Abstract: The invention relates to a method of producing an agglomerate of drug and solid binder. The process involves producing individual agglomerate particles and then converting the convertible amorphous content of same, following agglomeration, by the application of, for example, moisture. Agglomerates capable of conversion as well as the finished agglomerates and oral and nasal dosing systems including same are also contemplated. The process produces agglomerates which are rugged but which will produce an acceptable fine particle fraction during dosing.

Abstract: The present invention relates to site-specific conjugation of synthetic particles to proteins.

Abstract: The use of a protein of vegetable origin suitable in capsule or microcapsule manufacture, which protein

Abstract: A formulation for non-invasive delivery of pharmaceutical agents, particularly proteins and peptides, by absorption through a membrane at a targeted site is provided, along with a process of making the formulation. The formulation comprises a suspension of solid-phase dehydrated particles in a delivery medium. The particles comprise the dehydration product of the pharmaceutical agent and at least one of a surfactant and permeation enhancer, and the delivery medium preferably comprises a propellant for pressurized aerosol delivery of the formulation. The formulation can be conveniently delivered to the patient's targeted site where the pharmaceutical agent is absorbed through the mucosa to achieve a desired bioavailability.

Abstract: This specification discloses resorbable calcium phosphate-based bio-compound particles and the manufacturing method thereof. Through the manufacturing process control, collagen has sufficient time to reconstruct and forms a network structure, which then combines with calcium phosphate-based ceramic powders that are controlled to have diameters ≦5 &mgr;m so as to provide a bio-compound acceptable by humans and having a similar structure and constituents to the bony tissues. There is no need for a second operation when such material is used in medical practice and the bony tissues can undergo fast and effective bone-genesis.

Abstract: The invention features core-shell microsphere compositions, hollow polymeric microspheres, and methods for making the microspheres. The microspheres are characterized as having a polymeric shell with consistent shell thickness.

Abstract: An excipient for lyophilizing a suspension of microparticles is provided comprising an oil-in-water emulsion of an aqueous phase and an organic phase where the organic phase has a freezing point of about or higher than the freezing point of the aqueous phase. When frozen and dried with a suspension of microparticles, the organic phase is substantially removed and a dry formulation is formed of discrete microparticles substantially free of aggregates.

Abstract: The present invention relates to protein-coated micro-crystals and their method of preparation. The protein-coated micro-crystals may find particular application in preparing enzymes for use as biocatalysts; preparation of therapeutic proteins for use in pharmaceutical formulations; production of cleansing agents comprising enzymes; production of paints, varnishes, coatings, films and the like comprising proteins which impart protective and/or antifouling properties; production of films, polymers, inks, coatings, electrodes and/or optical materials comprising proteins for diagnostic kits and/or biosensor applications; use of proteins for studies of molecular recognition, molecular binding and inhibitor binding in non-aqueous media; and preparation of protein based food additives.

Abstract: The invention relates to a sustained release composition and methods of forming and using said composition for the sustained release of biologically active agent. The sustained release compositions of the invention comprise a biocompatible polymer and a biologically active agent characterized by a porous center and a less porous outer layer wherein the center and outer layer consist of essentially the same materials. The sustained release compositions can be prepared by annealing at least a substantial portion of the exterior surface of a polymer/active agent matrix. The compositions which have been annealed exhibit a decrease in the release of agent over the first 24 hours following administration (i.e., reduced burst) and as a result can show an increase in the duration of sustained release thereby providing increased therapeutic benefits.

Abstract: The present invention relates to insoluble compositions containing acylated proteins selected from the group consisting of acylated insulin, acylated insulin analog, and acylated proinsulin, and formulations thereof. The formulations are suitable for parenteral delivery or other means of delivery, to a patient for extended control of blood glucose levels. More particularly, the present invention relates to compositions comprised of an acylated protein complexed with zinc, protamine, and a phenolic compound such that the resulting microcrystal is analogous to the neutral protamine Hagedorn (NPH) insulin crystal form. Surprisingly, it has been discovered that compositions of such acylated proteins have therapeutically superior subcutaneous release pharmacokinetics, and more extended and flatter glucodynamics, than presently available commercial preparations of NPH insulin.

Abstract: A method for making a suspension, dispersion or emulsion of non-agglomerated particles comprising forming particles in a liquid medium, wherein sonic energy is applied to the liquid medium at the point of contact of the reactants during the particle forming step to produce the suspension, dispersion or emulsion of non-agglomerated particles. The invention is also directed to a method for making a suspension of non-agglomerated pyrithione salt particles, comprising the steps of forming pyrithione salt particles in a liquid medium, wherein sonic energy is applied to the liquid medium during the forming step to produce the suspension of non-agglomerated pyrithione salt particles.

