US20140086849A1 - Naturally-Occurring CpG Oligonucleotide Compositions and Therapeutic Applications Thereof - Google Patents

Naturally-Occurring CpG Oligonucleotide Compositions and Therapeutic Applications Thereof Download PDF

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US20140086849A1
US20140086849A1 US14/034,044 US201314034044A US2014086849A1 US 20140086849 A1 US20140086849 A1 US 20140086849A1 US 201314034044 A US201314034044 A US 201314034044A US 2014086849 A1 US2014086849 A1 US 2014086849A1
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lactobacillus
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therapeutic agent
tlr
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Elizabeth McKenna
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LABYRINTH HOLDINGS LLC
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Assigned to LABYRINTH HOLDINGS, LLC reassignment LABYRINTH HOLDINGS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MCKENNA, ELIZABETH
Publication of US20140086849A1 publication Critical patent/US20140086849A1/en
Priority to US14/640,075 priority patent/US9931398B2/en
Priority to US15/348,005 priority patent/US20170232047A1/en
Priority to US15/703,607 priority patent/US20180064767A1/en
Priority to US15/703,611 priority patent/US20180064769A1/en
Priority to US15/703,608 priority patent/US20180064768A1/en
Priority to US15/862,209 priority patent/US10688177B2/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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/522—Bacterial cells; Fungal cells; Protozoal cells avirulent or attenuated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/17—Immunomodulatory nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2330/00—Production
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2330/00—Production
    • C12N2330/10—Production naturally occurring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the inventions disclosed and taught herein relate generally to combinations and methods of treating disorders in mammals, particularly humans.
  • this invention provides combination therapies and treatment regimens for the treatment of hepatic disorders and human immunodeficiency virus (HIV) using a naturally-occurring immunostimulatory oligodeoxynucleotide and a cell-wall fraction of a gram positive bacteria.
  • HIV human immunodeficiency virus
  • An alternative approach to treating such disorders is to target the immune system of the subject (“immunotherapy”), rather than, or in addition to, targeting the virus itself.
  • immunotherapy is to provide improved efficacy by enhancing the patient's own immune response to tumors while minimizing deleterious effects to normal, healthy cells.
  • Bacterial DNA has immune stimulatory effects to activate B cells and natural killer cells [Tokunaga, T., et al., 1988. Jpn. J. Cancer Res. 79:682-686; Tokunaga, T., et al., 1984, JNCI 72:955-962; Messina, J. P., et al., 1991, J. Immunol. 147:1759-1764, and reviewed in Krieg, 1998, In: Applied Oligonucleotide Technology , C. A. Stein and A. M. Krieg, (Eds.), John Wiley and Sons, Inc., New York, N.Y., pp. 431-448].
  • CpG motifs unmethylated CpG dinucleotides in particular base contexts (CpG motifs), which are common in bacterial DNA, but methylated and underrepresented in vertebrate DNA [Krieg et al, Nature, Vol. 374, pp. 546-549 (1995); Krieg, Biochim. Biophys. Acta, 93321:1-10 (1999)].
  • ODN synthetic oligodeoxynucleotides
  • CpG ODNs have been shown to have high stimulatory effects on a number of mammalian biological functions, inducing B cell proliferation, cytokine and immunoglobulin secretion, natural killer (NK) cell lytic activity, IFN- ⁇ secretion, and activation of dendritic cells (DCs) and other antigen presenting cells to express costimulatory molecules and secrete cytokines, especially the Th1-like cytokines that are important in promoting the development of Th1-like T cell responses.
  • DCs dendritic cells
  • the immune stimulatory effects of native phosphodiester backbone CpG ODN are highly CpG specific in that the effects are dramatically reduced if the CpG motif is methylated, changed to a GpC, or otherwise eliminated or altered [see, Krieg, et al, Nature, Vol. 374, pp. 546-549 (1995); Hartmann, et al, 1999 Proc. Natl. Acad. Sci. USA, Vol. 96, pp. 9305-9310 (1999)].
