WO1998021951A1 - Methods and compositions for inducing oral tolerance in mammals - Google Patents

Methods and compositions for inducing oral tolerance in mammals

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Publication number
WO1998021951A1
WO1998021951A1 PCT/US1997/014676 US9714676W WO9821951A1 WO 1998021951 A1 WO1998021951 A1 WO 1998021951A1 US 9714676 W US9714676 W US 9714676W WO 9821951 A1 WO9821951 A1 WO 9821951A1
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WIPO (PCT)
Prior art keywords
alkenyl
alkyl
amino acid
phenyl
antigen
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Application number
PCT/US1997/014676
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English (en)
French (fr)
Inventor
Susan Haas
Sam J. Milstein
Original Assignee
Emisphere Technologies, Inc.
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Publication date
Application filed by Emisphere Technologies, Inc. filed Critical Emisphere Technologies, Inc.
Priority to EP97939468A priority Critical patent/EP0886471A4/en
Priority to US09/101,921 priority patent/US6391303B1/en
Publication of WO1998021951A1 publication Critical patent/WO1998021951A1/en

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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
    • A61K39/35—Allergens
    • 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
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46434—Antigens related to induction of tolerance to non-self
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • the present invention relates to methods and compositions useful for the induction of oral tolerance to a coadministered antigen in mammals.
  • Immunological antibody responses to pathogens are required to prevent infections in the body, whereas, immunological tolerance is a property of the immune system that allows for the discrimination of self from non-self.
  • a breakdown in immunological tolerance to self antigens allows the onset of anti-self immunological responses through the generation of anti-self antibodies and/or cellular immune responses. This breakdown is responsible for auto-immune diseases seen in both humans and other mammals.
  • allergens such as those classically observed in, for example, hay fever, reactions to insect bites and common food allergies is suppressed through the generation of immunological tolerance to the antigen responsible for the allergy, i.e., the allergen.
  • allergens i.e., the allergen.
  • Repeated exposure to a particular allergen through controlled administration of allergen can induce tolerance in some patients.
  • Oral tolerance has been characterized in the literature as a state of antigen- specific systemic immunological unresponsiveness or tolerance, which is induced by prior oral administration or feeding of antigen.
  • A.M. Mowat Immunology Today, Vol. 8, No. 3, 1987, pp. 93-98.
  • Such a state of systemic hypo-responsiveness to an administered protein or antigen has been observed and reviewed in the art.
  • H.L. Weiner Proc. Natl. Acad. Sci. USA, Vol. 91, 1994, pp. 10762-10765; and H.L. Weiner and L.F. Mayer, eds., Annals of NY Acad. Sci ' ., Vol. 778, 1996, pp. xiii-xviii.
  • sheep red blood cells SRBC
  • horse red blood cells HRBC
  • purified human gamma-globulin HGG
  • the SRBC-CTB, HRBC-CTB or HGG- CTB were administered orally to mice to induce oral tolerance to these antigens.
  • EAE Eryelinating autoimmune disease
  • CNS central nervous system
  • MBP Myelin Basic Protein
  • encephalitogenic proteins derived from brain or spinal cord
  • synthetic peptides whose amino acid sequences resemble those of encephalitogenic components of CNS tissues.
  • EAE is widely used as a model for human autoimmune inflammatory demyelinating disorders such as Multiple Sclerosis (J-B. Sun, et al, Proc.
  • Determination of synergistic or immune enhancing agents to be administered together with MBP in order to reduce the number or magnitude of the MBP doses required to modulate the disease symptoms is desirable.
  • agents that can deliver consistent concentrations of antigen to the gut are also desirable. If such agents could be identified, immunogenic tolerance to these and other types of autoimmune diseases could be promoted.
  • the present invention relates to methods and formulations for inducing oral tolerance in an animal, comprising orally administering to the animal a pharmaceutical formulation comprising an antigen and a delivery agent or agents comprising at least one derivatized amino acid or a salt thereof in an amount sufficient to induce oral tolerance.
  • delivery agents allow the administration of lower or fewer doses of antigen than are required to induce the same degree of systemic immune suppression with the antigen alone.
  • the immune responses involved include, but are not limited to, systemic antibody production or delayed-type hypersensitivity reactions.
  • the antigens for use in the induction of oral tolerance do not have to be covalently linked to the delivery agents.
  • the invention relates to methods of inducing oral tolerance in an animal wherein the deriviatized amino acid is comprised of an amino acid bearing a free carboxyl group, an amide linkage and a hydrophobic chain comprised of aromatic and/or aliphatic components.
  • a preferred embodiment of the invention relates to methods of inducing oral tolerance in an animal wherein the deriviatized amino acid is an acylated amino acid compound of the formula o U
  • Ar-C-(R) - OH I wherein: Ar is a substituted or unsubstituted phenyl,
  • R is NH(R')-C-
  • R 1 is C, to C, 0 alkyl, C, to C 10 alkenyl, phenyl, naphthyl, (C, to C, 0 alkyl) phenyl, (C, to C, 0 alkenyl) phenyl, (C, to C, 0 alkyl) naphthyl, (C, to C, 0 alkenyl) naphthyl;
  • R 1 is optionally substituted with C, to C 4 alkyl, C, to C 4 alkenyl, C, to C 4 alkoxy, -OH, -SH and -CO 2 R 2 , cycloalkyl, cycloalkenyl, heteroalkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof; and
  • R 2 is hydrogen, C, to C 4 alkyl or C, to C 4 alkenyl.
  • the present invention also relates to pharmaceutical formulations for inducing oral tolerance in an animal, comprising an antigen and a delivery agent or agents comprising at least one derivatized amino acid or a salt thereof in an amount sufficient to induce oral tolerance.
  • the invention relates to pharmaceutical formulations for inducing oral tolerance, wherein the derivatized amino acid is administered at a dose of about 100-1000 mg per kg of the subject's body weight, preferably at a dose of about 250-750 mg per kg of body weight.