Abstract: The present invention provides a technique enabling a drug of protein derivatives such as an interferon-&bgr; to be effectively applied to intraocular diseases such as diseases of a vitreous body, retina, and the like. Namely, the present invention provides a composition comprising a drug of protein derivatives adsorbed on a surface of fine particles of a lactic acid copolymer, and also a scleral plug formed from the composition. The average diameter of the fine particles is less than 1,000 nanometers, preferably within a range of 50 to 500 nanometers. The drug of protein derivatives is, for example, an interferon, particularly an interferon-&bgr;. The lactic acid copolymer preferably comprises lactic acid units and glycolic acid units.

Abstract: The present invention relates to an oral drug delivery system, and in particular to modified amino acids and modified amino acid derivatives for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids and derivatives can form non-covalent mixtures with active biological agents and in an alternate embodiment can releasably carry active agents. Modified amino acids can also form durg containing microspheres. These mixtures are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids are also disclosed.

Abstract: Methods for preparing microspheres containing imidazole derivatives are provided. Also provided is the use of imidazole derivatives containing microspheres for treating fungal infections. Oral dosage forms for oral administration are also provided.

Abstract: A mucin peptide, such as MUC-1, encapsulated in a biodegradable polymeric microsphere is disclosed. The encapsulated mucin peptide breaks tolerance of helper T cells as it elicits a stronger immune response and provides improved protection against tumor challenge than direct administration of peptide, alone or with an adjuvant. The encapsulated mucin peptide can be used in a vaccine composition, and can be used in a method for delivering a mucin peptide to a subject, as well as in a method treating or preventing a cancer associated with reduced glycosylation of MUC-1.

Abstract: Albumin particles in the nanometer and micrometer size range in an aqueous suspension are rendered stable against resolubilization without the aid of a cross-linking agent and witout denaturation, by the incorporation of a stabilizing agent in the particle composition. Stabilizing agents disclosed include reducing agents, oxdizing agents, hydrogen-accepting molecules, high molecular weight polymers, and sulfur-containing ring compounds. Also disclosed are fibrinogen-coated particles, cross-linked or non-cross-linked, and their use as co-aggregants with platelets and with themselves for purposes of shortening bleeding time and enhancing the effect of thrombin.

Abstract: This invention provides reagents and methods for specifically delivering antibiotic, antimicrobial and antiviral compounds, drugs and agents to phagocytic mammalian cells. The invention also relates to specific delivery to and uptake of such compounds by phagocytic cells. The invention specifically relates to reagents and methods for facilitating the entry of antibiotic, antimicrobial and antiviral compounds, drugs and agents into phagocytic cells. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising such antibiotic, antimicrobial or antiviral compounds, drugs and agents conjugated to, impregnated with or coated onto particulate carriers generally termed microparticles. In particular embodiments, the antibiotic, antimicrobial and antiviral compounds, drugs and agents are covalently linked to a microparticle via a specifically-degradable linker molecule which is the target of a microorganism-specific protein having enzymatic activity.

Abstract: Methods are provided for purifying peptides and proteins by incorporating the peptide or protein into a diketopiperazine or competitive complexing agent to facilitate removal one or more impurities, i.e. undesirable components, from the peptide or protein. In a preferred embodiment, a peptide, such as insulin, containing one or more impurities, e.g., zinc ions, is entrapped in diketopiperazine to form a precipitate of peptide/diketopiperazine/impurity, which is then washed with a solvent for the impurity to be removed, which is a nonsolvent for the diketopiperazine and a nonsolvent for the peptide. Formulations and methods also are provided for the improved transport of active agents across biological membranes, resulting for example in a rapid increase in blood agent concentration.

Abstract: Improved porous particles for drug delivery to the pulmonary system, and methods for their synthesis and administration are provided. In a preferred embodiment, the porous particles are made of a biodegradable material and have a mass density less than 0.4 g/cm3/. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of a functionalized polyester graft copolymer consisting of a linear &agr;-hydroxy-acid polyester backbone having at least one amino acid group incorporated therein and at least one poly(amino acid) side chain extending from an amino acid group in the polyester backbone. In one embodiment, porous particles having a relatively large mean diameter, for example greater than 5 &mgr;m, can be used for enhanced delivery of a therapeutic agent to the alveolar region of the lung.

Abstract: The invention relates to methods and products for preventing and treating tumors. In particular the invention relates to the use of slow release microparticles containing cytokines, which are directly injected into a tumor, in order to treat the tumor, e.g., cause tumor regression or to prevent tumor growth or metastasis.

