Abstract: Amphiphilic copolymer, containing at least a hydrophilic chain segment (A) and a hydrophobic chain segment (B), wherein the hydrophilic chain segment (A) contains peptides and wherein the hydrophobic chain segment (B) contains acetal groups or orthoester groups. The hydrophilic chain segment (A) preferably contains glutamine/glutamic acid units or asparagines/aspartic acid units, making a biodegradable copolymer which can form a thermogel.

Abstract: This invention relates to the use of 4-amidino benzylamine derivatives as cosmetic ingredients and to cosmetic compositions, as well as to non-therapeutic methods for the cosmetic treatment of the skin and the scalp. Said derivatives and compositions can be used as urokinase inhibitors to prevent and restore damage of the epidermal barrier. Barrier abnormalities and disruptions respectively are often the starting point of a dry skin state, of itching, of dandruff and of the perception of sensitive skin. These 4-amidino benzylamine derivatives can be used for topical skin and scalp care applications in form of creams, lotions, gels, shampoos and the like.

Abstract: This invention provides a method for administration of an effective amount of RANKL-binding molecules that act on prechondrocytes and/or mesenchymal stem cells, accelerate cartilage differentiation, proliferation, and maturation of such cells, enhance chondrocyte differentiation, and induce chondrocyte proliferation to induce chondrocyte proliferation and differentiation or increase cartilage matrix production and a pharmaceutical composition used for inducing chondrocyte proliferation and differentiation or increasing cartilage matrix production.

Abstract: The invention relates to methods and compositions for improving wound healing and in particular for preventing scar formation and thus loss of function that can occur in injured tissues during the natural wound healing process. Particularly, although by no means exclusively, the invention relates to the healing of chronic wounds such as diabetic ulcers.

Abstract: The current invention relates to the use of a peptide comprising an amino acid sequence in the preparation of a medicament for the regeneration of tissue, preferably for the treatment of a wound. Further the invention relates to compositions comprising such peptides, and use of said peptides in both medical and nonmedical (cosmetic) applications.

Abstract: An antibody of the invention interacts with human DR5 or with human DR4 to produce agonistic or antagonistic effects downstream of the receptor including inhibition of cell proliferation and apoptosis. Methods and uses for the antibodies, optionally in combination with various therapeutic agents, are detailed, including treatment of apoptosis-related disease and treatment of dysregulated cell growth.

Abstract: The invention provides new methods of treatment using TGF-?3 to inhibit scarring in humans, and TGF-?3 for new uses in the inhibition of scarring in humans. In a first incidence of treatment TGF-?3 is provided to each centimetre of a wound margin or each centimetre of a site at which a wound is to be formed in a first therapeutically effective amount; and in a subsequent incidence of treatment TGF-?3 is provided to each centimetre of wound margin in a larger therapeutically effective amount of TGF-?3. The incidences of treatment occur between 8 hours and 48 hours apart from one another. The TGF-?3 may be provided by intradermal injection. Also provided are kits and methods of selecting an appropriate treatment regime for inhibiting scarring associated with the healing of a human wound.

Abstract: The invention provides products of manufacture, e.g., biomaterials and implants, for cartilage maintenance and/or formation in-vivo, in-vitro, and ex-vivo, using nanotechnology, e.g., using nanotube, nanowire, nanopillar and/or nanodepots configured on surface structures of the products of manufacture.

Abstract: The invention provides new methods of treatment using TGF-?3 to inhibit scarring in humans, and TGF-?3 for new uses in the inhibition of scarring in humans. In a first incidence of treatment each centimetre of wound margin, or each centimetre of a site at which a wound is to be formed, is provided with between approximately 350 ng and 1000 ng of TGF-?3; and in a second incidence of treatment, occurring after a wound is formed, and between 8 and 48 hours after the first incidence of treatment, the wound is provided with an amount of between approximately 350 ng and 1000 ng of TGF-?3 per centimetre of wound margin in which scarring is to be inhibited. The amount of TGF-?3 provided may be the same in each incidence of treatment. The amount of TGF-?3 provided per centimetre in each incidence of treatment may preferably be approximately 500 ng. The TGF-?3 may be provided by intradermal injection.