  • compositions are particularly advantageous for inducing oral tolerance to antigens which otherwise would require large and/or chronic dosing of antigen to induce such tolerance and which, by themselves, do not pass or are not taken up in the gastrointestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastrointestinal tract.
  • antigens include those associated with or responsible for the induction of auto-immune diseases, clinical (allergic) hypersensitivities, and allograft rejection, and subunits or extracts therefrom; or recombinantly generated whole proteins, subunits or fragments thereof; or any combination thereof.
  • Figure 1 provides formulas of preferred derivatized amino acids useful in the invention.
  • Figure 2 is a graphic representation of the titer of serum anti-sheep red blood cell (anti-SRBC) IgG antibodies (determined through the indirect IgG assay) and IgM antibodies (determined through the direct IgM assay) in mice fed SRBC with or without salicyloyl-phenylalanine (E94) derivatized amino acid delivery agent in accordance with Examples 1 and 2 and Comparative Examples A, B, C, and D.
  • anti-SRBC serum anti-sheep red blood cell
  • IgM antibodies determined through the direct IgM assay
  • Figure 3 is a graphic representation of the titer of anti-influenza antibodies (determined through the hemagglutination inhibition assay) present in pooled sera of mice pre-immunized with influenza antigen and fed influenza antigen with or without salicyloyl- phenylalanine (E94) derivatized amino acid delivery agent in accordance with Example 3 and Comparative Example E.
  • Figure 4 is a graphic representation of the titer of serum anti-HA (influenza) IgG antibodies following single-dose feeding of influenza vaccine A/Johannesburg/39/94 (H3N2) with or without N-salicyloyl-4-amino-phenyl butyric acid (E352) derivatized amino acid delivery agent in accordance with Example 4 and Comparative Example F.
  • H3N2 influenza vaccine A/Johannesburg/39/94
  • E352 N-salicyloyl-4-amino-phenyl butyric acid
  • Figure 5 is a graphic representation of the titer of serum anti-ovalbumin IgG antibodies at week 12 in mice fed two doses of ovalbumin at weeks 0 and 4 with or without salicyloyl-phenylalanine (E94) derivatized amino acid delivery agent and challenged intramuscularly at week 9 with ovalbumin and Complete Freund's Adjuvant (CFA) in accordance with Example 5 and Comparative Examples G and I.
  • E94 salicyloyl-phenylalanine
  • Figure 6 is a graphic representation of the titer of serum anti-ovalbumin IgG antibodies at week 4 in mice fed a single dose of ovalbumin with or without salicyloyl- phenylalanine (E94) derivatized amino acid delivery agent and challenged subcutaneously at week 1 with ovalbumin in CFA in accordance with Example 6 and Comparative Examples H and I.
  • E94 salicyloyl- phenylalanine
  • Figure 7 is a graphic representation of the titer of serum anti-sheep red blood cell (anti-SRBC) IgG antibodies (determined through the indirect IgG assay) on day 14 in mice fed SRBC with or without 3-[4-(N-2 methoxybenzoyl)] aminophenyl propionic acid (E594) derivatized amino acid delivery agent in accordance with Example 7 and Comparative Examples J and K.
  • anti-SRBC serum anti-sheep red blood cell
  • Figure 8 is a graphic representation of footpad thickness in a DTH assay at day 14 in mice fed a single dose of SRBC with or without 4-[4-(N-benzenesulfonyl)] aminophenyl butyric acid (El 98) and challenged in the footpad at day 7 in accordance with Examples 8 and 9 and Comparative Examples L and M.
  • Figure 9 is a graphic representation of footpad thickness in a DTH assay at week 5 in mice fed a single dose of ovalbulmin with or without 3-[4-(N-2,3- dimethoxybenzoyl)] aminophenyl propionic acid (E702) derivatized amino acid delivery agent and challenged subcutaneously at week 3 with ovalbumin in CFA in accordance with Example 10 and Comparative Examples N and O.
  • Figure 10 is a graphic representation of the Mean Clinical Score for the progression of EAE over time in Lewis rats fed a single dose of MPB with N-salicyloyl phenylalamne (E94) or 3-[4-(N-2,3-dimethoxybenzoyl)] aminophenyl propionic acid (E702) derivatized amino acid delivery agents; MBP alone in 1 dose; or MBP given in 5 doses in accordance with Example 11.
  • E94 N-salicyloyl phenylalamne
  • E702 3-[4-(N-2,3-dimethoxybenzoyl)] aminophenyl propionic acid
  • Figure 11 is a graphic representation of the Mean Clinical Score for the progression of EAE over time in Lewis rats fed a single dose of MPB with 4-[4-(N- saiicyloyl)] aminophenyl butyric acid (E352) derivatized amino acid delivery agent; MBP alone in 1 dose; or MBP given in 5 doses in accordance with Example 11.
  • Figure 12 is a graphic representation of the mean Maximal Score per group and the Mean Disease Index per group (defined as the highest mean score multiplied by the duration of symptoms) for Lewis rats dosed with a single dose of MBP and with 4-[4-(N- salicyloyl)]aminophenyl butyric acid (E352) derivatized amino acid delivery agent; MBP alone in 1 dose; or MBP given in 5 doses in accordance with Example 11.
  • the subscripts in the group labels refer to the number of paralyzed rats in each group, and the "% protection", i.e. the percent of animals that were not paralyzed.
  • the present invention uses readily available and inexpensive delivery agents to provide animals with oral tolerance to antigens.
  • Oral tolerance is characterized as a state of antigen-specific systemic immunological hypo-responsiveness induced by the feeding of an antigen.
  • Oral tolerance generally results from large or chronic doses of antigens.
  • the present invention is directed to methods and pharmaceutical formulations comprising an antigen and an derivatized amino acid or salt delivery agent useful to induce oral tolerance to the antigen when the antigen and delivery agent are fed simultaneously.