Abstract: A powdery nasal composition comprising a drug and colloidal cellulose is provided. The composition is a nasal composition providing a superior absorption activity for the drug.

Abstract: The present invention relates to capsules encapsulating antibody-producing cells, and to use of such capsules and encapsulated cells, respectively, for implantation in vivo for long term delivery or sustained delivery of antibodies of therapeutic interest.

Abstract: A process for preparing ultrafine powders of biological macromolecules comprises atomizing liquid solutions of the macromolecules, drying the droplets formed in the atomization step, and collecting the particles which result from drying. By properly controlling each of the atomization, drying, and collection steps, ultrafine dry powder compositions having characteristics particularly suitable for pulmonary delivery for therapeutic and other purposes may be prepared.

Abstract: Microcapsules having a wall thickness of no more than 500 nm, and a bulk density of no more than 0.2 g.cm−3, are suitable for therapeutic or diagnostic use. They are aerodynamically light, and can be used for delivery to the lung, or diagnosis by ultrasound.

Abstract: Various materials, including generally non-compatible materials may be provided from a single delivery system by a unique encapsulation system. An encapsulation system is advantageously constructed as a core of aqueous liquid having at least 5% by weight water therein, and an encapsulant surrounding the core to form a stable encapsulated particle, the encapsulant comprising at least one layer of hydrophobic particles in contact with and surrounding the core, the core and hydrophobic particles providing an encapsulated system that has an average weight average particle diameter of from 0.05 to 25 micrometers and can support its own weight. The encapsulation system may be provided by a novel method of manufacture comprising providing a mass of hydrophobic particles having average mass diameter size of between 0.

Abstract: Methods of coating core materials by providing target materials and core materials; ablating the target materials to form ablated particulate target materials; and coating the core materials with said ablated particulate target materials; wherein the method is performed at a pressure of about 10 Torr or higher. Methods of coating particles with nanometer to multiple nanometer thick coatings in atmospheric pressure, and using pneumatic fluidization, are also provided.

Abstract: The present invention relates to mucosal immune protection, mucosal vaccine delivery, and mucosal drug delivery. Novel calcium phosphate core particles, particularly nanoparticles are used as vaccine adjuvants and compositions for inducing protective mucosal immunity. Methods of inducing an immune response to an antigen by delivering the antigen to a mucosal surface using the particles of this invention, and to methods of making such particles are also provided. The particles of this invention are also useful for delivering compositions, such as a pharmacologically active agent, to the mucosal surfaces of a patient in need thereof, to methods of delivering such compositions, and to methods of making such particles.

Abstract: The invention provides a particle comprising fibrinogen bound on the surface of an albumin matrix, wherein said particle is capable of coaggregation with platelet, and of aggregation in a solution containing soluble fibrinogen at a concentration of soluble fibrinogen not capable by it self of formation of a clot upon activation by thrombin.

Abstract: Use of microparticles having a protein and an antibody adsorbed thereon for preparing a pharmaceutical composition for intranasal administration.

Abstract: Adhesive material from the fimbriae (esp. Type 1) of bacteria or synthetic analogues or fragments thereof is combined with a drug to provide for attachment to the gut of a mammal, thereby prolonging the transit time of the drug through the gut. The 28 kDa polypeptide from E. coli Type 1 fimbriae is the preferred adhesive material (“adhesin”). The drug is presented in a carrier such as albumin, a polylactide/glycolide copolymer or alginate microcapsules. The adhesin may be incorporated in the carrier during preparation thereof, adsorbed onto the carrier after preparation, or covalently linked thereto, for example with carbodiimide.

Abstract: This invention provides a stable aqueous/aqueous emulsion system which is prepared with a hydrophilic polymer. This invention also provides the method of preparing a stable aqueous/aqueous emulsion. Finally, this invention provides an encapsulation comprising the emulsion system which is prepared with a hydrophilic polymer.

Abstract: The present invention relates generally to an oral drug delivery system which incorporates a therapeutic bioactive agent with biodegradable calcium phosphate particles, the particles then encapsulated by casein. The resulting particles provide a carrier designed to protect the therapeutic agent in the harsh, acidic environment of the stomach before releasing the agent into the small intestine. The therapeutic agent may be any therapeutically effective agent, such as a natural isolate or synthetic chemical or biological agent, such as a therapeutic agent, and in particular, may be a protein or a peptide such as insulin. Also incorporated with the particles may be additional surface modifying agents to assist binding, controlled release, or to otherwise modify the particles.

