W.A. Hammond Drierite Co, Ltd.
- FIG. 1 of the attached drawings the particle sizes in reconstituted foam dried samples containing PhtD protein and sucrose (B) or containing PhtD protein, Alum and sucrose (C) were compared with liquid samples that had not been subjected to foam drying.
- the liquid samples that had not been foam dried included Alum alone (A), PhtD protein, Alum and sucrose (D), and PhtD protein and Alum (E).
- the mean particle size shown for the non- foam dried Alum (A) was indicative of the particle size for Alum that is neither degraded nor aggregated.
- the mean particle sizes for non-foam dried samples containing PhtD protein, Alum and sucrose (D), and PhtD protein and Alum (E) were similar to those for the non-foam dried Alum alone (A).
- the mean particle size for the reconstituted foam dried sample containing PhtD protein, Alum and sucrose (C) were also similar to those of non-foam dried samples (A), (D) and (E). These data indicated that foam drying did not result in significant degradation or aggregation of aluminum adjuvants.
- the mean particle size of the reconstituted foam dried sample containing PhtD protein and sucrose (B) did appear smaller than the other samples tested.
- Example 4 Appearance of reconstituted foam dried adjuvant preparations by transmission electron microscopy TTEM
- foam dried aluminum phosphate adjuvant (3 mg/ml), PhtD protein (200 ⁇ g), and sucrose at a concentration of 40%, 30% or 5% were foam dried in substantial accordance with the disclosure in Example 1.
- the samples were then reconstituted and analyzed using a particle analyzer (Malvern Mastersizer 2000), calibrated with respect to standards of known sizes, to determine the mean size of the particles contained within the samples.
- the mean particle size of the reconstituted sample that had been foam dried in the presence of 5 % sucrose (D) was larger than that of the other samples. This may indicate that, at lower concentrations of the polyols (in this example, sucrose), that some aggregation of the aluminum adjuvant (in this example, aluminum phosphate adjuvant) may occur.
- PhtD protein and aluminum phosphate adjuvant, in 40% sucrose were foam dried in substantial accordance with the disclosure in Example 1. The dried samples were then reconstituted in solution. As a control, an identical solution of PhtD protein, aluminum adjuvant and 40% sucrose, that was not foam dried, was incubated at 2-8°C with rotation for 3.5 h. Both the foam dried and non-foam dried samples were then centrifuged to pellet the aluminum adjuvant contained in the sample, along with any protein adjuvant that was bound or adsorbed to the adjuvant. The supernatant from the centrifugation was analyzed for protein content using the Micro BCA Protein Assay Kit (Product No.
- PhtD protein and aluminum adjuvant were foam dried in substantial accordance with the disclosure in Example 1.
- the foam dried samples were stored at 25 0 C for a period of from 0 to 52 weeks and were then reconstituted.
- non-foam dried liquid samples PhtD protein, aluminum phosphate adjuvant, 40% sucrose
- PBS phosphate-buffered saline
- both the foam dried and non-foam dried samples were centrifuged to pellet the aluminum adjuvant contained in the sample, along with any protein adjuvant that was bound to the adjuvant.
- the supernatant from the centrifugation was analyzed by reverse phase high performance liquid chromatography (RP-HPLC) to determine, through comparison to standards, the amount of protein present in the supernatant.
- RP-HPLC reverse phase high performance liquid chromatography
- the amount of protein in the supernatant was used to calculate the amount of protein adsorbed to the adjuvant.
- the amount of protein antigen adsorbed to the aluminum adjuvant was found to be approximately 70% at both 8 and 26 weeks in the foam dried samples, while the amount of protein antigen adsorbed to aluminum adjuvant in the non-foam dried, liquid samples remained below 20% at both time points.
- the amount of protein antigen adsorbed to aluminum adjuvant was found to have decreased at 52 weeks in the foam dried sample, but was still higher than the non-foam dried, liquid control at this time point.
- Example 8 Effect of storage temperature on the association between antigen and aluminum adjuvant in foam dried preparations over time
- the supernatant from the centrifugation was analyzed by RP-HPLC, to determine the amount of protein present in the supernatant, and the amount of protein adsorbed to the adjuvant, as described in Example 7. At each time point, the amount of protein adsorbed to adjuvant in foam dried samples was compared to the amount of protein adsorbed to adjuvant in non-foam dried, liquid samples as a control.
- Example 9 Effects of different stabilizing agents, secondary drying temperatures, and different storage temperatures on protein antigen in foam dried preparations
- the foam dried samples were then stored at either 23-27°C (indicated as 25°C), 35- 39°C (indicated as 37°C), or 53-57°C (indicated as 55°C) over a period of 12 months. During this time period, the appearance of the samples stored at 25 and 37°C did not appear to change substantially, except for some changes in coloration. However, for the samples stored at 55 0 C, the foams generally appeared "melted" after 12 months. The F6 sample, however, did still appear as a foam after storage at 55°C for 12 months.
- the foam dried samples were reconstituted as aqueous solutions at various times and then analyzed by RP-HPLC. Percent purity of the protein antigen was calculated by determining the amount of protein present in the main protein peak obtained from the RP-HPLC column and dividing this value by the amount of protein present in all protein peaks obtained from the column. Percent purity is an indicator of stability of the protein over time.
Abstract
Description
Claims
Priority Applications (9)
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CN200880108192A CN101801343A (en) | 2007-07-26 | 2008-07-23 | antigen-adjuvant compositions and methods |
JP2010517245A JP2010534622A (en) | 2007-07-26 | 2008-07-23 | Antigen-adjuvant compositions and methods |
BRPI0814594-6A2A BRPI0814594A2 (en) | 2007-07-26 | 2008-07-23 | ADJUVANT ANTIGEN COMPOSITIONS AND METHODS |
CA2694083A CA2694083A1 (en) | 2007-07-26 | 2008-07-23 | Antigen-adjuvant compositions and methods |
EP08783297A EP2182922A4 (en) | 2007-07-26 | 2008-07-23 | Antigen-adjuvant compositions and methods |
MX2010001054A MX2010001054A (en) | 2007-07-26 | 2008-07-23 | Antigen-adjuvant compositions and methods. |
AU2008280755A AU2008280755B9 (en) | 2007-07-26 | 2008-07-23 | Antigen-adjuvant compositions and methods |
IL203428A IL203428A (en) | 2007-07-26 | 2010-01-21 | Method for preparing a vitreous composition comprising an antigen |
ZA2010/01300A ZA201001300B (en) | 2007-07-26 | 2010-02-23 | Antigen-asjuvant compositions and methods |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070084897A1 (en) | 2003-05-20 | 2007-04-19 | Shelton Frederick E Iv | Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism |
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WO2010090940A1 (en) | 2009-02-06 | 2010-08-12 | Ethicon Endo-Surgery, Inc. | Driven surgical stapler improvements |
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US9517063B2 (en) | 2012-03-28 | 2016-12-13 | Ethicon Endo-Surgery, Llc | Movable member for use with a tissue thickness compensator |