  • the delivery agents allow the administration of lower or fewer doses of antigen than are required to induce the same degree of systemic immune suppression with the antigen alone.
  • the delivery agents allow the administration of more consistent dosing concentration of antigen.
  • the immune responses involved include, but are not limited to, systemic antibody production and delayed-type hypersensitivity reactions.
  • the induction of oral tolerance may be applied clinically for the prevention or treatment of auto-immune diseases and clinical (allergic) hypersensitivities, and for the prevention of allograft rejection.
  • Antigens suitable for use in the present invention include, but are not limited to, synthetic or naturally derived proteins and peptides, and particularly those which by themselves require high doses to induce oral tolerance; carbohydrates including, but not limited to, polysaccharides; lipopolysaccharides; and antigens isolated from biological sources such as, for example, those associated with or responsible for the induction of auto- immune diseases, clinical (allergic) hypersensitivities, and allograft rejection and subunits or extracts therefrom; or any combination thereof.
  • self-antigens include: nucleic acid; oligodeoxynucleotide; thyroglobulin; thyroid cell surface or cytoplasm; parietal cell; adrenal cell; epidermal cell; uvea cell; basement membrane cell; red cell surface; platelet cell surface; muscle cell; thymus myeloid cell; mitochondria; secretory duct cell; deoxyribonucleic acid-protein; acetylcholine receptor substance; insulin; central nervous system antigens such as, myelin basic protein, proteolypid protein, and myelin oligodendrocyte glycoprotein; and other normal hormone and tissue factors.
  • Allergens include: benzylpenicilloyl, insulin, ovalbumin, lactalbumin, bermuda grass pollen, timothy grass pollen, orchard grass pollen, and combinations of grass pollen, ragweed pollen, ragweed antigen E, birch tree pollen, bee venom, snake venom, horse dander, cat epithelial, haddock, house dust mite, Chrysanthemum leucanthemum, Alternari tenuis, trypsin, chymotrypsin, dry rot, baker's yeast, tetanus toxoid, diphtheria toxin, ficin and derivatives thereof.
  • the delivery agents employed in the practice of the present invention are derivatized amino acids or salts thereof.
  • the derivatized amino acids include amino acid amides.
  • Amino acids which may be used to prepare the delivery agents employed in the methods and compositions of the invention include any carboxylic acid having at least one free amino group, including both naturally occurring and synthetic amino acids. Many amino acids and amino acid esters are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis; MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA). Methods useful for derivatization of the amino acids identified herein are disclosed in U.S. Serial No. 08/438,644, filed May 10, 1995; U.S. Serial No. 08/372,208, filed January 13, 1995; and PCT/US96/00871, filed January 16, 1996, published July 18, 1996 under International Publication Number WO96/21464
  • the preferred naturally occurring amino acids used for derivatization to produce the delivery agents used in the methods and compositions hereof in the present invention are alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalamne, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxyproline, ⁇ -carboxyglutamate, phenylglycine, or o-phosphoserine. It is particularly desirable to utilize arginine, leucine, lysine, phenylalamne, tyrosine, tryptophan, valine, or phenylglycine as substrates.
  • the prefe ⁇ ed non-naturally occurring amino acids which may be derivatized for use as delivery agents in the present invention are ⁇ -alanine, ⁇ -amino butyric acid, ⁇ - amino butyric acid, ⁇ -(aminophenyl) butyric acid, ⁇ -amino isobutyric acid, 6-aminocaproic acid, 7-amino heptanoic acid, ⁇ -aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, ⁇ -glutamic acid, cysteine (ACM), e-lysine, e-lysine, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, l,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid and thioproline.
  • prefe ⁇ ed derivatized amino acids to employ in the methods and formulations of the present invention are those of Formulas I and II above.
  • Particularly prefe ⁇ ed derivatized amino acids useful as delivery agents are those refe ⁇ ed to above and in Figure 1 as E352; E94; E198; E702; E597; E445; E579; E594; and E623.
  • Adjuvants which assist in inducing tolerance include lipopolysaccharides (LPS) and cholera toxin ⁇ -subunit.
  • Delivery of pharmaceutical formulations comprised of an antigen and a delivery agent (with or without an adjuvant), with the delivery agent or agents described herein are, preferably a derivatized amino acid of Formulas I and II administered in a dose of about 100-1,000 mg/kg of body weight, results in the induction of oral tolerance.
  • the derivatized amino acids or salts thereof may be used as delivery agents by simply mixing one or more derivatized amino acids or salts thereof with the antigen (with or without adjuvant) prior to oral administration.
  • the derivatized amino acids or salts thereof may be used to form microspheres or microcapsules containing the antigen (with or without adjuvant).
  • Microspheres containing antigen with or without adjuvant can generally be of the matrix form or the microcapsule form.
  • the matrix form includes both a hollow matrix sphere in which the delivery agent forms a matrix shell around a hollow center with the antigen (with or without adjuvant) distributed throughout the matrix and a solid matrix sphere in which the delivery agent forms a spherical matrix continuum in which the antigen (without or without adjuvant) is distributed.
  • the microcapsule form is one in which the encapsulated antigen (either with or without adjuvant) is either in solution or in solid form, with the delivery agent forming a shell around the encapsulated material.
  • the formulations of the present invention may also include one or more enzyme inhibitors.
  • enzyme inhibitors include, but are not limited to, compounds such as actinonin, aprotinin or epiactinonin and derivatives thereof. Derivatives of these compounds are disclosed in U.S. Patent No. 5,206,384 and are described in the above- identified U.S. Patent Applications Serial Nos. 08/438,644 and 08/372,208; and in PCT/US96/00871, International Publication Number WO96/21464.
  • the formulations of the present invention may be formulated into oral dosage units by the addition of one or more excipients, diluents, disintegrants, lubricants, plasticizers, colorants, or dosing vehicles.