Abstract: According to a first embodiment, there is provided a sustained-release preparation comprising a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble physiologically active substance which is not an endothelin antagonist, and a biodegradable polymer. The sustained-release preparation of the first embodiment is highly efficient in incorporating the water-soluble physiologically active substance and suppresses the initial burst of the water-soluble physiologically active substance. The sustained-release preparation of the present invention is capable of releasing the water-soluble physiologically active substance while retaining its bioactivity after administration in vivo. Furthermore, the water-soluble physiologically active substance in the sustained-release preparation is kept stable for a long period of time, with little loss of bioactivity.

Abstract: Bioadhesive polymers in the form of, or as a coating on, microcapsules containing drugs or bioactive substances which may serve for therapeutic, or diagnostic purposes in diseases of the gastrointestinal tract, are described. The polymeric microspheres all have a bioadhesive force of at least 11 mN/cm2 (110 N/m2) Techniques for the fabrication of bioadhesive microspheres, as well as a method for measuring bioadhesive forces between microspheres and selected segments of the gastrointestinal tract in vitro are also described. This quantitative method provides a means to establish a correlation between the chemical nature, the surface morphology and the dimensions of drug-loaded microspheres on one hand and bioadhesive forces on the other, allowing the screening of the most promising materials from a relatively large group of natural and synthetic polymers which, from theoretical consideration, should be used for making bioadhesive microspheres.

Abstract: The invention relates to a sustained release composition and methods of forming and using said composition for the sustained release of biologically active agent. The sustained release compositions of the invention comprise a biocompatible polymer and a biologically active agent characterized by a porous center and a less porous outer layer wherein the center and outer layer consist of essentially the same materials. The sustained release compositions can be prepared by annealing at least a substantial portion of the exterior surface of a polymer/active agent matrix. The compositions which have been annealed exhibit a decrease in the release of agent over the first 24 hours following administration (i.e., reduced burst) and as a result can show an increase in the duration of sustained release thereby providing increased therapeutic benefits.

Abstract: A composition and method of fabrication are presented with which nanoparticles may be used as a tool to deliver drugs to a specific target within or on a mammalian body Specifically, by using stabilizers other than Dextran 70.000 during the polymerization process, according to the present invention, surfactants, which were deemed necessary coating material in the prior art, are no longer required. This is a significant simplification of the fabrication procedure. Many substances are useful as stabilizers, but the preferred stabilizers comprise Dextran 12.000 or polysorbate 85. In the present invention a drug is either incorporated into or adsorbed onto the stabilized nanoparticles. This drug/nanoparticle complex is then administered to the organism on any route such as by oral application, injection or inhalation, whereupon the drug exerts its effect at the desired site of pharmacological action.

Abstract: Dispersibility of a respirable powder, administrable by inhalation, is increased by including a pharmaceutically acceptable water-soluble polypeptide.

Abstract: A process for the manufacturing of microcapsules for sustained release of water soluble peptides, with adjustable release periods of between 1 to 18 weeks. The microcapsule wall are made of a biodegradable polymer. The process is based on the formation of an intermediate complex water/oil/water emulsion. By evaporating the solvent in the emulsion by pressure reduction the microcapsules consolidate, retaining the active peptides in the polymeric matrix. The process produces the complex emulsion in a two mixer, continuous operation. In the first mixer a water/oil emulsion is formed and it is used to form the complex emulsion in the second mixer. By operating in a continuous manner, the process overcome the problems found in existing processes regarding particle size distribution, material losses and process control, among others.

Abstract: Adhesive material from the fimbriae (esp. Type 1) of bacteria or synthetic analogues or fragments thereof is combined with a drug to provide for attachment to the gut of a mammal, thereby prolonging the transit time of the drug through the gut. The 28 kDa polypeptide from E. coli Type 1 fimbriae is the preferred adhesive material (“adhesin”). The drug is presented in a carrier such as albumin, a polylactide/glycolide copolymer or alginate microcapsules. The adhesin may be incorporated in the carrier during preparation thereof, adsorbed onto the carrier after preparation, or covalently linked thereto, for example with carbodiimide.

Abstract: Novel calcium phosphate core particles, methods of making them, and methods of using them as vaccine adjuvants, as cores, as carriers of biologically active material, and as controlled release matrices for biologically active material are disclosed. The core particles may have a surface modifying agent and/or biologically active material, such as antigenic material or natural immunoenhancing factor, polynucleotide material, or therapeutic proteins or peptides, partially coating the particle or impregnated therein. The core particles have a diameter between about 300 nm and about 4000 nm, more particularly between about 300 nm and about 2000 nm, and even more particularly between about 300 nm and about 1000 nm, are substantially spherical in shape, and have a substantially smooth surface.