US9320523B2 (en) | 2012-03-28 | 2016-04-26 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator comprising tissue ingrowth features |
US11849952B2 (en) | 2010-09-30 | 2023-12-26 | Cilag Gmbh International | Staple cartridge comprising staples positioned within a compressible portion thereof |
US10945731B2 (en) | 2010-09-30 | 2021-03-16 | Ethicon Llc | Tissue thickness compensator comprising controlled release and expansion |
US9211120B2 (en) | 2011-04-29 | 2015-12-15 | Ethicon Endo-Surgery, Inc. | Tissue thickness compensator comprising a plurality of medicaments |
US8695866B2 (en) | 2010-10-01 | 2014-04-15 | Ethicon Endo-Surgery, Inc. | Surgical instrument having a power control circuit |
CA2834649C (en) | 2011-04-29 | 2021-02-16 | Ethicon Endo-Surgery, Inc. | Staple cartridge comprising staples positioned within a compressible portion thereof |
US11207064B2 (en) | 2011-05-27 | 2021-12-28 | Cilag Gmbh International | Automated end effector component reloading system for use with a robotic system |
US9072535B2 (en) | 2011-05-27 | 2015-07-07 | Ethicon Endo-Surgery, Inc. | Surgical stapling instruments with rotatable staple deployment arrangements |
US9044230B2 (en) | 2012-02-13 | 2015-06-02 | Ethicon Endo-Surgery, Inc. | Surgical cutting and fastening instrument with apparatus for determining cartridge and firing motion status |
JP6224070B2 (en) | 2012-03-28 | 2017-11-01 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | Retainer assembly including tissue thickness compensator |
CN104321024B (en) | 2012-03-28 | 2017-05-24 | 伊西康内外科公司 | Tissue thickness compensator comprising a plurality of layers |
JP6105041B2 (en) | 2012-03-28 | 2017-03-29 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | Tissue thickness compensator containing capsules defining a low pressure environment |
MX370579B (en) | 2012-05-01 | 2019-12-17 | Univ Pittsburgh Commonwealth Sys Higher Education | Tip-loaded microneedle arrays for transdermal insertion. |
US9101358B2 (en) | 2012-06-15 | 2015-08-11 | Ethicon Endo-Surgery, Inc. | Articulatable surgical instrument comprising a firing drive |
US9282974B2 (en) | 2012-06-28 | 2016-03-15 | Ethicon Endo-Surgery, Llc | Empty clip cartridge lockout |
RU2636861C2 (en) | 2012-06-28 | 2017-11-28 | Этикон Эндо-Серджери, Инк. | Blocking of empty cassette with clips |
BR112014032776B1 (en) | 2012-06-28 | 2021-09-08 | Ethicon Endo-Surgery, Inc | SURGICAL INSTRUMENT SYSTEM AND SURGICAL KIT FOR USE WITH A SURGICAL INSTRUMENT SYSTEM |
US9289256B2 (en) | 2012-06-28 | 2016-03-22 | Ethicon Endo-Surgery, Llc | Surgical end effectors having angled tissue-contacting surfaces |
US11202631B2 (en) | 2012-06-28 | 2021-12-21 | Cilag Gmbh International | Stapling assembly comprising a firing lockout |
US20140005718A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Multi-functional powered surgical device with external dissection features |
US20140005678A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Rotary drive arrangements for surgical instruments |
US20140001231A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Firing system lockout arrangements for surgical instruments |
RU2669463C2 (en) | 2013-03-01 | 2018-10-11 | Этикон Эндо-Серджери, Инк. | Surgical instrument with soft stop |
JP6382235B2 (en) | 2013-03-01 | 2018-08-29 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | Articulatable surgical instrument with a conductive path for signal communication |
US9351726B2 (en) | 2013-03-14 | 2016-05-31 | Ethicon Endo-Surgery, Llc | Articulation control system for articulatable surgical instruments |
US9629629B2 (en) | 2013-03-14 | 2017-04-25 | Ethicon Endo-Surgey, LLC | Control systems for surgical instruments |
EP2968507A2 (en) | 2013-03-15 | 2016-01-20 | Sanofi Pasteur, Inc. | Toxoid, compositions and related methods |
CN105308066A (en) | 2013-03-15 | 2016-02-03 | 圣诺菲·帕斯图尔公司 | Toxoid, compositions and related methods |
BR112015026109B1 (en) | 2013-04-16 | 2022-02-22 | Ethicon Endo-Surgery, Inc | surgical instrument |
US9801626B2 (en) | 2013-04-16 | 2017-10-31 | Ethicon Llc | Modular motor driven surgical instruments with alignment features for aligning rotary drive shafts with surgical end effector shafts |
MX369362B (en) | 2013-08-23 | 2019-11-06 | Ethicon Endo Surgery Llc | Firing member retraction devices for powered surgical instruments. |
US9775609B2 (en) | 2013-08-23 | 2017-10-03 | Ethicon Llc | Tamper proof circuit for surgical instrument battery pack |
US9962161B2 (en) | 2014-02-12 | 2018-05-08 | Ethicon Llc | Deliverable surgical instrument |
JP6462004B2 (en) | 2014-02-24 | 2019-01-30 | エシコン エルエルシー | Fastening system with launcher lockout |
BR112016021943B1 (en) | 2014-03-26 | 2022-06-14 | Ethicon Endo-Surgery, Llc | SURGICAL INSTRUMENT FOR USE BY AN OPERATOR IN A SURGICAL PROCEDURE |
US20150272557A1 (en) | 2014-03-26 | 2015-10-01 | Ethicon Endo-Surgery, Inc. | Modular surgical instrument system |
US20150272571A1 (en) | 2014-03-26 | 2015-10-01 | Ethicon Endo-Surgery, Inc. | Surgical instrument utilizing sensor adaptation |
US9826977B2 (en) | 2014-03-26 | 2017-11-28 | Ethicon Llc | Sterilization verification circuit |
JP6636452B2 (en) | 2014-04-16 | 2020-01-29 | エシコン エルエルシーEthicon LLC | Fastener cartridge including extension having different configurations |
BR112016023825B1 (en) | 2014-04-16 | 2022-08-02 | Ethicon Endo-Surgery, Llc | STAPLE CARTRIDGE FOR USE WITH A SURGICAL STAPLER AND STAPLE CARTRIDGE FOR USE WITH A SURGICAL INSTRUMENT |
US20150297222A1 (en) | 2014-04-16 | 2015-10-22 | Ethicon Endo-Surgery, Inc. | Fastener cartridges including extensions having different configurations |
CN106456159B (en) | 2014-04-16 | 2019-03-08 | 伊西康内外科有限责任公司 | Fastener cartridge assembly and nail retainer lid arragement construction |
US10010324B2 (en) | 2014-04-16 | 2018-07-03 | Ethicon Llc | Fastener cartridge compromising fastener cavities including fastener control features |
US10426476B2 (en) | 2014-09-26 | 2019-10-01 | Ethicon Llc | Circular fastener cartridges for applying radially expandable fastener lines |
US20160058992A1 (en) * | 2014-08-29 | 2016-03-03 | Corium International, Inc. | Microstructure array for delivery of active agents |
US11311294B2 (en) | 2014-09-05 | 2022-04-26 | Cilag Gmbh International | Powered medical device including measurement of closure state of jaws |
BR112017004361B1 (en) | 2014-09-05 | 2023-04-11 | Ethicon Llc | ELECTRONIC SYSTEM FOR A SURGICAL INSTRUMENT |
US20160066913A1 (en) | 2014-09-05 | 2016-03-10 | Ethicon Endo-Surgery, Inc. | Local display of tissue parameter stabilization |
US10105142B2 (en) | 2014-09-18 | 2018-10-23 | Ethicon Llc | Surgical stapler with plurality of cutting elements |
BR112017005981B1 (en) | 2014-09-26 | 2022-09-06 | Ethicon, Llc | ANCHOR MATERIAL FOR USE WITH A SURGICAL STAPLE CARTRIDGE AND SURGICAL STAPLE CARTRIDGE FOR USE WITH A SURGICAL INSTRUMENT |
US11523821B2 (en) | 2014-09-26 | 2022-12-13 | Cilag Gmbh International | Method for creating a flexible staple line |
US10076325B2 (en) | 2014-10-13 | 2018-09-18 | Ethicon Llc | Surgical stapling apparatus comprising a tissue stop |
US9924944B2 (en) | 2014-10-16 | 2018-03-27 | Ethicon Llc | Staple cartridge comprising an adjunct material |
US10517594B2 (en) | 2014-10-29 | 2019-12-31 | Ethicon Llc | Cartridge assemblies for surgical staplers |
US11141153B2 (en) | 2014-10-29 | 2021-10-12 | Cilag Gmbh International | Staple cartridges comprising driver arrangements |
US9844376B2 (en) | 2014-11-06 | 2017-12-19 | Ethicon Llc | Staple cartridge comprising a releasable adjunct material |