  • Prefe ⁇ ed oral unit dosage forms include, but are not limited to, tablets, capsules, or liquids.
  • the oral unit dosage forms can include biologically effective amounts of the antigen (with or without a biologically effective amount of an adjuvant) but can include less than such amounts if multiple unit dosage forms are to be used to administer a total dosage of the antigen with or without adjuvant.
  • Oral unit dosage forms are prepared by methods conventional in the art.
  • the delivery agents of the present invention do not alter the physiological and biological properties of the antigen or the adjuvant. Furthermore encapsulation, if used, need not permanently alter the structure of the antigen.
  • the delivery agents of the invention are capable of promoting suppression of EAE through oral tolerance.
  • EAE is widely used as a model for human autoimmune inflammatory demyelinating diseases.
  • the derivatized amino acid delivery agents of the invention act by increasing the fraction of an administered dose of MBP that is absorbed across the GI epithelia. This is very significant, since tolerance is known to be a highly dose- dependent phenomenon. The presence of delivery agents may also lead to a decrease in the variability in responses that accompanies normal GI absorption.
  • the invention thus provides for modulation of immunogenic response, and thus clinical disease, by oral administration of autoantigens accomplished in the presence of delivery agents using smaller or fewer administered doses than are required with the antigen alone. It will be understood that the methods and compositions of the invention are not limited by the foregoing possible mode of action.
  • mice Five female BALB/c mice were fed a single dose suspension of 2.5 x 10 9 sheep red blood cells (SRBC) + E94 (600 mg/Kg) in Phosphate Buffered Saline (PBS), 0.1 M phosphate and 0.15 M sodium chloride, pH 7.2. Seven days after completion of oral dosing, mice were primed by footpad injection of 1 X 10 7 SRBC. They were bled on day 14. On day 21 the mice were tested in a Delayed Type Hypersensitivity (DTH) test through challenge by injection in the footpad not previously used in priming with 1 X 10 8 SRBC. Footpad thickness was measured before and 24 hours after challenge using a Vernier caliper.
  • DTH Delayed Type Hypersensitivity
  • IgM + IgG positive controls (Rabbit anti-SRBC IgM and Rabbit anti-SRBC IgG), 25 ⁇ each diluted 1/20 in PBS e) Serially 2x dilute the sera or controls (50 ⁇ ) across each row f) Add 50 ⁇ of 0.5% SRBC to each well g) Cover with pressure-sensitive adhesive plate sealer (COSTARTM)Shake briefly at low speed to mix h) Incubate overnight at room temperature, taking care not to disturb the plate at all i) Carefully examine for IgM hemagglutination patterns. A positive response appears as a uniform coating of cells adhering to the bottom of wells.
  • COSTARTM pressure-sensitive adhesive plate sealer
  • Indirect hemagglutination assay for non-agglutinating anti-SRBC serum IgG antibodies a) In a 15 ml tube, add 11 ⁇ of goat anti-mouse IgG (Fc y specific) (2.3 mg/ml) to 5.05 ml PBS (1/460 dilution; approximate amount needed per plate)
  • Example 2 Five female BALB/c mice were fed a single dose suspension of SRBC alone with no delivery agent precisely as described in Example 1. The mice were bled and assayed as described in Example 1. Assay data for Comparative Example A are found in Figure 2.
  • Example 2 Five female BALB/c mice were fed a suspension of SRBC alone with no delivery agent for five consecutive days as described in Example 2. The mice were bled and assayed as described in Example 1. Assay data for Comparative Example B are found in Figure 2.
  • Example 2 Five female BALB/c mice were fed a single oral dose of saline solution with no delivery agent as an unfed control. The mice were bled and assayed as described in Example 1. Assay data for Comparative Example D are found in Figure 2.
  • Figure 2 also shows that for IgG, on Day 28, the Example 1 (E94 + SRBCxl) group was lower than the Comparative Example D control (90% significance) while no other groups were significantly different from the Comparative Example D control.
  • Hemagglutination Inhibition Assay for Anti-HA Antibodies A. Hemagglutination assay to determine virus HA titer
  • This titer provides the dilution of virus suspension which contains one HA unit per 50 ⁇ l. Divide this titer by 8 to get the dilution which will contain 4 HA units per 0.025 ⁇ l for the actual Hemagglutination Inhibition (HI) assay. On the day of the HI assay, prepare just enough diluted virus for back-titration. If the back- titration assay is satisfactory, dilute enough virus for the HI assay of the sera samples.
  • HI Hemagglutination Inhibition
  • RDE* treat all test sera, reference sera and negative control sera on the day before the HI assay will be done.
  • Negative control (naive) serum all wells should show complete agglutination (i.e. no inhibition since there is no anti-HA antibody).
  • Positive control (reference) serum should see uniform inhibition in the dilution series up to the theoretical titer of the reference serum.
  • mice were pre-immunized with a lower dose of antigen than would be required to fully immunize them.
  • mice were administered a single oral dose of 15 ⁇ g of influenza antigen [influenza vaccine A/Johannesburg/39/94 (H3N2)] per mouse with 500 mg/kg of E352. Sera were collected every two weeks, pooled, and assayed for anti-hemagglutinin (HA) IgG. (See assay description below.) Assay data for Example 4 are found in Figure 4.
  • Example 4 Ten BALB/c mice were fed a single dose preparation of influenza antigen [influenza vaccine A/ Africa/39/94 (H3N2)] alone with no delivery agent as described in Example 4. The mice were bled and assayed as described in Example 4. Assay data for Comparative Example F are found in Figure 4.
  • a stock solution was prepared by dissolving Ovalbumin, 10 mg/ml, in 10 mM phosphate buffer (pH 7.4). This solution was diluted with buffer to provide 1.0 mg in a volume of 0.2 ml.