Abstract: Liquid formulations of bone morphogenetic proteins are provided for prolonged use at elevated temperatures. More specifically, the invention relates to liquid formulations comprising rhGDF-5, trehalose, and one or more biocompatible excipients that provide stability to the protein for at least 30 days at temperatures up to body temperature.

Abstract: Pharmaceutical compositions and methods for delivering a polypeptide to the central nervous system of a mammal via intranasal administration are provided. The polypeptide can be a catalytically active protein or an antibody, antibody fragment or antibody fragment fusion protein. The polypeptides are formulated with one or more specific agents.

Abstract: Disclosed is a mixture of: a bone/cartilage formation promoting agent containing sulfated galactosaminoglycan having greater than or equal to 0.6 numbers of ester sulfate groups on average per constituent monosaccharide or a salt thereof as an active ingredient; a factor having a bone/cartilage formation promoting action; or a bone filler (BMP, TGF-?, FGF, IGF, insulin, PDGF, HGF, midkine, pleiotrophin, collagen, gelatin, proteoglycan, fibronectin, osteocalcin, osteopontin, osteonectin, bone sialoprotein, hydroxyapatite, dicalcium phosphate anhydride, dicalcium phosphate dehydrate, ?-tricalcium phosphate, amorphous calcium phosphate, octacalcium phosphate, ?-tricalcium phosphate, PLLA, PLGA, titanium, decalcified bone, autogeneous bone, or the like).

Abstract: The present invention is directed to method of modulating a heat shock response in a first cell of a multicellular organism comprising stimulating or inhibiting an HSR signaling activity of a second cell, wherein the second cell is a neuronal cell that regulates heat shock response activation in the first cell and that does not directly innervate the first cell.

Abstract: The invention relates to IHG-1 (induced by high glucose-1) a novel gene which encodes a protein that amplifies fibrotic responses in in vitro and in vivo models of fibrotic disorders and in human diabetic nephropathy. In particular the invention relates to modifications of the IHG-1 structure which are potential fibrosuppressant biotherapeutics and modify cellular invasiveness. The invention also relates to a method of screening a therapeutic agent for suitability for the treatment of fibrotic disease comprising testing a candidate therapeutic agent for the ability to reduce the expression of IHG-1 levels in a model system.

Abstract: Methods of identifying immune response modulators are disclosed. Some methods comprise identifying chemical candidates that modulate oligomerization of FOXP3 and/or fragments thereof comprising the Zinc-LeuZip domains. Some methods comprise identifying chemical candidates that modulate the hetero-oligomerization of FOXP1 with FOXP3 and/or fragments thereof comprising the Zinc-LeuZip domains. Some methods comprise identifying chemical candidates that modulate interaction of IL-2 promoter with FOXP3 and/or fragments thereof comprising the Zinc-LeuZip domains. Method of treating individuals who have or are suspected of having autoimmune disease, inflammatory disease, cell, tissue or organ transplantation, or coronary artery disease, and methods of treating individuals who have or are suspected of having infectious disease, cancer, or who are immunocompromised or undergoing vaccination are disclosed.

Abstract: Improved formulations and methods are provided for stabilizing a solution of bone morphogenetic protein. The compositions comprise an acetate buffered solution of GDF-5 and other excipients wherein the solution has a pH of from about 4.2 to about 5.3, thereby providing for a biologically isotonic solution having improved stability of the GDF-5 protein during storage, handling, and use.

Abstract: The invention provides methods and compositions for reducing or preventing fibrosis in a subject suffering from a fibrotic disorder by administering a therapeutically effective amount of at least one antagonist to the cytokine thymic stromal lymphopoietin to the subject. In one embodiment, the methods and compositions further comprise administering at least one additional antagonist to an additional profibrotic cytokine, growth factor or chemokine.

Abstract: The present invention comprises compositions, methods, and devices for delivering angiogenic factors and signaling molecules to a target tissue, and controlling the release of these factors and signaling molecules to spatially and temporally restrict their release and dissemination, for the purposed promoting angiogenesis in target tissues.

Abstract: The present invention relates to a method for the production of functional dendritic cells wherein CD34 positive cells are contacted with compounds inducing and accelerating the differentiation of these CD34 positive cells into functional dendritic cells. More in particular, the CD34 positive cells are contacted with anthracyclines and/or anthracenediones. In another aspect, the current invention relates to the cells obtainable by the method according to the invention. In a further aspect the current invention relates to the use of compounds such as anthracyclines and/or anthracenediones that induce and accelerate the differentiation of CD34 positive cells into functional dendritic cells in the manufacture of a medicament for inducing an immune response in human in need thereof.