  • GpG ODN is potent for activating B cells but is relatively weak in inducing IFN-alpha and NK cell activation; this class has been termed the B class.
  • the B class CpG oligonucleotides typically are fully stabilized and include an unmethylated CpG dinucleotide within certain preferred base contexts. See, e.g., U.S. Pat. Nos. 6,194,388; 6,214,806; 6,239,116; and 6,339,068.
  • CpG-containing oligodeoxynucleotides CpG ODN
  • TLR toll-like receptor
  • inventions disclosed and taught herein are directed to therapies and treatment regimens for the treatment of hepatic disorders, cancer, lyme disease, and/or human immunodeficiency virus (HIV), as well as compositions for such methods of treatment using a naturally-occurring immunostimulatory oligodeoxynucleotide and a cell-wall fraction of a gram positive bacteria.
  • HIV human immunodeficiency virus
  • a method of treating or preventing one or more disorders in a patient in need of such treatment comprises (a) a therapeutic regimen comprising administering to the patient, simultaneously, semi-simultaneously, separately or sequentially a therapeutically effective amount of one or more naturally-occurring CpG OGNs in combination with a therapeutically effective amount of one or more gram-positive bacterial lysates; and, optionally (b) administering to the patient a maintenance regimen comprising a maintenance dose of a CpG OGN, a gram-positive bacterial lysate, or a combination thereof.
  • the CpG ODN is a naturally occurring CpG ODN, which in accordance with certain aspects of the disclosure, comes from the gram-positive bacterial lysate.
  • the therapeutic regimen may further include a therapeutically effective amount of a synthetic CpG ODN, or a CpG ODN from a source separate from the bacterial lysate.
  • compositions for use in treating or preventing one or more disorders in a patient in need of such treatment comprising a therapeutically effective amount of a bacterial cell-wall lysate or fraction, and a therapeutically effective amount of a naturally-occurring CpG ODN.
  • compositions for delivery of a therapeutic agent across the mucosa of a subject for the treatment of a hepatic disorder in the subject comprising (a) a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and (b) a naturally-occurring immunostimulatory oligodeoxynucleotide (ODN); wherein the cell wall lysate and the ODN are present in an amount effective to treat an immune disorder.
  • the composition is a dietary supplement.
  • compositions for the treatment of complications of a hepatic disorder in a subject suffering from one or more hepatic disorders comprising a therapeutically effective amount of a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and at least one Toll Like receptor (TLR) 9 agonist, the gram-positive bacteria being selected from the Lactobacillus family of bacteria.
  • TLR 9 agonist is a CpG oligodeoxynucleotide (CpG ODN).
  • the CpG ODN is naturally-occurring within the bacterial lysate.
  • methods of inducing an immune response to a tumor in a subject comprising selecting a subject with a tumor; and administering to the subject a therapeutically effective amount of a composition comprising (a) a lysate or cell wall extract derived from or isolated from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof; and (b) a naturally-occurring CpG oligodeoxynucleotide (ODN), thereby inducing the immune response to the tumor in the subject.
  • the naturally-occurring CpG oligodeoxynucleotide is derived from a bacterial lysate.
  • FIG. 1 illustrates an exemplary, generic structure of a CpG ODN suitable for use in accordance with the present disclosure.
  • FIG. 2 illustrates various CpG motifs and their effects on the innate and adaptive immune systems.
  • FIG. 3 illustrates a graph of exemplary stimulatory effects of a composition of the present invention on select TLR/NLR cell lines; the values in the graph correspond to an average of screenings 1-3.
  • FIG. 4 illustrates a graph of stimulatory effects of control and sample compositions of the present invention against NF- ⁇ B control cells; the values in the graph correspond to an average of screenings 1-3.
  • FIG. 5 illustrates the results of the Human TLR/NLR Ligand screening.
  • FIG. 6 illustrates the results of the NF- ⁇ B Control Cell screening.