  • Ten BALB/c female mice were administered two oral doses of 1 mg ovalbumin per mouse with 600 mg/kg of E94 delivery agent at weeks 0 and 4.
  • mice Ten BALB/c female mice were fed two oral doses of 1 mg ovalbumin per mouse alone with no delivery agent at weeks 0 and 4 as described in Example 5. The mice were challenged, bled and assayed as described in Example 5. Assay data for Comparative Example G are found in Figure 5.
  • Figure 5 illustrates the anti-Ova IgG response in mice immunized orally with two doses of 1 mg Ovalbumin each with or without delivery agent E94, four weeks apart. They were then challenged intramuscularly with Ovalbumin in complete Freund's adjuvant. The response to the challenge with antigen alone (Comp. Ex. G) was the same as in mice given the intramuscular dose alone. However, following feeding in the presence of delivery agent (Ex. 5), the response was significantly suppressed compared to both unfed and antigen- alone fed (Comp. Ex. G) animals. This indicates induction of tolerance in the presence of delivery agent following feeding of a dose which is non-tolerizing in the absence of the delivery agent.
  • a stock solution of ovalbumin was prepared by dissolving Ovalbumin, 125 mg/ml, in 10 mM phosphate buffer (pH 7.4). This solution was used to provide 25 mg in a volume of 0.2 ml.
  • Five BALB/c mice were administered a single oral dose of 25 mg ovalbumin per mouse with 600 mg/kg of E94 delivery agent.
  • Challenge was achieved by subcutaneous (SC) injection of 0.1 mg ovalbumin with 50%) Complete Freund's Adjuvant (CFA) at week 1. Serum samples were collected at week 4 and assayed for anti-ovalbumin total IgG isotypes as described in Example 5. Assay data for Example 6 are found in Figure 6.
  • Example 6 Five BALB/c female mice were fed a single oral dose of 25 mg ovalbumin per mouse alone with no delivery agent as described in Example 6. The mice were challenged, bled and assayed as described in Example 6. Assay data for Comparative Example E are found in Figure 6.
  • mice Five BALB/c female mice were fed nothing for use as a control. The mice were challenged, bled and assayed as described in Example 5 for data described in Figure 5. The mice were challenged, bled and assayed as described in Example 6 for data described in Figure 6.
  • Figure 6 illustrates that animals fed 25 mg Ovalbumun with delivery agent E94 and then challenged subcutaneously one week later with Ovalbumin in complete Freund's adjuvant show significantly suppressed serum anti-Ova IgG titers than those which were not pre-fed. While mice fed antigen alone were also suppressed (Comp. Ex. H), this suppression was not statistically significant, while that induced in the presence of E94 (Ex. 6) was significant. Thus, E94 allowed a more consistent suppression of antibody induction than the antigen alone.
  • Example 7
  • mice Five female BALB/c mice were fed a single dose suspension of 2.5 x 10 9 sheep red blood cells (SRBC) + E594 (600 mg/Kg) in Phosphate Buffered Saline (PBS), 0.1 M phosphate and 0.15 M sodium chloride, pH 7.2. Seven days after completion of oral dosing, mice were primed by footpad injection of 1 X 10 7 SRBC. They were bled on day 14. Sera were placed into Eppendorf tubes and assayed for anti-SRBC IgG (day 14) by the indirect hemagglutination assays. (See assay description in Example 1 above.) Prior to assaying, the samples were heat inactivated at 56°C for 60 minutes. Assay data for Example 7 are found in Figure 7.
  • mice Five female BALB/c mice were fed a single dose suspension of 2.5 x 10 9 sheep red blood cells (SRBC) + E594 (600 mg/Kg) as described in Example 7. Seven days after completion of oral dosing, mice were primed by footpad injection of 1 X 10 7 SRBC. On day 14. Footpad thickness was measured according to the Delayed Type Hypersensitivity (DTH) method outlined in Example 1. The DTH data for Example 8 are found in Figure 8.
  • DTH Delayed Type Hypersensitivity
  • Example 8 Five female BALB/c mice were fed a single dose suspension of 2.5 x 10 9 sheep red blood cells (SRBC) + El 98 (600 mg/Kg) and tested for footpad thickness (DTH) as described in Example 8. The DTH data for Example 9 are found in Figure 8.
  • SRBC sheep red blood cells
  • El 98 600 mg/Kg
  • DTH footpad thickness
  • Example 8 Five female BALB/c mice were fed a single oral dose of saline solution with no delivery agent as an unfed control and tested for footpad thickness (DTH) as described in Example 8.
  • the DTH data for Comparative Example L are found in Figure 8.
  • Example 8 Five female BALB/c mice were fed a single dose suspension of SRBC alone with no delivery agent and tested for footpad thickness (DTH) as described in Example 8. The DTH data for Comparative Example M are found in Figure 8.
  • a stock solution of ovalbumin was prepared by dissolving Ovalbumin, 10 mg/ml in 10 mM phosphate buffer (pH 7.4). This solution was diluted 2-fold and used to provide 1.0 mg in a volume of 0.2 ml. Five BALB/c mice were administered a single oral dose of 1.0 mg ovalbumin per mouse with 600 mg/kg of E702 delivery agent.
  • mice Five BALB/c female mice were fed a single oral dose of saline with no delivery agent as an unfed control. The mice were challenged and assayed for DTH as described in Example 10. Assay data for Comparative Example O are found in Figure 9.
  • Figure 9 illustrates that animals fed 1.0 mg Ovalbumun with delivery agent E702 and then challenged subcutaneously 3 weeks later with Ovalbumin in complete Freund's adjuvant show significantly suppressed response in the DTH than those which were not pre-fed. Mice fed antigen alone at this dosage were not suppressed (Comparative Example N).
  • MBP Basic Protein
  • E94 E352 or E702.
  • MBP Basic Protein
  • E94 E352 or E702.