US10736636B2 (en) | 2014-12-10 | 2020-08-11 | Ethicon Llc | Articulatable surgical instrument system |
BR112017012996B1 (en) | 2014-12-18 | 2022-11-08 | Ethicon Llc | SURGICAL INSTRUMENT WITH AN ANvil WHICH IS SELECTIVELY MOVABLE ABOUT AN IMMOVABLE GEOMETRIC AXIS DIFFERENT FROM A STAPLE CARTRIDGE |
US9943309B2 (en) | 2014-12-18 | 2018-04-17 | Ethicon Llc | Surgical instruments with articulatable end effectors and movable firing beam support arrangements |
US9987000B2 (en) | 2014-12-18 | 2018-06-05 | Ethicon Llc | Surgical instrument assembly comprising a flexible articulation system |
US9844375B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Drive arrangements for articulatable surgical instruments |
US10085748B2 (en) | 2014-12-18 | 2018-10-02 | Ethicon Llc | Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors |
US9844374B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member |
US10188385B2 (en) | 2014-12-18 | 2019-01-29 | Ethicon Llc | Surgical instrument system comprising lockable systems |
US10180463B2 (en) | 2015-02-27 | 2019-01-15 | Ethicon Llc | Surgical apparatus configured to assess whether a performance parameter of the surgical apparatus is within an acceptable performance band |
US11154301B2 (en) | 2015-02-27 | 2021-10-26 | Cilag Gmbh International | Modular stapling assembly |
US10045779B2 (en) | 2015-02-27 | 2018-08-14 | Ethicon Llc | Surgical instrument system comprising an inspection station |
US9808246B2 (en) | 2015-03-06 | 2017-11-07 | Ethicon Endo-Surgery, Llc | Method of operating a powered surgical instrument |
US10617412B2 (en) | 2015-03-06 | 2020-04-14 | Ethicon Llc | System for detecting the mis-insertion of a staple cartridge into a surgical stapler |
US9993248B2 (en) | 2015-03-06 | 2018-06-12 | Ethicon Endo-Surgery, Llc | Smart sensors with local signal processing |
US10052044B2 (en) | 2015-03-06 | 2018-08-21 | Ethicon Llc | Time dependent evaluation of sensor data to determine stability, creep, and viscoelastic elements of measures |
JP2020121162A (en) | 2015-03-06 | 2020-08-13 | エシコン エルエルシーEthicon LLC | Time dependent evaluation of sensor data to determine stability element, creep element and viscoelastic element of measurement |
US9924961B2 (en) | 2015-03-06 | 2018-03-27 | Ethicon Endo-Surgery, Llc | Interactive feedback system for powered surgical instruments |
US9901342B2 (en) | 2015-03-06 | 2018-02-27 | Ethicon Endo-Surgery, Llc | Signal and power communication system positioned on a rotatable shaft |
US10441279B2 (en) | 2015-03-06 | 2019-10-15 | Ethicon Llc | Multiple level thresholds to modify operation of powered surgical instruments |
US10245033B2 (en) | 2015-03-06 | 2019-04-02 | Ethicon Llc | Surgical instrument comprising a lockable battery housing |
US10687806B2 (en) | 2015-03-06 | 2020-06-23 | Ethicon Llc | Adaptive tissue compression techniques to adjust closure rates for multiple tissue types |
US10441768B2 (en) | 2015-03-18 | 2019-10-15 | University of Pittsburgh—of the Commonwealth System of Higher Education | Bioactive components conjugated to substrates of microneedle arrays |
US10433844B2 (en) | 2015-03-31 | 2019-10-08 | Ethicon Llc | Surgical instrument with selectively disengageable threaded drive systems |
CA2986025A1 (en) | 2015-05-15 | 2016-11-24 | Sanofi Pasteur Inc. | Methods for immunization against clostridium difficile |
US11058425B2 (en) * | 2015-08-17 | 2021-07-13 | Ethicon Llc | Implantable layers for a surgical instrument |
US10327769B2 (en) | 2015-09-23 | 2019-06-25 | Ethicon Llc | Surgical stapler having motor control based on a drive system component |
US10238386B2 (en) | 2015-09-23 | 2019-03-26 | Ethicon Llc | Surgical stapler having motor control based on an electrical parameter related to a motor current |
US10105139B2 (en) | 2015-09-23 | 2018-10-23 | Ethicon Llc | Surgical stapler having downstream current-based motor control |
US10363036B2 (en) | 2015-09-23 | 2019-07-30 | Ethicon Llc | Surgical stapler having force-based motor control |
US10299878B2 (en) | 2015-09-25 | 2019-05-28 | Ethicon Llc | Implantable adjunct systems for determining adjunct skew |
US10433846B2 (en) | 2015-09-30 | 2019-10-08 | Ethicon Llc | Compressible adjunct with crossing spacer fibers |
US10980539B2 (en) | 2015-09-30 | 2021-04-20 | Ethicon Llc | Implantable adjunct comprising bonded layers |
US10524788B2 (en) | 2015-09-30 | 2020-01-07 | Ethicon Llc | Compressible adjunct with attachment regions |
US11890015B2 (en) | 2015-09-30 | 2024-02-06 | Cilag Gmbh International | Compressible adjunct with crossing spacer fibers |
US11684763B2 (en) | 2015-10-16 | 2023-06-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Multi-component bio-active drug delivery and controlled release to the skin by microneedle array devices |
US10265068B2 (en) | 2015-12-30 | 2019-04-23 | Ethicon Llc | Surgical instruments with separable motors and motor control circuits |
US10368865B2 (en) | 2015-12-30 | 2019-08-06 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10292704B2 (en) | 2015-12-30 | 2019-05-21 | Ethicon Llc | Mechanisms for compensating for battery pack failure in powered surgical instruments |
WO2017120322A1 (en) | 2016-01-05 | 2017-07-13 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Skin microenvironment targeted delivery for promoting immune and other responses |
US10433837B2 (en) | 2016-02-09 | 2019-10-08 | Ethicon Llc | Surgical instruments with multiple link articulation arrangements |
JP6911054B2 (en) | 2016-02-09 | 2021-07-28 | エシコン エルエルシーEthicon LLC | Surgical instruments with asymmetric joint composition |
US11213293B2 (en) | 2016-02-09 | 2022-01-04 | Cilag Gmbh International | Articulatable surgical instruments with single articulation link arrangements |
US10448948B2 (en) | 2016-02-12 | 2019-10-22 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US11224426B2 (en) | 2016-02-12 | 2022-01-18 | Cilag Gmbh International | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10258331B2 (en) | 2016-02-12 | 2019-04-16 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10617413B2 (en) | 2016-04-01 | 2020-04-14 | Ethicon Llc | Closure system arrangements for surgical cutting and stapling devices with separate and distinct firing shafts |
US11064997B2 (en) | 2016-04-01 | 2021-07-20 | Cilag Gmbh International | Surgical stapling instrument |
US11179150B2 (en) | 2016-04-15 | 2021-11-23 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10405859B2 (en) | 2016-04-15 | 2019-09-10 | Ethicon Llc | Surgical instrument with adjustable stop/start control during a firing motion |
US10335145B2 (en) | 2016-04-15 | 2019-07-02 | Ethicon Llc | Modular surgical instrument with configurable operating mode |
US11607239B2 (en) | 2016-04-15 | 2023-03-21 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10357247B2 (en) | 2016-04-15 | 2019-07-23 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US10492783B2 (en) | 2016-04-15 | 2019-12-03 | Ethicon, Llc | Surgical instrument with improved stop/start control during a firing motion |
US10456137B2 (en) | 2016-04-15 | 2019-10-29 | Ethicon Llc | Staple formation detection mechanisms |
US10828028B2 (en) | 2016-04-15 | 2020-11-10 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US10426467B2 (en) | 2016-04-15 | 2019-10-01 | Ethicon Llc | Surgical instrument with detection sensors |
US20170296173A1 (en) | 2016-04-18 | 2017-10-19 | Ethicon Endo-Surgery, Llc | Method for operating a surgical instrument |
US10368867B2 (en) | 2016-04-18 | 2019-08-06 | Ethicon Llc | Surgical instrument comprising a lockout |