  • CpG motif means a nucleotide sequence which contains unmethylated cytosine-guanine dinucleotides (that is, a cytosine (C) followed by a guanine (G)) linked by a phosphate bond, or a phosphodiester backbone. These motifs are also referred to equivalently as “unmethylated cytosine-phosphate-guanine dinucleotide”) and activates a biological response, such as an immune response.
  • CpG oligodeoxynucleotide means an oligodeoxynucleotide (ODN) comprising at least two of the above CpG motifs.
  • ODN oligodeoxynucleotide
  • Such CpG ODN's may be class-A (Type D), class-B (Type K), class-C, class P, or class S, as appropriate.
  • CpG oligonucleotides have recently been described.
  • One class contains poly G motifs at one or both ends, and has been termed the A-class.
  • One class is potent for activating B cells but is relatively weak in inducing IFN- ⁇ and NK cell activation; this class has been termed the B class.
  • the B class CpG oligonucleotides are typically fully stabilized and include an unmethylated CpG dinucleotide within certain preferred base contexts. See, e.g., U.S. Pat. Nos. 6,194,388; 6,207,646; 6,214,806; 6,218,371; 6,239,116; and 6,339,068.
  • CpG oligonucleotides activates B cells and NK cells and induces IFN- ⁇ ; this class has been termed the C-class.
  • the C-class CpG oligonucleotides as first characterized, are typically fully stabilized; they include a B class-type sequence and a GC-rich palindrome or near-palindrome. This class has been described in International Patent Publication Number WO 03/015711.
  • the A-Class oligonucleotides can form very complex higher ordered structures such as nanoparticles [Kerkmann, et al., J. Biol. Chem. 280(9):8086-93 (2005)], and the C-Class may form intermolecular duplexes or hairpins.
  • FIG. 2 illustrates various CpG motifs and their effects on the innate and adaptive immune systems.
  • composition refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefore.
  • phrases “pharmaceutically acceptable carrier, diluent or excipient” as used herein includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • an effective amount is meant an amount that when administered to a mammal, preferably a human, mediates a detectable therapeutic response compared to the response detected in the absence of the compound.
  • a therapeutic response such as, but not limited to, increased overall survival, inhibition of and/or decreased tumor growth (including tumor size stasis), tumor size, metastasis, and the like, can be readily assessed by a plethora of art-recognized methods, including, e.g., such methods as disclosed herein.
  • the effective amount of the CpG ODN, compound or composition administered herein varies and can be readily determined based on a number of factors such as the disease or condition being treated, the stage of the disease, the age and health and physical condition of the mammal being treated, the severity of the disease, the particular CpG ODN compound being administered, and the like.
  • the dose administered to an animal should be sufficient to prevent the targeted disease or disorder, e.g., cancer, delay its onset, slow its progression, or treat the disease or disorder (e.g., reverse or negate the condition).
  • dosage will depend upon a variety of factors including the strength of the particular composition employed, as well as the age, species, condition, and body weight of the animal.
  • the size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular composition and the desired physiological effect.
  • Bioactive agent refers to any amino acid, peptide, protein, or antibody (including chimeric, monoclonal, isolated, or humanized antibodies), natural or synthetic, which exhibits a therapeutically useful effect.
  • biologically active agents may include recombinant proteins, enzymes, peptoids, or PNAs, as well as combinations of such agents.
  • phrases “pharmaceutically acceptable” or “pharmacologically-acceptable” refers to compositions that do not produce an allergic or similar unexpected reaction when administered to a human or animal in a medical or veterinary setting.
  • to “prevent” means inhibiting the onset or development of symptoms of a disease (i.e., tumor growth and/or metastasis, or other effect mediated by the numbers and/or activity of immune cells, and the like) experienced by a patient.
  • the term includes the administration of the CpG ODN, compounds or agents of the present invention to inhibit or delay the onset of the symptoms, complications, or biochemical indicia of a disease (e.g., elevation of PSA level in prostate cancer).
  • ligand as used herein means a molecular group that is associated with a central metal atom.
  • bidentate or didentate
  • tridentate tetradentate
  • multidentate are used to indicate the number of potential binding sites of the ligand.