  • Clinical signs of disease were observed starting on Day 11 after the challenge and rated on a scale of 0 (no disease) to 5 (death). Data for Example 11 are provided in Figures 10, 11 and 12.
  • Figures 10 and 11 show the suppression of clinical disease by a single dose of MPB with E94 and E702 ( Figure 10) and E352 ( Figure 11).
  • the presence of delivery agents suppressed disease symptoms to a degree statistically identical to 5 doses of MBP alone, and significantly more than a single dose of MBP alone at the time points indicated.
  • the mean day of onset of paralysis (defined as a clinical disease score less than or equal to 1) was delayed from Day 13 after a single dose of MBP alone to Day 15 in the presence of E94 or E702 and Day 16 in the presence of E352.
  • Figure 12 shows the mean Maximal Score per group and the Mean Disease Index per group (defined as the highest mean score multiplied by the duration of symptoms) for rats dosed with a single dose of MBP and E352 vs. one or five doses of MBP alone. In both cases, the presence of E352 suppressed these disease parameters significantly compared with the dose of MBP alone, and was statistically identical to the five-dose MBP group.
  • the subscripts in the group labels refer to the number of paralyzed rats in each group, and the "% protection", i.e. the percent of animals that were not paralyzed.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0979080A1 (en) * 1997-01-02 2000-02-16 Thomas Jefferson University A method of modulating an immune response in an infected mammal by transmucosal administration of modulating agent
WO2000007979A2 (en) * 1998-08-07 2000-02-17 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO2000059538A2 (en) * 1999-04-08 2000-10-12 The John Hopkins University Antigen-specific induction of peripheral immune tolerance
WO2005077410A1 (en) 2004-02-06 2005-08-25 Greer Laboratories, Inc. Methods and compositions for dosing of allergens
US6960355B2 (en) 1996-03-29 2005-11-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO2005112937A1 (en) 2004-05-19 2005-12-01 Emisphere Technologies, Inc. Acyclovir formulations
US7005141B2 (en) 1993-04-22 2006-02-28 Emisphere Technologies Inc. Oral drug delivery compositions and methods
WO2006072070A2 (en) 2004-12-29 2006-07-06 Emisphere Technologies, Inc. Pharmaceutical formulations of gallium salts
US7151191B2 (en) 2000-01-13 2006-12-19 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US7351741B2 (en) 2000-06-29 2008-04-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO2011017346A2 (en) 2009-08-03 2011-02-10 Emisphere Technologies, Inc. Fast-acting naproxen composition with reduced gastrointestinal effects
US8110547B2 (en) 2005-01-12 2012-02-07 Emisphere Technologies, Inc. Compositions for buccal delivery of parathyroid hormone
US8927015B2 (en) 2006-04-12 2015-01-06 Emisphere Technologies, Inc. Formulations for delivering insulin
US8975227B2 (en) 2005-07-15 2015-03-10 Emisphere Technologies, Inc. Intraoral dosage forms of glucagon
US9364502B2 (en) 2006-06-28 2016-06-14 Emisphere Technologies, Inc. Gallium nitrate formulations
US9498487B2 (en) 2004-05-19 2016-11-22 Emisphere Technologies, Inc. Topical cromolyn formulations

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6221367B1 (en) * 1992-06-15 2001-04-24 Emisphere Technologies, Inc. Active agent transport systems
US6916489B2 (en) * 1992-06-15 2005-07-12 Emisphere Technologies, Inc. Active agent transport systems
US6001347A (en) * 1995-03-31 1999-12-14 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6991798B1 (en) 1998-08-07 2006-01-31 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
JP2005209106A (ja) * 2004-01-26 2005-08-04 Nec Corp 携帯通信端末、受信メール管理方法、プログラムおよび記録媒体
KR20070008720A (ko) * 2004-05-06 2007-01-17 에미스페어 테크놀로지스, 인코포레이티드 습윤 헤파린의 고체 투여형
KR101299707B1 (ko) 2004-05-14 2013-08-28 에미스페어 테크놀로지스, 인코포레이티드 활성제 전달용 화합물 및 조성물
US20060269576A1 (en) * 2005-05-27 2006-11-30 Curalogic, A/S Non-injection immunotherapy
WO2007133944A2 (en) 2006-05-09 2007-11-22 Emisphere Technologies, Inc. Topical administration of acyclovir
US8895777B2 (en) * 2006-08-31 2014-11-25 Emisphere Technologies Inc Compounds and compositions for delivering active agents
CA2663377A1 (en) 2006-09-18 2008-03-27 Raptor Pharmaceutical Inc. Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates
WO2010056143A1 (en) * 2008-11-13 2010-05-20 Instituto De Medicina Molecular The use of adjuvant to facilitate the induction of immune tolerance
US20120077778A1 (en) 2010-09-29 2012-03-29 Andrea Bourdelais Ladder-Frame Polyether Conjugates
BR112014027983B1 (pt) 2012-05-08 2022-05-24 Aeromics, Inc Uso de inibidores de aquaporina seletivos