US11317917B2 (en) | 2016-04-18 | 2022-05-03 | Cilag Gmbh International | Surgical stapling system comprising a lockable firing assembly |
US10877037B2 (en) | 2016-11-21 | 2020-12-29 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Fungal toxins and methods related to the same |
US20180168577A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Axially movable closure system arrangements for applying closure motions to jaws of surgical instruments |
JP7010956B2 (en) | 2016-12-21 | 2022-01-26 | エシコン エルエルシー | How to staple tissue |
US20180168609A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Firing assembly comprising a fuse |
CN110087565A (en) | 2016-12-21 | 2019-08-02 | 爱惜康有限责任公司 | Surgical stapling system |
US10888322B2 (en) | 2016-12-21 | 2021-01-12 | Ethicon Llc | Surgical instrument comprising a cutting member |
US11419606B2 (en) | 2016-12-21 | 2022-08-23 | Cilag Gmbh International | Shaft assembly comprising a clutch configured to adapt the output of a rotary firing member to two different systems |
US11179155B2 (en) | 2016-12-21 | 2021-11-23 | Cilag Gmbh International | Anvil arrangements for surgical staplers |
US10568625B2 (en) | 2016-12-21 | 2020-02-25 | Ethicon Llc | Staple cartridges and arrangements of staples and staple cavities therein |
CN110099619B (en) | 2016-12-21 | 2022-07-15 | 爱惜康有限责任公司 | Lockout device for surgical end effector and replaceable tool assembly |
US11160551B2 (en) | 2016-12-21 | 2021-11-02 | Cilag Gmbh International | Articulatable surgical stapling instruments |
US10779823B2 (en) | 2016-12-21 | 2020-09-22 | Ethicon Llc | Firing member pin angle |
US11090048B2 (en) | 2016-12-21 | 2021-08-17 | Cilag Gmbh International | Method for resetting a fuse of a surgical instrument shaft |
US10675025B2 (en) | 2016-12-21 | 2020-06-09 | Ethicon Llc | Shaft assembly comprising separately actuatable and retractable systems |
US10426471B2 (en) | 2016-12-21 | 2019-10-01 | Ethicon Llc | Surgical instrument with multiple failure response modes |
US10588630B2 (en) | 2016-12-21 | 2020-03-17 | Ethicon Llc | Surgical tool assemblies with closure stroke reduction features |
US20180168598A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Staple forming pocket arrangements comprising zoned forming surface grooves |
US11134942B2 (en) | 2016-12-21 | 2021-10-05 | Cilag Gmbh International | Surgical stapling instruments and staple-forming anvils |
US20180168625A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Surgical stapling instruments with smart staple cartridges |
US20180168615A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Method of deforming staples from two different types of staple cartridges with the same surgical stapling instrument |
CN108504638B (en) * | 2017-02-28 | 2021-09-17 | 中国科学院过程工程研究所 | Method for purifying or storing foot-and-mouth disease inactivated virus antigen |
USD890784S1 (en) | 2017-06-20 | 2020-07-21 | Ethicon Llc | Display panel with changeable graphical user interface |
US10624633B2 (en) | 2017-06-20 | 2020-04-21 | Ethicon Llc | Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument |
USD879809S1 (en) | 2017-06-20 | 2020-03-31 | Ethicon Llc | Display panel with changeable graphical user interface |
US11090046B2 (en) | 2017-06-20 | 2021-08-17 | Cilag Gmbh International | Systems and methods for controlling displacement member motion of a surgical stapling and cutting instrument |
US10646220B2 (en) | 2017-06-20 | 2020-05-12 | Ethicon Llc | Systems and methods for controlling displacement member velocity for a surgical instrument |
US10980537B2 (en) | 2017-06-20 | 2021-04-20 | Ethicon Llc | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified number of shaft rotations |
US10881399B2 (en) | 2017-06-20 | 2021-01-05 | Ethicon Llc | Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument |
US10390841B2 (en) | 2017-06-20 | 2019-08-27 | Ethicon Llc | Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation |
USD879808S1 (en) | 2017-06-20 | 2020-03-31 | Ethicon Llc | Display panel with graphical user interface |
US10368864B2 (en) | 2017-06-20 | 2019-08-06 | Ethicon Llc | Systems and methods for controlling displaying motor velocity for a surgical instrument |
US11517325B2 (en) | 2017-06-20 | 2022-12-06 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured displacement distance traveled over a specified time interval |
US10888321B2 (en) | 2017-06-20 | 2021-01-12 | Ethicon Llc | Systems and methods for controlling velocity of a displacement member of a surgical stapling and cutting instrument |
US11653914B2 (en) | 2017-06-20 | 2023-05-23 | Cilag Gmbh International | Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument according to articulation angle of end effector |
US10813639B2 (en) | 2017-06-20 | 2020-10-27 | Ethicon Llc | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on system conditions |
US11382638B2 (en) | 2017-06-20 | 2022-07-12 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified displacement distance |
US10307170B2 (en) | 2017-06-20 | 2019-06-04 | Ethicon Llc | Method for closed loop control of motor velocity of a surgical stapling and cutting instrument |
US10881396B2 (en) | 2017-06-20 | 2021-01-05 | Ethicon Llc | Surgical instrument with variable duration trigger arrangement |
US10327767B2 (en) | 2017-06-20 | 2019-06-25 | Ethicon Llc | Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation |
US10779820B2 (en) | 2017-06-20 | 2020-09-22 | Ethicon Llc | Systems and methods for controlling motor speed according to user input for a surgical instrument |
US11071554B2 (en) | 2017-06-20 | 2021-07-27 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on magnitude of velocity error measurements |
US11266405B2 (en) | 2017-06-27 | 2022-03-08 | Cilag Gmbh International | Surgical anvil manufacturing methods |
US10772629B2 (en) | 2017-06-27 | 2020-09-15 | Ethicon Llc | Surgical anvil arrangements |
US10993716B2 (en) | 2017-06-27 | 2021-05-04 | Ethicon Llc | Surgical anvil arrangements |
US11324503B2 (en) | 2017-06-27 | 2022-05-10 | Cilag Gmbh International | Surgical firing member arrangements |
US11090049B2 (en) | 2017-06-27 | 2021-08-17 | Cilag Gmbh International | Staple forming pocket arrangements |
US10856869B2 (en) | 2017-06-27 | 2020-12-08 | Ethicon Llc | Surgical anvil arrangements |
US11259805B2 (en) | 2017-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical instrument comprising firing member supports |
USD906355S1 (en) | 2017-06-28 | 2020-12-29 | Ethicon Llc | Display screen or portion thereof with a graphical user interface for a surgical instrument |
US10716614B2 (en) | 2017-06-28 | 2020-07-21 | Ethicon Llc | Surgical shaft assemblies with slip ring assemblies with increased contact pressure |
US11246592B2 (en) | 2017-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical instrument comprising an articulation system lockable to a frame |
US10765427B2 (en) | 2017-06-28 | 2020-09-08 | Ethicon Llc | Method for articulating a surgical instrument |
USD854151S1 (en) | 2017-06-28 | 2019-07-16 | Ethicon Llc | Surgical instrument shaft |
US11696759B2 (en) | 2017-06-28 | 2023-07-11 | Cilag Gmbh International | Surgical stapling instruments comprising shortened staple cartridge noses |
US10639037B2 (en) | 2017-06-28 | 2020-05-05 | Ethicon Llc | Surgical instrument with axially movable closure member |
US10211586B2 (en) | 2017-06-28 | 2019-02-19 | Ethicon Llc | Surgical shaft assemblies with watertight housings |
US11564686B2 (en) | 2017-06-28 | 2023-01-31 | Cilag Gmbh International | Surgical shaft assemblies with flexible interfaces |