Abstract: Compositions and methods for tissue repair are provided including cell binding peptides and growth factor binding peptides. The cell binding peptides bind to one or more of stem cells, fibroblasts, or endothelial cells. The growth factor binding peptides include platelet derived growth factor (PDGF) binding peptides and growth differentiation factor (GDF) binding peptides. The tissue for repair includes tendon, muscle, connective tissue, ligament, cardiac tissue, vascular tissue, or dermis. Implantable devices for tissue repair are provided to which the cell and growth factor binding peptides are attached, such as acellular extracellular matrix having attached binding peptide.

Abstract: Compositions and methods for repairing a ruptured connective tissue are disclosed. The composition may include a first biocompatible material to provide a scaffold for connective tissue cell growth and tissue repair. This first biocompatible material may withstand a tensile load of up to 250 N. The composition may also include a second biocompatible material including at least one bioactive agent that can stimulate connective tissue cell growth and tissue repair. The method may include positioning a first end of the first biocompatible material adjacent a first end of a ruptured connective tissue, positioning a second end of the first biocompatible material adjacent a second end of the ruptured connective tissue, and anchoring the first biocompatible material to the first and second tendon ends. The method may alternatively comprise or further include positioning a second biocompatible material between the first and second ends of the ruptured connective tissue.

Abstract: A system and method for producing a scaffold coated and/or impregnated with at least one bioactive agent. This is accomplished by culturing at least one cell in the same medium as a scaffold, but without physical contact between the at least one cell and the scaffold. The system includes a container having a surface defining an interior compartment. A medium is disposed within the interior compartment. At least one cell is disposed within the medium, the at least one cell being capable of producing at least one bioactive agent. Further, a scaffold is disposed within the medium. The scaffold is physically separated from the at least one cell such that there is no contact between the scaffold and the at least one cell. Thus, as the at least one cell produces at least one bioactive agent, such as a growth factor, the at least one bioactive agent enters the medium, and contacts and coats and/or impregnates the scaffold.

Abstract: The invention provides methods of treating a subject having a disease, disorder or condition of the central nervous system. The methods include administering TGF-? polypeptides, related polypeptides, fragments and mimetics thereof useful in stimulating progenitor cell or stem cell proliferation, migration and differentiation. The methods of the invention are useful to treat and prophylactically ameliorate neurological tissue injury in vivo.

Abstract: Methods of determining a subjects ototoxicity risk from administration of platinum-coordinating compounds having an ototoxicity risk, methods of administering a platinum-coordinating compound having an ototoxicity risk and oligonucleotides, peptide nucleic acids, arrays and addressable collections for performing embodiments of the methods are provided herein.

Abstract: The invention provides TGF-?3s, or fragments or derivatives thereof, wherein the alpha-helix-forming domain between amino acid residues (58) and (67) of full-length wild type TGF-?3 comprises at least one alpha-helix-stabilising substitution. The invention also provides TGF-?3s, or fragments or derivatives thereof, wherein the Glycine residue at position (63) of full-length wild type TGF-?3 is replaced with Proline. Further still, the invention provides TGF-?3s, or fragments or derivatives thereof, comprising a substitution of the Glutamic acid residue at position (12) of full-length wild type TGF-?3 and/or the Arginine residue at position (52) of full-length wild type TGF-?3. The invention also provides medicaments and methods of treatment using such TGF-?3s.

Abstract: The present invention is directed to methods for treating a viral respiratory infection in a subject, preventing polymicrobial synergy in a subject, or preventing a bacterial infection in a subject. These methods include selecting a subject with a viral respiratory infection, a subject susceptible to polymicrobial synergy, or a subject susceptible to bacterial infection, respectively. In each case a therapeutic agent that inhibits interferon-gamma (IFN?) is provided and administered to the selected subject under conditions effective to treat the viral respiratory infection, to prevent polymicrobial synergy, or to prevent a bacterial infection, respectively.