ES2834131T3 (es) 2013-11-06 2021-06-16 Aeromics Inc Nuevas sales de profármacos

Family Cites Families (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4061466A (en) 1974-10-16 1977-12-06 Ingvar Gosta Holger Sjoholm Biologically active composition and the use thereof
DE2517229A1 (de) 1975-04-18 1976-10-28 Boehringer Mannheim Gmbh Phenylalkylcarbonsaeure-derivate und verfahren zu ihrer herstellung
CA1077842A (en) 1975-10-09 1980-05-20 Minnesota Mining And Manufacturing Company Albumin medicament carrier system
FR2374910A1 (fr) 1976-10-23 1978-07-21 Choay Sa Preparation a base d'heparine, comprenant des liposomes, procede pour l'obtenir et medicaments contenant de telles preparations
NZ196349A (en) 1980-03-07 1984-08-24 Interx Research Corp Enhancement of absorption rate of orally administered polar bioactive agents
US4442090A (en) 1980-11-09 1984-04-10 Kyoto Yakuhin Kogyo Kabushiki Kaisha Absorption-promoting compounds, compositions thereof with pharmaceuticals and/or bases for rectal administration and method of use
US4900730A (en) 1981-01-14 1990-02-13 Toyo Jozo Co., Ltd. Preparation which promotes the absorption of peptides
FR2509175B1 (fr) 1981-03-06 1987-01-16 Toyo Jozo Kk Preparation therapeutique ayant d'excellentes proprietes d'absorption
JPS58140026A (ja) 1982-01-14 1983-08-19 Toyo Jozo Co Ltd 吸収性良好な製剤
US4886663A (en) 1983-01-03 1989-12-12 Scripps Clinic And Research Foundation Synthetic heat-stable enterotoxin polypeptide of Escherichia coli and multimers thereof
DE3331009A1 (de) 1983-08-27 1985-03-14 Basf Ag, 6700 Ludwigshafen Verfahren zur erhoehung der enteralen resorbierbarkeit von heparin bzw. heparinoiden sowie das so erhaeltliche heparin- bzw. heparinoidpraeparat
US4692433A (en) 1983-10-12 1987-09-08 The Regents Of The University Of California Method and composition for regulating serum calcium levels of mammals
US4703042A (en) 1984-05-21 1987-10-27 Bodor Nicholas S Orally active heparin salts containing multivalent cationic units
US4757066A (en) 1984-10-15 1988-07-12 Sankyo Company Limited Composition containing a penem or carbapenem antibiotic and the use of the same
US4689182A (en) 1985-12-20 1987-08-25 Warner-Lambert Company Benzoic acid and benzoic acid ester derivatives having anti-inflammatory and analgesic activity
USRE35862E (en) 1986-08-18 1998-07-28 Emisphere Technologies, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
AU610083B2 (en) 1986-08-18 1991-05-16 Clinical Technologies Associates, Inc. Delivery systems for pharmacological agents
GB8705477D0 (en) 1987-03-09 1987-04-15 Carlton Med Prod Drug delivery systems
US4895725A (en) 1987-08-24 1990-01-23 Clinical Technologies Associates, Inc. Microencapsulation of fish oil
US4983402A (en) 1989-02-24 1991-01-08 Clinical Technologies Associates, Inc. Orally administerable ANF
US4976968A (en) 1989-02-24 1990-12-11 Clinical Technologies Associates, Inc. Anhydrous delivery systems for pharmacological agents
US5122367A (en) 1989-03-31 1992-06-16 Massachusetts Institute Of Technology Polyanhydride bioerodible controlled release implants for administration of stabilized growth hormone
US5271961A (en) 1989-11-06 1993-12-21 Alkermes Controlled Therapeutics, Inc. Method for producing protein microspheres
US5541155A (en) 1994-04-22 1996-07-30 Emisphere Technologies, Inc. Acids and acid salts and their use in delivery systems
US5629020A (en) 1994-04-22 1997-05-13 Emisphere Technologies, Inc. Modified amino acids for drug delivery
US5451410A (en) 1993-04-22 1995-09-19 Emisphere Technologies, Inc. Modified amino acids for encapsulating active agents
US5714167A (en) 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5578323A (en) 1992-06-15 1996-11-26 Emisphere Technologies, Inc. Proteinoid carriers and methods for preparation and use thereof
US5447728A (en) 1992-06-15 1995-09-05 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5443841A (en) 1992-06-15 1995-08-22 Emisphere Technologies, Inc. Proteinoid microspheres and methods for preparation and use thereof
US6099856A (en) 1992-06-15 2000-08-08 Emisphere Technologies, Inc. Active agent transport systems
US5693338A (en) 1994-09-29 1997-12-02 Emisphere Technologies, Inc. Diketopiperazine-based delivery systems
WO1992019263A1 (en) 1991-04-24 1992-11-12 The United States Of America, As Represented By The Secretary Of The Army Oral-intestinal vaccines against diseases caused by enteropathogenic organisms using antigens encapsulated within biodegradable-biocompatible microspheres
CA2070061C (en) 1991-06-07 2004-02-10 Shigeyuki Takama Physiologically active polypeptide-containing pharmaceutical composition
ZA93929B (en) 1992-02-18 1993-09-10 Akzo Nv A process for the preparation of biologically active materialcontaining polymeric microcapsules.