  • a carboxylic acid can be a bidentate or other multidentate ligand because it has at least two binding sites, the carboxyloxygen and hydroxyloxygen.
  • an amide has at least two binding sites, the carboxyloxygen and the nitrogen atom.
  • An amino sugar can have at least two binding sites and many amino sugars will have multiple binding sites including the amino nitrogen, a hydroxyloxygen, an ethereal oxygen, an aldehyde carbonyl, and/or a ketone carbonyl.
  • amino sugar refers to monosaccharides having one alcoholic hydroxyl group (commonly but not necessarily in the ‘2-position’) replaced by an amino group, systematically known as x-deoxy-x-monosaccharides.
  • D-glucosamine or 2-amino-2-deoxy-D-glucopyranose is an amino sugar.
  • amino sugars include but are not limited to erythrosamine, threosamine, ribosamine, arabinosamine, xylosamine, lyxosamine, allosamine, altrosamine, glucosamine, mannosamine, idosamine, galactosamine, talosamine, and their derivatives, all of which are suitable for use within the compositions of the present disclosure.
  • the amino sugars include both aldose and ketose sugars.
  • the amino sugars may be of a straight-chain structure; however, the aldehyde or ketone group of the amino sugar may react with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, in which case there is an oxygen bridge between the two carbon atoms, forming a heterocyclic ring.
  • Amino sugar rings with five and six atoms are called furanose and pyranose forms, respectively and exist in equilibrium with their corresponding straight-chain form. It should be noted that the ring form has one more optically active carbon than the straight-chain form, and so has both an ⁇ - and a ⁇ -form, which interconvert in equilibrium.
  • amino sugar also means glycosylamines, amino sugars where the nitrogen is substituted with a functional group other than H.
  • glycosylamines include N-acetylglucosamine (NAG) and N-methylglucosamine.
  • glycosaminoglycans as used herein means any of any of a group of polysaccharides that contain amino sugars. Glycosaminoglycans can also form complexes with proteins.
  • hydrate or “n-hydrate” as used herein means a molecular entity with some degree of hydration, where n is an integer representing the number of waters of hydration, e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, septahydrate, octahydrate, nonahydrate, etc.
  • compositions of the present invention may be prepared for pharmaceutical administration by methods and with excipients generally known in the art, such as described in Remington's Pharmaceutical Sciences [Troy, David B., Ed.; Lippincott, Williams and Wilkins; 21st Edition, (2005)].
  • Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest, e.g., tissue injury, in a mammal, preferably a human, having the disease or condition of interest, as well as prophylactic, or suppressive measures for the disease or disorder and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition.
  • the disease or condition of interest e.g., tissue injury
  • a mammal preferably a human
  • prophylactic, or suppressive measures for the disease or disorder covers the treatment of the disease or condition of interest, e.g., tissue injury, in a mammal, preferably a human
  • treatment includes the administration of an agent prior to or following the onset of a disease or disorder, thereby preventing or removing all signs of the disease or disorder.
  • administration of the agent after clinical manifestation of the disease to combat the symptoms of the disease comprises “treatment” of the disease.
  • administration of the agent after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amelioration of the disease, comprises “treatment” of the disease.
  • the phrase “in need of treatment” includes mammals, such as humans, or animals, already having the disease or disorder, including those in which the disease or disorder is to be prevented.
  • the terms “disease,” “disorder,” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • agent As used herein, the expressions “agent”, “composition”, and “antagonist” are used interchangeably within the scope of the present disclosure, and are meant to include any molecule or substance which results in a therapeutic effect when administered to a subject suffering from a lymphatic disorder.
  • iatrogenic disorder refers to those disorders induced by exposure to a therapeutic compound intended to treat some other disorder.
  • drug induced liver diseases or disorders include, for example, chronic active hepatitis associated with the administration of Amineptine, Clometacine, Dantrolene, Diclofenac, and Fenofibrate to name a few; chronic cholestasis associated with the administration of Aceprometazine, Ajmaline and related drugs, Amitryptyline, and Ampicillin to name but a few; or hepatic granulomas associated with the administration of Allopurinal, Aspirin, and Diazepam.