Abstract: Methods for promoting osteogenesis to accelerate or enhance bone fracture healing, treat bone defects, and enhance bone formation are disclosed. The methods rely on in vivo or ex vivo modulation of an arachidonic acid metabolic or signaling pathway in general, and, in particular, utilize 5-lipoxygenase inhibitors, leukotriene A4 hydrolase inhibitors, and/or leukotriene B4 receptor antagonists. These molecules can be delivered alone or in combination with one or more agents that inhibit bone resorption, regulate calcium resorption from bone, enhance bone accumulation, enhance bone formation, induce bone formation, impair growth of microorganisms, reduce inflammation, and/or reduce pain.

Abstract: A carrier matrix may be delivered to a target position within a patient in a minimally invasive manner by first cutting a collagen sponge sheet into a plurality of relatively small pieces. These pieces are sized so that, when wet, they are capable of flowing through a cannula and/or reduced-diameter syringe tip. The pieces are placed into a syringe and wetted, say with a morphogenic solution, and optionally mixed with a bulking material, which is similarly sized to fit through the cannula. The thoroughly mixed and wetted product forms a viscous aggregate which may then be injected into the patient at the target site.

Abstract: The present invention relates to the expression and regulating growth factors in chrondrocytes and developing cartilage, particularly granulin-epithelin precursor (GEP). The invention relates to the modulation and manipulation of these growth factors, GEP, and/or the molecules they interact with, for instance COMP, in cartilage disorders, including arthritis. Assays and screening methods for the determination of the expression and activity of GEP, or of GEP-COMP, are provided, including for screening for the presence or extent of cartilage or arthritic disease and for identifying modulators or compounds/agents for treatment or prevention of cartilage or arthritic diseases.

Abstract: The present invention relates to the design and composition of a depot implant for optimal delivery of growth factors to treat bone avascular necrosis, in that such depot implant is constructed to be in a cylinder (rod) or sphere shape and have a natural or synthetic polymer scaffold with or without impregnated calcium phosphate particles. The density of the depot is higher than a typical BMP sponge carrier to facilitate its implantation and slower release of the growth factor. The scaffold is such that it has adequate porosity and pore size to facilitate growth factor seeding and diffusion throughout the whole of the bone structure resulting in increased new blood vessel growth and density in the avascular necrotic bone. In addition, the shape of the depot implant allows for delivery through a cannula or large bore needle.

Abstract: The present invention provides implantable receptacle devices (and methods) for use in bone and tissue regeneration which provide immediate structural stability and strength to a zone where tissue regeneration is required. By virtue of their size, shape and construction, the devices are scalable, modular, structurally stable, self-stacking in three dimensions, can be aggregated to an anatomically accurate shape, and hold various materials delivered into the implant area so as to create a highly regenerative micro-environment. They can be implanted via less invasive surgical procedures, and because they act as external scaffolding as well as being imbedded as an integral part of a matrix for the effective and rapid regeneration of bone and cartilage in vivo, they may provide significant advantages to patients or subjects in terms of reduced pain, faster healing and fewer complications.

Abstract: The present invention is directed to treatment methods for a disease or condition, in a subject in need of such treatment, that provide alternatives to treatment by injection that give, relative to treatment by injection, improved treatment outcomes, 100% treatment compliance, reduced side effects, and rapid establishment and/or termination of substantial steady-state drug delivery. The method typically includes providing continuous delivery of a drug from an implanted osmotic delivery device, wherein substantial steady-state delivery of the drug at therapeutic concentrations is typically achieved within about 7 days or less after implantation of the osmotic delivery device in the subject and the substantial steady-state delivery of the drug from the osmotic delivery device is continuous over a period of at least about 3 months. In one embodiment, the present invention is directed to treatment of type 2 diabetes mellitus using incretin mimetics.

Abstract: The present invention relates to compositions and methods for preventing and treating a condition in a mammalian subject that include at least one inhibitor of double stranded RNA dependent protein kinase (PKR-I) prior to or concurrently with the treatment, wherein the treatment results to an inhibition of activation of dsRNA-dependent protein kinase. The compositions and methods of the present invention further include at least one potentiator that further enhances the inhibition of phosphorylation by PKR-I.

Abstract: The present invention features methods and compositions for treating a patient who has a neurological deficit. The method can be carried out, for example, by contacting (in vivo or in culture) a neural progenitor cell of the patient's central nervous system (CNS) with a polypeptide that binds the epidermal growth factor (EGF) receptor and directing progeny of the proliferating progenitor cells to migrate en masse to a region of the CNS in which they will reside and function in a manner sufficient to reduce the neurological deficit. The method may include a further step in which the progeny of the neural precursor cells are contacted with a compound that stimulates differentiation.