US5352461A (en) 1992-03-11 1994-10-04 Pharmaceutical Discovery Corporation Self assembling diketopiperazine drug delivery system
US5792451A (en) 1994-03-02 1998-08-11 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5811127A (en) 1992-06-15 1998-09-22 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5401516A (en) 1992-12-21 1995-03-28 Emisphere Technologies, Inc. Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof
US5643957A (en) 1993-04-22 1997-07-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
AU6819294A (en) 1993-04-22 1994-11-08 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5709861A (en) 1993-04-22 1998-01-20 Emisphere Technologies, Inc. Compositions for the delivery of antigens
US5958457A (en) * 1993-04-22 1999-09-28 Emisphere Technologies, Inc. Compositions for the delivery of antigens
AU4657096A (en) * 1995-01-10 1996-07-31 Academy Of Finland Collagen-based methods and formulations for the treatment of immune system-mediated diseases
CN1151836C (zh) 1995-03-31 2004-06-02 艾米斯菲尔技术有限公司 用作传送活性剂的化合物和组合物
US6090958A (en) 1995-03-31 2000-07-18 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5650386A (en) 1995-03-31 1997-07-22 Emisphere Technologies, Inc. Compositions for oral delivery of active agents
US6001347A (en) 1995-03-31 1999-12-14 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5989539A (en) 1995-03-31 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5965121A (en) 1995-03-31 1999-10-12 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5866536A (en) 1995-03-31 1999-02-02 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5820881A (en) 1995-04-28 1998-10-13 Emisphere Technologies, Inc. Microspheres of diamide-dicarboxylic acids
US6051258A (en) 1995-06-07 2000-04-18 Emisphere Technologies, Inc. Proteinoid emulsions and methods for preparation and use thereof
US5750147A (en) 1995-06-07 1998-05-12 Emisphere Technologies, Inc. Method of solubilizing and encapsulating itraconazole
US5667806A (en) 1995-06-07 1997-09-16 Emisphere Technologies, Inc. Spray drying method and apparatus
US5824345A (en) 1995-06-07 1998-10-20 Emisphere Technologies, Inc. Fragrances and flavorants
WO1997010197A1 (en) 1995-09-11 1997-03-20 Emisphere Technologies, Inc. METHOD FOR PREPARING φ-AMINOALKANOIC ACID DERIVATIVES FROM CYCLOALKANONES
US5773647A (en) 1997-02-07 1998-06-30 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5776888A (en) 1997-02-07 1998-07-07 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5876710A (en) 1997-02-07 1999-03-02 Emisphere Technologies Inc. Compounds and compositions for delivering active agents
US5879681A (en) 1997-02-07 1999-03-09 Emisphere Technolgies Inc. Compounds and compositions for delivering active agents
US6060513A (en) 1997-02-07 2000-05-09 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5990166A (en) 1997-02-07 1999-11-23 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5939381A (en) 1997-02-07 1999-08-17 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US6051561A (en) 1997-02-07 2000-04-18 Emisphere Technologies Inc. Compounds and compositions for delivering active agents
US5804688A (en) 1997-02-07 1998-09-08 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5863944A (en) 1997-04-30 1999-01-26 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US5962710A (en) 1997-05-09 1999-10-05 Emisphere Technologies, Inc. Method of preparing salicyloylamino acids

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE ON HCAPLUS ON STN, Cancer Research Campaign Technology Ltd., UK, Document No. 111:146800, BAGSHAWE et al., "Targeted Delivery of Antineoplastic Prodrugs Using an Antibody-Enzyme Conjugate"; & WO,A,88 07378, 06 October 1988. *
DATABASE ON HCAPLUS ON STN, Emisphere Technologies, Inc., Document No. 125:96071, LEONE-BAY et al., "Modified Amino Acids as Absorption Enhancers for Delivering Active Agents"; & WO,A,96 12437, 02 May 1996. *
See also references of EP0886471A4 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7005141B2 (en) 1993-04-22 2006-02-28 Emisphere Technologies Inc. Oral drug delivery compositions and methods
US6960355B2 (en) 1996-03-29 2005-11-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
EP0979080A4 (en) * 1997-01-02 2005-06-01 Univ Jefferson METHOD FOR MODULATING THE IMMUNE REACTION IN AN INFECTIVE MAMMALIAN BY THE TRANSMUCOSAL ENTERING A MODULATING AGENT
EP0979080A1 (en) * 1997-01-02 2000-02-16 Thomas Jefferson University A method of modulating an immune response in an infected mammal by transmucosal administration of modulating agent
CN1313439C (zh) * 1998-08-07 2007-05-02 艾米斯菲尔技术有限公司 用于送递活性剂的化合物和组合物
WO2000007979A2 (en) * 1998-08-07 2000-02-17 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
WO2000007979A3 (en) * 1998-08-07 2000-05-18 Emisphere Tech Inc Compounds and compositions for delivering active agents
CZ302280B6 (cs) * 1998-08-07 2011-01-26 Emisphere Technologies, Inc. Slouceniny a prostredky pro dodávání aktivních látek
WO2000059538A2 (en) * 1999-04-08 2000-10-12 The John Hopkins University Antigen-specific induction of peripheral immune tolerance
WO2000059538A3 (en) * 1999-04-08 2001-03-22 Univ Johns Hopkins Antigen-specific induction of peripheral immune tolerance
US7977506B2 (en) 2000-01-13 2011-07-12 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US7151191B2 (en) 2000-01-13 2006-12-19 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US7351741B2 (en) 2000-06-29 2008-04-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
US8491909B2 (en) 2004-02-06 2013-07-23 Greer Laboratories, Inc. Methods and compositions for dosing of allergens
EP1718331A4 (en) * 2004-02-06 2009-11-11 Greer Lab Inc METHOD AND COMPOSITIONS FOR DOSING ALLERGENS
WO2005077410A1 (en) 2004-02-06 2005-08-25 Greer Laboratories, Inc. Methods and compositions for dosing of allergens
EP1718331A1 (en) * 2004-02-06 2006-11-08 Greer Laboratories, Inc. Methods and compositions for dosing of allergens
US9345761B2 (en) 2004-02-06 2016-05-24 Greer Laboratories, Inc. Methods and compositions for dosing of allergens
WO2005112937A1 (en) 2004-05-19 2005-12-01 Emisphere Technologies, Inc. Acyclovir formulations
US9498487B2 (en) 2004-05-19 2016-11-22 Emisphere Technologies, Inc. Topical cromolyn formulations
WO2006072070A2 (en) 2004-12-29 2006-07-06 Emisphere Technologies, Inc. Pharmaceutical formulations of gallium salts
US8110547B2 (en) 2005-01-12 2012-02-07 Emisphere Technologies, Inc. Compositions for buccal delivery of parathyroid hormone
US8975227B2 (en) 2005-07-15 2015-03-10 Emisphere Technologies, Inc. Intraoral dosage forms of glucagon
US8927015B2 (en) 2006-04-12 2015-01-06 Emisphere Technologies, Inc. Formulations for delivering insulin
US9364502B2 (en) 2006-06-28 2016-06-14 Emisphere Technologies, Inc. Gallium nitrate formulations
WO2011017346A2 (en) 2009-08-03 2011-02-10 Emisphere Technologies, Inc. Fast-acting naproxen composition with reduced gastrointestinal effects

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