USD869655S1 (en) | 2017-06-28 | 2019-12-10 | Ethicon Llc | Surgical fastener cartridge |
EP3420947B1 (en) | 2017-06-28 | 2022-05-25 | Cilag GmbH International | Surgical instrument comprising selectively actuatable rotatable couplers |
US10903685B2 (en) | 2017-06-28 | 2021-01-26 | Ethicon Llc | Surgical shaft assemblies with slip ring assemblies forming capacitive channels |
USD851762S1 (en) | 2017-06-28 | 2019-06-18 | Ethicon Llc | Anvil |
US10258418B2 (en) | 2017-06-29 | 2019-04-16 | Ethicon Llc | System for controlling articulation forces |
US10932772B2 (en) | 2017-06-29 | 2021-03-02 | Ethicon Llc | Methods for closed loop velocity control for robotic surgical instrument |
US10898183B2 (en) | 2017-06-29 | 2021-01-26 | Ethicon Llc | Robotic surgical instrument with closed loop feedback techniques for advancement of closure member during firing |
US11007022B2 (en) | 2017-06-29 | 2021-05-18 | Ethicon Llc | Closed loop velocity control techniques based on sensed tissue parameters for robotic surgical instrument |
US10398434B2 (en) | 2017-06-29 | 2019-09-03 | Ethicon Llc | Closed loop velocity control of closure member for robotic surgical instrument |
US11304695B2 (en) | 2017-08-03 | 2022-04-19 | Cilag Gmbh International | Surgical system shaft interconnection |
US11974742B2 (en) | 2017-08-03 | 2024-05-07 | Cilag Gmbh International | Surgical system comprising an articulation bailout |
US11944300B2 (en) | 2017-08-03 | 2024-04-02 | Cilag Gmbh International | Method for operating a surgical system bailout |
US11471155B2 (en) | 2017-08-03 | 2022-10-18 | Cilag Gmbh International | Surgical system bailout |
US10743872B2 (en) | 2017-09-29 | 2020-08-18 | Ethicon Llc | System and methods for controlling a display of a surgical instrument |
US10765429B2 (en) | 2017-09-29 | 2020-09-08 | Ethicon Llc | Systems and methods for providing alerts according to the operational state of a surgical instrument |
US10729501B2 (en) | 2017-09-29 | 2020-08-04 | Ethicon Llc | Systems and methods for language selection of a surgical instrument |
USD907648S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
USD917500S1 (en) | 2017-09-29 | 2021-04-27 | Ethicon Llc | Display screen or portion thereof with graphical user interface |
USD907647S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
US11399829B2 (en) | 2017-09-29 | 2022-08-02 | Cilag Gmbh International | Systems and methods of initiating a power shutdown mode for a surgical instrument |
US10796471B2 (en) | 2017-09-29 | 2020-10-06 | Ethicon Llc | Systems and methods of displaying a knife position for a surgical instrument |
US11134944B2 (en) | 2017-10-30 | 2021-10-05 | Cilag Gmbh International | Surgical stapler knife motion controls |
US11090075B2 (en) | 2017-10-30 | 2021-08-17 | Cilag Gmbh International | Articulation features for surgical end effector |
US10842490B2 (en) | 2017-10-31 | 2020-11-24 | Ethicon Llc | Cartridge body design with force reduction based on firing completion |
US10779903B2 (en) | 2017-10-31 | 2020-09-22 | Ethicon Llc | Positive shaft rotation lock activated by jaw closure |
US10743875B2 (en) | 2017-12-15 | 2020-08-18 | Ethicon Llc | Surgical end effectors with jaw stiffener arrangements configured to permit monitoring of firing member |
US11071543B2 (en) | 2017-12-15 | 2021-07-27 | Cilag Gmbh International | Surgical end effectors with clamping assemblies configured to increase jaw aperture ranges |
US10869666B2 (en) | 2017-12-15 | 2020-12-22 | Ethicon Llc | Adapters with control systems for controlling multiple motors of an electromechanical surgical instrument |
US10779826B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Methods of operating surgical end effectors |
US10779825B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Adapters with end effector position sensing and control arrangements for use in connection with electromechanical surgical instruments |
US10743874B2 (en) | 2017-12-15 | 2020-08-18 | Ethicon Llc | Sealed adapters for use with electromechanical surgical instruments |
US10966718B2 (en) | 2017-12-15 | 2021-04-06 | Ethicon Llc | Dynamic clamping assemblies with improved wear characteristics for use in connection with electromechanical surgical instruments |
US11006955B2 (en) | 2017-12-15 | 2021-05-18 | Ethicon Llc | End effectors with positive jaw opening features for use with adapters for electromechanical surgical instruments |
US11197670B2 (en) | 2017-12-15 | 2021-12-14 | Cilag Gmbh International | Surgical end effectors with pivotal jaws configured to touch at their respective distal ends when fully closed |
US11033267B2 (en) | 2017-12-15 | 2021-06-15 | Ethicon Llc | Systems and methods of controlling a clamping member firing rate of a surgical instrument |
US10828033B2 (en) | 2017-12-15 | 2020-11-10 | Ethicon Llc | Handheld electromechanical surgical instruments with improved motor control arrangements for positioning components of an adapter coupled thereto |
US10687813B2 (en) | 2017-12-15 | 2020-06-23 | Ethicon Llc | Adapters with firing stroke sensing arrangements for use in connection with electromechanical surgical instruments |
USD910847S1 (en) | 2017-12-19 | 2021-02-16 | Ethicon Llc | Surgical instrument assembly |
US10835330B2 (en) | 2017-12-19 | 2020-11-17 | Ethicon Llc | Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly |
US11020112B2 (en) | 2017-12-19 | 2021-06-01 | Ethicon Llc | Surgical tools configured for interchangeable use with different controller interfaces |
US11045270B2 (en) | 2017-12-19 | 2021-06-29 | Cilag Gmbh International | Robotic attachment comprising exterior drive actuator |
US10729509B2 (en) | 2017-12-19 | 2020-08-04 | Ethicon Llc | Surgical instrument comprising closure and firing locking mechanism |
US10716565B2 (en) | 2017-12-19 | 2020-07-21 | Ethicon Llc | Surgical instruments with dual articulation drivers |
US11076853B2 (en) | 2017-12-21 | 2021-08-03 | Cilag Gmbh International | Systems and methods of displaying a knife position during transection for a surgical instrument |
US10743868B2 (en) | 2017-12-21 | 2020-08-18 | Ethicon Llc | Surgical instrument comprising a pivotable distal head |
US11311290B2 (en) | 2017-12-21 | 2022-04-26 | Cilag Gmbh International | Surgical instrument comprising an end effector dampener |
US11129680B2 (en) | 2017-12-21 | 2021-09-28 | Cilag Gmbh International | Surgical instrument comprising a projector |
US11039834B2 (en) | 2018-08-20 | 2021-06-22 | Cilag Gmbh International | Surgical stapler anvils with staple directing protrusions and tissue stability features |
US10856870B2 (en) | 2018-08-20 | 2020-12-08 | Ethicon Llc | Switching arrangements for motor powered articulatable surgical instruments |
US11324501B2 (en) | 2018-08-20 | 2022-05-10 | Cilag Gmbh International | Surgical stapling devices with improved closure members |
US10842492B2 (en) | 2018-08-20 | 2020-11-24 | Ethicon Llc | Powered articulatable surgical instruments with clutching and locking arrangements for linking an articulation drive system to a firing drive system |
US11207065B2 (en) | 2018-08-20 | 2021-12-28 | Cilag Gmbh International | Method for fabricating surgical stapler anvils |
US10912559B2 (en) | 2018-08-20 | 2021-02-09 | Ethicon Llc | Reinforced deformable anvil tip for surgical stapler anvil |
US10779821B2 (en) | 2018-08-20 | 2020-09-22 | Ethicon Llc | Surgical stapler anvils with tissue stop features configured to avoid tissue pinch |
US11045192B2 (en) | 2018-08-20 | 2021-06-29 | Cilag Gmbh International | Fabricating techniques for surgical stapler anvils |