Abstract: There is provided the use of monomeric TGF-?s, or there fragments or derivatives, as medicaments. These medicaments preferably comprise monomeric TGF-?3, or fragments or derivatives thereof. The medicaments provided may be used in the acceleration of wounding and/or the inhibition of scarring, in the promotion of epithelial regeneration, or in the prevention and/or treatment of fibrotic disorders.

Abstract: Embodiments of this invention provide methods for therapeutic use of cyclic G-2-allylProline (cG-2-allylP) to treat peripheral neuropathies, including toxin-induced peripheral neuropathy and diabetic as well as manufacture of medicaments including tablets, capsules, and other orally active compositions containing cG-2-allylP, as well as injectable solutions that are useful for treatment of such conditions.

Abstract: Disclosed are methods of treating subjects having conditions related to angiogenesis including administering an effective amount of a polymeric nanoparticle form of thyroid hormone agonist, partial agonist or an antagonist thereof, to promote or inhibit angiogenesis in the subject. Nanoparticle forms of thyroid hormone or thyroid hormone analogs as well as uses thereof are also disclosed.

Abstract: The present invention provides methods and compositions for expanding Treg cells ex vivo or in vivo using one or more conjugates comprising a costimulatory moiety that stimulates at least one of three signals involved in Treg cell development and/or using dendritic cells pulsed with antigens and modified to display TGF-?, or hematopoetic stem cells or bone marrow cells modified to display TGF-?. The methods and compositions are useful, for example, in the treatment and prevention of autoimmune disease, including Type 1 diabetes and in preventing foreign graft rejection, as well as to establish mixed chimerism, induce tolerance to autoantigens, alloantigens or xenoantigens, beta cell regeneration, prevention of foreign graft rejection, and treatment of a genetically inherited hematopoietic disorder.

Abstract: The present invention relates generally to tissue differentiation factor (TDF) analogs. More specifically, the invention relates to structure-based methods and compositions useful in designing, identifying, and producing molecules which act as functional modulators of TDF-like receptors. The invention further relates to methods of detecting, preventing, and treating TDF-associated disorders.

Abstract: Embodiments of this invention provide novel peptidomimetics that contain a macrocycle. Such compounds are neuroprotective and have utility as therapeutic agents for treatment of diseases, injuries and other conditions characterised by neuronal degeneration and/or death. Compounds are also useful for manufacture of medicaments useful for treatment of such conditions.

Abstract: The present invention relates to a bone graft material and a scaffold for tissue engineering applications, which have an osteogenesis-promoting peptide immobilized on the surface. More particularly, the invention relates to a bone graft material and a scaffold for tissue engineering applications, which have a cell adhesion-inducing peptide and/or tissue growth factor-derived peptide immobilized on the surface. By the osteogenesis-promoting peptide immobilized on the surface, the inventive bone graft material and scaffold for tissue engineering applications can promote the transition, proliferation and differentiation of cells associated with regeneration, and eventually maximize the regeneration of tissue. Moreover, the peptide immobilized on the surface has low molecular weight, indicating a reduced risk of immune responses upon its application in the body, and can be present in a stable form within the body, thus showing lasting effects.

Abstract: Compositions for nucleus pulposus regeneration is provided. Such composition may comprise a scaffolding material and a pore creating agent dispersed within the scaffolding material. The pore creating agent is removed from the scaffolding material in vivo, after the composition is administered to a patient. The pore creating agent may include an active agent, such as a growth factor, which may be released as the pore creating agent is being gradually removed from the scaffolding material. In addition, removal of the pore creating agent results in a porous scaffold for cells capable of regeneration of nucleus pulposus, either existing in situ or delivered separately, to attach to for further proliferation and regeneration.

Abstract: Catheter injectable depot compositions are provided that include a bioerodible, biocompatible polymer, a solvent having miscibility in water of less than or equal to 7 wt. % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, a thixotropic agent, and a beneficial agent. The solvent comprises an aromatic alcohol, an ester of an aromatic acid, an aromatic ketone, or mixtures thereof. The compositions are have substantially improved the shear thinning behavior and reduced injection force, rendering the compositions readily implanted beneath a patient's body surface by injection.