Abstract: This invention relates to a novel granulate and a novel oral solid dosage formulation, each comprising an active ingredient and one or more carriers prepared by a novel wet granulation method. This method provides that the mixture of active ingredient and carrier be kept below 40° C. during the granulation process such that a more stable formulation is obtained.

Abstract: A controlled or sustained release of L-Histidine is provided by coating the L-Histidine with a hydrophobic coating or acid-resistant coating such as a glyceride material derived from rapeseed. Other therapeutic amino acids are coated with hydrophobic or acid-resistant coatings for providing a sustained or controlled release in the gastrointestinal tract to avoid overloading the transport system for the amino acid. In the case of L-Histidine, the overloading of the L-system is avoided and a more constant concentration of L-Histidine can be provided in the gastrointestinal tract. Further, because the L-Histidine provided in a controlled or a sustained release form, a lower overall dose may be administered to the patient.

Abstract: Lysine derivatives, salts of the derivatives, their optical isomers of D or L configuration, or their mixtures, the derivatives containing an Ne-alkoxy or Ne-alkenoxycarbonyl group and having the formula: 1

Abstract: A microsphere containing an immunogen bound to an inert particle having a mesh size of greater than about 35 mesh for site-specific release and induction of an immune response. The immune response may be an overall enhanced T lymphocyte immune response or a selective response. The physical and chemical characterigticg and/or modes of administration of the microsphere may be engineered to increase TH1 lymphocytes for treatment of cancer or infectious disease. The microencapsulated immunogen has an enteric coating for oral administration.

Abstract: The invention provides compositions and methods for inducing MHC class I-restricted cytotoxic T lymphocyte responses in a mammalian host by immunization with non-replicating protein antigens. The compositions of the invention comprise a two-component complex including a particle component, which is not a prokaryotic or eukaryotic cell, or a micellar, multimicellar, or liposome vesicle composed of detergents and/or lipids, ranging in size from about 10 nm to about 50 &mgr;m, and a non-replicating protein antigen. The non-replicating protein antigen is attached to the particle component through a covalent or non-covalent association to form particulate protein antigen complexes and the complexes are administered to a mammalian host in conjunction with a pharmaceutically acceptable excipient, in a CTL-stimulatory amount. The invention also provides non-replicating vaccines and methods of vaccinating a mammalian host for CTL immunity.

Abstract: A microparticulate composition comprises a biodegradable synthetic polymer microparticle, a proteinaceous antigen and an enteric polymer, wherein the enteric polymer forms a coating layer on a surface of the microparticle.

Abstract: A method for producing nanocapsules with cross-linked protein-based walls, comprising preparing emulsions of said proteins and crosslinking these with a crosslinking agent having reactive groups which react with the reactive groups of said proteins, particularly acylatable groups, to cause an interfaced crosslinking reaction between the proteins and the crosslinking agent, and thereby form capsules with walls based on the proteins crosslinked by the crosslinking agent. A fine emulsion of said proteins is prepared by adjusting the surface tension of the various liquid phases. Biocompatible and biodegradable nanocapsules having improved controlled release are thereby obtained.

Abstract: Preparation of a stable aqueous dispersion, or a stable water-dispersible dry powder, of xanthophylls, which comprises a) preparing a molecularly dispersed solution of at least one xanthophyll, with or without an emulsifier and/or an edible oil, in a water-miscible organic solvent, or a mixture of water and a water-miscible organic solvent, at above 30° C., b) mixing this solution with an aqueous solution of a mixture of protective colloids, b1) in which the mixture comprises at least one low-molecular-weight protective colloid component and at least one high-molecular-weight protective colloid component, whose mean molecular weights differ by at least 10,000, b2) the solvent component being transferred to the aqueous phase and the hydrophobic phase of the xanthophyll being formed as a nanodispersed phase c) and if appropriate, to prepare a water-dispersible dry powder, freeing the resulting dispersion from the solvent and the water and drying it in the presence or absence of a coating material.

Abstract: The invention relates to medicament excipient particles which are suitable for tissue-specific application of a medicament, especially to the central nervous system (CNS). The invention particles can be loaded with or be free pf the active substance. At least one detection protein is bonded to the particle surface or alternatively, the particle surface is modified in such a way that a detection protein bonds with it on contact.

Abstract: A novel lipid vesicle system is described. This system consists of a lipid shell that is anchored on the surface of a polymer matrix. The system has potential applications in drug delivery, drug targeting, protein separation, enzyme immobilization and blood cell substitution.