US11253256B2 (en) | 2018-08-20 | 2022-02-22 | Cilag Gmbh International | Articulatable motor powered surgical instruments with dedicated articulation motor arrangements |
US11291440B2 (en) | 2018-08-20 | 2022-04-05 | Cilag Gmbh International | Method for operating a powered articulatable surgical instrument |
US11083458B2 (en) | 2018-08-20 | 2021-08-10 | Cilag Gmbh International | Powered surgical instruments with clutching arrangements to convert linear drive motions to rotary drive motions |
USD914878S1 (en) | 2018-08-20 | 2021-03-30 | Ethicon Llc | Surgical instrument anvil |
US11147553B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11172929B2 (en) | 2019-03-25 | 2021-11-16 | Cilag Gmbh International | Articulation drive arrangements for surgical systems |
US11696761B2 (en) | 2019-03-25 | 2023-07-11 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11147551B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11471157B2 (en) | 2019-04-30 | 2022-10-18 | Cilag Gmbh International | Articulation control mapping for a surgical instrument |
US11452528B2 (en) | 2019-04-30 | 2022-09-27 | Cilag Gmbh International | Articulation actuators for a surgical instrument |
US11432816B2 (en) | 2019-04-30 | 2022-09-06 | Cilag Gmbh International | Articulation pin for a surgical instrument |
US11903581B2 (en) | 2019-04-30 | 2024-02-20 | Cilag Gmbh International | Methods for stapling tissue using a surgical instrument |
US11253254B2 (en) | 2019-04-30 | 2022-02-22 | Cilag Gmbh International | Shaft rotation actuator on a surgical instrument |
US11648009B2 (en) | 2019-04-30 | 2023-05-16 | Cilag Gmbh International | Rotatable jaw tip for a surgical instrument |
US11426251B2 (en) | 2019-04-30 | 2022-08-30 | Cilag Gmbh International | Articulation directional lights on a surgical instrument |
US11684434B2 (en) | 2019-06-28 | 2023-06-27 | Cilag Gmbh International | Surgical RFID assemblies for instrument operational setting control |
US11259803B2 (en) | 2019-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical stapling system having an information encryption protocol |
US11497492B2 (en) | 2019-06-28 | 2022-11-15 | Cilag Gmbh International | Surgical instrument including an articulation lock |
US11627959B2 (en) | 2019-06-28 | 2023-04-18 | Cilag Gmbh International | Surgical instruments including manual and powered system lockouts |
US11298132B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Inlernational | Staple cartridge including a honeycomb extension |
US11376098B2 (en) | 2019-06-28 | 2022-07-05 | Cilag Gmbh International | Surgical instrument system comprising an RFID system |
US11399837B2 (en) | 2019-06-28 | 2022-08-02 | Cilag Gmbh International | Mechanisms for motor control adjustments of a motorized surgical instrument |
US11241235B2 (en) | 2019-06-28 | 2022-02-08 | Cilag Gmbh International | Method of using multiple RFID chips with a surgical assembly |
US11553971B2 (en) | 2019-06-28 | 2023-01-17 | Cilag Gmbh International | Surgical RFID assemblies for display and communication |
US11523822B2 (en) | 2019-06-28 | 2022-12-13 | Cilag Gmbh International | Battery pack including a circuit interrupter |
US11224497B2 (en) | 2019-06-28 | 2022-01-18 | Cilag Gmbh International | Surgical systems with multiple RFID tags |
US11298127B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Interational | Surgical stapling system having a lockout mechanism for an incompatible cartridge |
US11426167B2 (en) | 2019-06-28 | 2022-08-30 | Cilag Gmbh International | Mechanisms for proper anvil attachment surgical stapling head assembly |
US11478241B2 (en) | 2019-06-28 | 2022-10-25 | Cilag Gmbh International | Staple cartridge including projections |
US11464601B2 (en) | 2019-06-28 | 2022-10-11 | Cilag Gmbh International | Surgical instrument comprising an RFID system for tracking a movable component |
US11219455B2 (en) | 2019-06-28 | 2022-01-11 | Cilag Gmbh International | Surgical instrument including a lockout key |
US11660163B2 (en) | 2019-06-28 | 2023-05-30 | Cilag Gmbh International | Surgical system with RFID tags for updating motor assembly parameters |
US11291451B2 (en) | 2019-06-28 | 2022-04-05 | Cilag Gmbh International | Surgical instrument with battery compatibility verification functionality |
US11246678B2 (en) | 2019-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical stapling system having a frangible RFID tag |
US11051807B2 (en) | 2019-06-28 | 2021-07-06 | Cilag Gmbh International | Packaging assembly including a particulate trap |
US11638587B2 (en) | 2019-06-28 | 2023-05-02 | Cilag Gmbh International | RFID identification systems for surgical instruments |
US11771419B2 (en) | 2019-06-28 | 2023-10-03 | Cilag Gmbh International | Packaging for a replaceable component of a surgical stapling system |
CN110665001A (en) * | 2019-11-14 | 2020-01-10 | 上海农林职业技术学院 | Water-based composite adjuvant, application thereof and vaccine for cats |
US11464512B2 (en) | 2019-12-19 | 2022-10-11 | Cilag Gmbh International | Staple cartridge comprising a curved deck surface |
US11529137B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11559304B2 (en) | 2019-12-19 | 2023-01-24 | Cilag Gmbh International | Surgical instrument comprising a rapid closure mechanism |
US11304696B2 (en) | 2019-12-19 | 2022-04-19 | Cilag Gmbh International | Surgical instrument comprising a powered articulation system |
US11844520B2 (en) | 2019-12-19 | 2023-12-19 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11911032B2 (en) | 2019-12-19 | 2024-02-27 | Cilag Gmbh International | Staple cartridge comprising a seating cam |
US11291447B2 (en) | 2019-12-19 | 2022-04-05 | Cilag Gmbh International | Stapling instrument comprising independent jaw closing and staple firing systems |
US11931033B2 (en) | 2019-12-19 | 2024-03-19 | Cilag Gmbh International | Staple cartridge comprising a latch lockout |
US11701111B2 (en) | 2019-12-19 | 2023-07-18 | Cilag Gmbh International | Method for operating a surgical stapling instrument |
US11234698B2 (en) | 2019-12-19 | 2022-02-01 | Cilag Gmbh International | Stapling system comprising a clamp lockout and a firing lockout |
US11607219B2 (en) | 2019-12-19 | 2023-03-21 | Cilag Gmbh International | Staple cartridge comprising a detachable tissue cutting knife |
US11576672B2 (en) | 2019-12-19 | 2023-02-14 | Cilag Gmbh International | Surgical instrument comprising a closure system including a closure member and an opening member driven by a drive screw |
US11504122B2 (en) | 2019-12-19 | 2022-11-22 | Cilag Gmbh International | Surgical instrument comprising a nested firing member |
US11446029B2 (en) | 2019-12-19 | 2022-09-20 | Cilag Gmbh International | Staple cartridge comprising projections extending from a curved deck surface |
US11529139B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Motor driven surgical instrument |
CN111175348A (en) * | 2019-12-27 | 2020-05-19 | 深圳康泰生物制品股份有限公司 | Detection method of isoelectric point of aluminum hydroxide adjuvant and application of detection method in preparation of vaccine |
WO2021187635A1 (en) * | 2020-03-16 | 2021-09-23 | 승경선 | Production of mixture for preventing and treating respiratory infectious diseases and viral pneumonia |
USD974560S1 (en) | 2020-06-02 | 2023-01-03 | Cilag Gmbh International | Staple cartridge |
USD975851S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
USD967421S1 (en) | 2020-06-02 | 2022-10-18 | Cilag Gmbh International | Staple cartridge |