Abstract: The present invention provides methods and compositions for sequentially and separately reducing infection and/or inflammation and regenerating tissue at a lesion site, by contacting the lesion site with a biodegradable scaffold that first delivers one or more agents at the lesion site to reduce infection and/or inflammation and then delivers one or more agents to regenerate tissue at the lesion site after inflammation is reduced.

Abstract: A method for targeted delivery of therapeutic compounds from hydrogels is presented. The method involves administering to a cell a hydrogel in which a therapeutic compound is noncovalently bound to heparin. The hydrogel may contain covalent and non-covalent crosslinks.

Abstract: Described is a spray-on hydrogel comprising water-soluble PEG polymers that cross-link in situ to form a hydrogel such that the cross-links are reversible. The hydrogel can be useful as a drug delivery composition, wound dressing or surgery adjuvant. Polyethylene glycol polymer and cross-linker solutions are sprayed simultaneously through a common orifice. Cross-linking via formation of thioether or disulfide bonds is initiated upon mixing, providing rapid gelation. The hydrogel components can be derivatized with RGD peptides or analogs thereof to promote retention in/on a body compartment such as the skin, surface of the eye, or a mucosa such as the vaginal mucosa. The cross-links are reversed using a reducing solution enabling easy removal of the hydrogel by dissolution. Processes for preparation of the cross-linker, RGD derivatized PEG and RGD-linked agents are also disclosed.

Abstract: The present invention provides a method of increasing neural stem cell numbers or neurogenesis by using prolactin. The method can be practiced in vivo to obtain more neural stem cells in situ, which can in turn produce more neurons or glial cells to compensate for lost or dysfunctional neural cells. The method can also be practiced in vitro to produce a large number of neural stem cells in culture. The cultured stem cells can be used, for example, for transplantation treatment of patients or animals suffering from neurodegenerative diseases or conditions. In addition, since neural stem cells are a source for olfactory neurons, the present invention also provides methods of increasing olfactory neurons and enhancing olfactory functions.

Abstract: The present disclosure relates to a clottable concentrate of platelet growth factors for therapeutic and/or cosmetic use, preferably comprising the growth factors PDGF, TGT-?, IGF, EGF, CTGF, bFGF and VEGF. In a preferred embodiment, the clottable concentrate of platelet growth factors does not induce blood cell-related transfusion reactions. The present disclosure also relates to a method for preparing a clottable concentrate of platelet growth factors including the steps of contacting a platelet concentrate with a solvent and/or a detergent, incubating the platelet concentrate with the solvent and/or detergent for a period of at least 5 minutes to 6 hours, at a pH maintained in a range from about 6.0 to about 9.0, and at a temperature within the range of from 2° C. to 50° C., preferably within the range of from 25° C. to 45° C., and removing the solvent and/or the detergent by oil extraction and/or chromatographic means.

Abstract: The common premise of synthetic implants in the restoration of diseased tissues and organs is to use inert and solid materials. Here, a porous titanium implant enables the delivery of microencapsulated bioactive cues. Control-released TGF?1 promoted the proliferation and migration of human mesenchymal stem cells into porous implants in vitro. Upon 4-wk implantation in the rabbit humerus, control-released TGF?1 from porous implants significantly increased BIC by 96% and bone ingrowth by 50% over placebos. Control-released 100 ng TGF?1 induced equivalent BIC and bone ingrowth to adsorbed 1 ?g TGF?1, suggesting that controlled release is effective at 10-fold less drug dose than adsorption. Histomorphometry, SEM and ?T showed that control-released TGF?1 enhanced bone ingrowth in the implant's pores and surface. These findings suggest that solid prostheses can be transformed into porous implants to serve as drug delivery carriers, from which control-released bioactive cues augment host tissue integration.

Abstract: A nutritional composition comprising a partially hydrolysed milk protein having a degree of hydrolysis between 15 and 25% and 50 to 1000 nanograms of TGF-? per 100 ml of ready to consume composition and methods for the primary prevention of allergic reactions to newly introduced dietary protein at weaning and the prevention of development of atopic diseases in a young mammal at weaning comprising feeding to the young mammal a therapeutic amount of the composition are disclosed.