USD976401S1 (en) | 2020-06-02 | 2023-01-24 | Cilag Gmbh International | Staple cartridge |
USD966512S1 (en) | 2020-06-02 | 2022-10-11 | Cilag Gmbh International | Staple cartridge |
USD975278S1 (en) | 2020-06-02 | 2023-01-10 | Cilag Gmbh International | Staple cartridge |
USD975850S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
US20220031320A1 (en) | 2020-07-28 | 2022-02-03 | Cilag Gmbh International | Surgical instruments with flexible firing member actuator constraint arrangements |
US11717289B2 (en) | 2020-10-29 | 2023-08-08 | Cilag Gmbh International | Surgical instrument comprising an indicator which indicates that an articulation drive is actuatable |
USD1013170S1 (en) | 2020-10-29 | 2024-01-30 | Cilag Gmbh International | Surgical instrument assembly |
US11779330B2 (en) | 2020-10-29 | 2023-10-10 | Cilag Gmbh International | Surgical instrument comprising a jaw alignment system |
US11517390B2 (en) | 2020-10-29 | 2022-12-06 | Cilag Gmbh International | Surgical instrument comprising a limited travel switch |
US11617577B2 (en) | 2020-10-29 | 2023-04-04 | Cilag Gmbh International | Surgical instrument comprising a sensor configured to sense whether an articulation drive of the surgical instrument is actuatable |
US11896217B2 (en) | 2020-10-29 | 2024-02-13 | Cilag Gmbh International | Surgical instrument comprising an articulation lock |
US11534259B2 (en) | 2020-10-29 | 2022-12-27 | Cilag Gmbh International | Surgical instrument comprising an articulation indicator |
US11452526B2 (en) | 2020-10-29 | 2022-09-27 | Cilag Gmbh International | Surgical instrument comprising a staged voltage regulation start-up system |
USD980425S1 (en) | 2020-10-29 | 2023-03-07 | Cilag Gmbh International | Surgical instrument assembly |
US11844518B2 (en) | 2020-10-29 | 2023-12-19 | Cilag Gmbh International | Method for operating a surgical instrument |
US11931025B2 (en) | 2020-10-29 | 2024-03-19 | Cilag Gmbh International | Surgical instrument comprising a releasable closure drive lock |
US11944296B2 (en) | 2020-12-02 | 2024-04-02 | Cilag Gmbh International | Powered surgical instruments with external connectors |
US11849943B2 (en) | 2020-12-02 | 2023-12-26 | Cilag Gmbh International | Surgical instrument with cartridge release mechanisms |
US11678882B2 (en) | 2020-12-02 | 2023-06-20 | Cilag Gmbh International | Surgical instruments with interactive features to remedy incidental sled movements |
US11744581B2 (en) | 2020-12-02 | 2023-09-05 | Cilag Gmbh International | Powered surgical instruments with multi-phase tissue treatment |
US11737751B2 (en) | 2020-12-02 | 2023-08-29 | Cilag Gmbh International | Devices and methods of managing energy dissipated within sterile barriers of surgical instrument housings |
US11653915B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Surgical instruments with sled location detection and adjustment features |
US11890010B2 (en) | 2020-12-02 | 2024-02-06 | Cllag GmbH International | Dual-sided reinforced reload for surgical instruments |
US11653920B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Powered surgical instruments with communication interfaces through sterile barrier |
US11627960B2 (en) | 2020-12-02 | 2023-04-18 | Cilag Gmbh International | Powered surgical instruments with smart reload with separately attachable exteriorly mounted wiring connections |
US11751869B2 (en) | 2021-02-26 | 2023-09-12 | Cilag Gmbh International | Monitoring of multiple sensors over time to detect moving characteristics of tissue |
US11701113B2 (en) | 2021-02-26 | 2023-07-18 | Cilag Gmbh International | Stapling instrument comprising a separate power antenna and a data transfer antenna |
US11793514B2 (en) | 2021-02-26 | 2023-10-24 | Cilag Gmbh International | Staple cartridge comprising sensor array which may be embedded in cartridge body |
US11812964B2 (en) | 2021-02-26 | 2023-11-14 | Cilag Gmbh International | Staple cartridge comprising a power management circuit |
US11950777B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Staple cartridge comprising an information access control system |
US11744583B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Distal communication array to tune frequency of RF systems |
US11950779B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Method of powering and communicating with a staple cartridge |
US11730473B2 (en) | 2021-02-26 | 2023-08-22 | Cilag Gmbh International | Monitoring of manufacturing life-cycle |
US11723657B2 (en) | 2021-02-26 | 2023-08-15 | Cilag Gmbh International | Adjustable communication based on available bandwidth and power capacity |
US11925349B2 (en) | 2021-02-26 | 2024-03-12 | Cilag Gmbh International | Adjustment to transfer parameters to improve available power |
US11696757B2 (en) | 2021-02-26 | 2023-07-11 | Cilag Gmbh International | Monitoring of internal systems to detect and track cartridge motion status |
US11749877B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Stapling instrument comprising a signal antenna |
US11806011B2 (en) | 2021-03-22 | 2023-11-07 | Cilag Gmbh International | Stapling instrument comprising tissue compression systems |
US11759202B2 (en) | 2021-03-22 | 2023-09-19 | Cilag Gmbh International | Staple cartridge comprising an implantable layer |
US11826012B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Stapling instrument comprising a pulsed motor-driven firing rack |
US11723658B2 (en) | 2021-03-22 | 2023-08-15 | Cilag Gmbh International | Staple cartridge comprising a firing lockout |
US11717291B2 (en) | 2021-03-22 | 2023-08-08 | Cilag Gmbh International | Staple cartridge comprising staples configured to apply different tissue compression |
US11826042B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Surgical instrument comprising a firing drive including a selectable leverage mechanism |
US11737749B2 (en) | 2021-03-22 | 2023-08-29 | Cilag Gmbh International | Surgical stapling instrument comprising a retraction system |
US11744603B2 (en) | 2021-03-24 | 2023-09-05 | Cilag Gmbh International | Multi-axis pivot joints for surgical instruments and methods for manufacturing same |
US11896219B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Mating features between drivers and underside of a cartridge deck |
US11896218B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Method of using a powered stapling device |
US11832816B2 (en) | 2021-03-24 | 2023-12-05 | Cilag Gmbh International | Surgical stapling assembly comprising nonplanar staples and planar staples |
US11849945B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Rotary-driven surgical stapling assembly comprising eccentrically driven firing member |
US11793516B2 (en) | 2021-03-24 | 2023-10-24 | Cilag Gmbh International | Surgical staple cartridge comprising longitudinal support beam |
US11849944B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Drivers for fastener cartridge assemblies having rotary drive screws |
US11786243B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Firing members having flexible portions for adapting to a load during a surgical firing stroke |
US11903582B2 (en) | 2021-03-24 | 2024-02-20 | Cilag Gmbh International | Leveraging surfaces for cartridge installation |
US11786239B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Surgical instrument articulation joint arrangements comprising multiple moving linkage features |
US11944336B2 (en) | 2021-03-24 | 2024-04-02 | Cilag Gmbh International | Joint arrangements for multi-planar alignment and support of operational drive shafts in articulatable surgical instruments |
US11857183B2 (en) | 2021-03-24 | 2024-01-02 | Cilag Gmbh International | Stapling assembly components having metal substrates and plastic bodies |
US20220378426A1 (en) | 2021-05-28 | 2022-12-01 | Cilag Gmbh International | Stapling instrument comprising a mounted shaft orientation sensor |
CN113750228B (en) * | 2021-09-25 | 2024-02-20 | 大连理工大学 | Application of cryoprotectant in aluminum adjuvant |
US11877745B2 (en) | 2021-10-18 | 2024-01-23 | Cilag Gmbh International | Surgical stapling assembly having longitudinally-repeating staple leg clusters |
US11957337B2 (en) | 2021-10-18 | 2024-04-16 | Cilag Gmbh International | Surgical stapling assembly with offset ramped drive surfaces |
US11937816B2 (en) | 2021-10-28 | 2024-03-26 | Cilag Gmbh International | Electrical lead arrangements for surgical instruments |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5766520A (en) | 1996-07-15 | 1998-06-16 | Universal Preservation Technologies, Inc. | Preservation by foam formation |
CA2312233A1 (en) * | 1997-11-26 | 1999-06-03 | Universal Preservation Technologies, Inc. | Preservation of sensitive biological samples by vitrification |
CA2365277A1 (en) * | 1999-05-04 | 2000-11-09 | Eric Edward Worrall | Method for the preservation of viruses and mycoplasma |
US6509146B1 (en) | 1996-05-29 | 2003-01-21 | Universal Preservation Technologies, Inc. | Scalable long-term shelf preservation of sensitive biological solutions and suspensions |
US6893657B2 (en) * | 1994-12-02 | 2005-05-17 | Quadrant Drug Delivery Ltd. | Solid dose delivery vehicle and methods of making same |
CA2564674A1 (en) * | 2004-04-30 | 2005-11-10 | Glaxosmithkline Biologicals S.A. | Drying process for preserving an active agent as a highly viscous liquid |
US6964771B1 (en) | 1995-06-07 | 2005-11-15 | Elan Drug Delivery Limited | Method for stably incorporating substances within dry, foamed glass matrices |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5997856A (en) * | 1988-10-05 | 1999-12-07 | Chiron Corporation | Method and compositions for solubilization and stabilization of polypeptides, especially proteins |
FR2734484B1 (en) * | 1995-05-24 | 1997-06-27 | Pasteur Merieux Serums Vacc | LIQUID VACCINE COMPOSITION AND MANUFACTURING METHOD |
NZ309841A (en) * | 1995-06-07 | 1999-10-28 | Quadrant Holdings Cambridge | Methods for producing foamed glass matrices (fgm) and compositions obtained thereby |
CA2256333A1 (en) | 1996-05-29 | 1997-12-04 | Victor Bronshtein | Long-term shelf preservation by vitrification |
ES2327693T3 (en) * | 1997-08-29 | 2009-11-02 | Antigenics Inc. | COMPOSITIONS THAT INCLUDE THE QS-21 ADJUSTER AND EXCIPIENT POLYSORBATE OR CYCLODEXTRINE. |
IL153241A0 (en) * | 2000-06-08 | 2003-07-06 | Powderject Vaccines Inc | Powder compositions |
GB0017999D0 (en) * | 2000-07-21 | 2000-09-13 | Smithkline Beecham Biolog | Novel device |
US6872357B1 (en) | 2000-11-22 | 2005-03-29 | Quadrant Drug Delivery Limited | Formulation of preservation mixtures containing sensitive biologicals to be stabilized for ambient temperature storage by drying |
DK2395073T3 (en) | 2002-11-01 | 2017-10-23 | Glaxosmithkline Biologicals Sa | Process for drying. |
CA2569276C (en) | 2004-06-02 | 2018-01-23 | Victor Bronshtein | Preservation by vaporization |
-
2008
- 2008-07-23 CN CN201510416884.3A patent/CN105147611A/en active Pending
- 2008-07-23 CN CN200880108192A patent/CN101801343A/en active Pending
- 2008-07-23 BR BRPI0814594-6A2A patent/BRPI0814594A2/en active Search and Examination
- 2008-07-23 CA CA2694083A patent/CA2694083A1/en not_active Abandoned
- 2008-07-23 EP EP08783297A patent/EP2182922A4/en not_active Withdrawn
- 2008-07-23 WO PCT/CA2008/001386 patent/WO2009012601A1/en active Application Filing
- 2008-07-23 JP JP2010517245A patent/JP2010534622A/en active Pending
- 2008-07-23 AU AU2008280755A patent/AU2008280755B9/en not_active Ceased
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- 2008-07-23 MX MX2010001054A patent/MX2010001054A/en unknown
- 2008-07-25 US US12/179,861 patent/US8790658B2/en not_active Expired - Fee Related
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6893657B2 (en) * | 1994-12-02 | 2005-05-17 | Quadrant Drug Delivery Ltd. | Solid dose delivery vehicle and methods of making same |
US6964771B1 (en) | 1995-06-07 | 2005-11-15 | Elan Drug Delivery Limited | Method for stably incorporating substances within dry, foamed glass matrices |
US6509146B1 (en) | 1996-05-29 | 2003-01-21 | Universal Preservation Technologies, Inc. | Scalable long-term shelf preservation of sensitive biological solutions and suspensions |
US5766520A (en) | 1996-07-15 | 1998-06-16 | Universal Preservation Technologies, Inc. | Preservation by foam formation |
CA2312233A1 (en) * | 1997-11-26 | 1999-06-03 | Universal Preservation Technologies, Inc. | Preservation of sensitive biological samples by vitrification |
CA2365277A1 (en) * | 1999-05-04 | 2000-11-09 | Eric Edward Worrall | Method for the preservation of viruses and mycoplasma |
CA2564674A1 (en) * | 2004-04-30 | 2005-11-10 | Glaxosmithkline Biologicals S.A. | Drying process for preserving an active agent as a highly viscous liquid |
Non-Patent Citations (2)
Title |
---|
ADAMOU ET AL., INFECT. IMMUN., vol. 69, 2001, pages 949 - 958 |
See also references of EP2182922A4 |
Cited By (10)
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US11419816B2 (en) | 2010-05-04 | 2022-08-23 | Corium, Inc. | Method and device for transdermal delivery of parathyroid hormone using a microprojection array |
WO2012075428A1 (en) | 2010-12-03 | 2012-06-07 | Sanofi Pasteur Limited | Composition for immunization against streptococcus pneumoniae |
WO2012156391A1 (en) | 2011-05-17 | 2012-11-22 | Glaxosmithkline Biologicals S.A. | Vaccine against streptococcus pneumoniae |
US9770505B2 (en) | 2011-07-13 | 2017-09-26 | Sanofi Pasteur | Vaccine composition with aluminium hydroxide nanoparticles |
WO2013184900A2 (en) | 2012-06-06 | 2013-12-12 | Sanofi Pasteur Biologics, Llc | Immunogenic compositions and related methods |
WO2014145906A2 (en) * | 2013-03-15 | 2014-09-18 | Phd Preventative Health Care And Diagnostics, Inc. | A prefilled medication device, method of making and using the same |
WO2014145906A3 (en) * | 2013-03-15 | 2014-11-13 | Phd Preventative Health Care And Diagnostics, Inc. | A prefilled medication device, method of making and using the same |
US11207241B2 (en) | 2013-03-15 | 2021-12-28 | Phd Preventative Health Care And Diagnostics, Inc. | Prefilled medication device, method of making and using the same |
US11565097B2 (en) | 2013-03-15 | 2023-01-31 | Corium Pharma Solutions, Inc. | Microarray for delivery of therapeutic agent and methods of use |
WO2017067962A1 (en) | 2015-10-21 | 2017-04-27 | Glaxosmithkline Biologicals S.A. | Vaccine |
Also Published As
Publication number | Publication date |
---|---|
EP2182922A4 (en) | 2010-07-28 |
JP2010534622A (en) | 2010-11-11 |
KR101540920B1 (en) | 2015-08-03 |
AU2008280755A1 (en) | 2009-01-29 |
US20090110699A1 (en) | 2009-04-30 |
US8790658B2 (en) | 2014-07-29 |
JP2015163652A (en) | 2015-09-10 |
AU2008280755B2 (en) | 2014-05-15 |
MX2010001054A (en) | 2010-04-21 |
CN101801343A (en) | 2010-08-11 |
AU2008280755B9 (en) | 2014-09-25 |
BRPI0814594A2 (en) | 2015-01-20 |
CN105147611A (en) | 2015-12-16 |
ZA201001300B (en) | 2010-11-24 |
CA2694083A1 (en) | 2009-01-29 |
EP2182922A1 (en) | 2010-05-12 |
KR20100038448A (en) | 2010-04-14 |
IL203428A (en) | 2016-10-31 |
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