  • water-insoluble encompasses the terms sparingly water-soluble, slightly or very slightly water-soluble, as well as practically or totally water-insoluble compounds [see, Remington: The Science and Practice of Pharmacy , vol. I, 194-195 (Gennaro, Ed., 1995)].
  • a compound is water-insoluble for the purposes of this invention if it requires at least 30 parts solvent (e.g., water or saline) to dissolve one part solute (Id.).
  • solvent e.g., water or saline
  • water-insoluble also encompasses oil- or lipid-soluble, as well as substantially oil- or lipid soluble.
  • % when used without qualification (as with w/v, v/v, or w/w) means % weight-in-volume for solutions of solids in liquids (w/v), % weight-in-volume for solutions of gases in liquids (w/v), % volume-in-volume for solutions of liquids in liquids (v/v) and weight-in-weight for mixtures of solids and semisolids (w/w), such as described in Remington's Pharmaceutical Sciences [Troy, David B., Ed.; Lippincott, Williams and Wilkins; 21st Edition, (2005)].
  • patient and “subject”, as used herein, are used interchangeably and refer generally to a mammal, and more particularly to human, ape, monkey, rat, pig, dog, rabbit, cat, cow, horse, mouse, sheep and goat.
  • lung surfaces or membranes described and referenced in accordance with this disclosure refer to those of a mammal, preferably a human or an animal test subject.
  • enhancing” and/or “providing relief” with respect to the therapeutic compositions disclosed means that the administration of the referenced composition to a subject provides an immediate and/or extended alleviation, amelioration, inhibition, or mitigation of one or more symptoms of a hepatitis disorder to the subject mammal.
  • drug as used in conjunction with the present disclosure means any compound which is biologically active, e.g., exhibits or is capable of exhibiting a therapeutic or prophylactic effect in vivo, or a biological effect in vitro.
  • dietary supplement refers to a compound or composition of either natural or synthetic origin which comprises a dietary or nutritional substance for use by people to supplement the diet by increasing the total dietary intake.
  • a dietary supplement may be a dietary supplement as defined under the Dietary Supplement Health and Education Act of 1994 (DSHEA), or the equivalent.
  • the DSHEA requires that the dietary supplement is as a product that is intended to supplement the diet and contains at least one of the following: a vitamin, a mineral, an herb or other botanical (excluding tobacco), an amino acid, a dietary substance for use by people to supplement the diet by increasing the total dietary intake, or a concentrate, metabolite, constituent, extract, or combination of any of the above.
  • DSHEA requires that the dietary supplement must also be intended for ingestion in pill, capsule, tablet, powder, liquid or other suitable oral form, not be represented for use as a conventional food or as the sole item of a meal or diet, and must be labeled as a “dietary supplement.”
  • oral mucosa refers to the mucous matrix that covers all structures inside the oral cavity except the teeth.
  • the oral mucosa generally varies in color from pink to brownish purple depending on an individual's skin color.
  • the structure of the oral mucosa varies depending on its location in the oral cavity and the function of that area.
  • the mucosa lining the cheeks is not designed to withstand the heavy force of mastication while the masticatory mucosa covering the jaws is structured to withstand the forces of mastication.
  • a specialized mucosa that includes taste buds covers the tongue.
  • Example of oral mucosa tissue include, but are not limited to, palate tissue, gingiva tissue, buccal mucosa tissue, tongue tissue, and floor of the mouth tissue.
  • controlled drug-delivery system refers to a formulation that controls the rate and period of therapeutic agent/drug delivery (i.e., time-release dosage), targets specific areas of the subjects body, and are designed to maintain therapeutic levels during the desired treatment period, such as described by M. Vallet-Reg ⁇ [ Chem. Eur. J ., Vol. 12, pp. 5934-5943 (2006)].
  • bioavailability refers to the rate and/or extent to which a drug is absorbed or becomes available to the treatment site in the body.
  • administering refers to administration of the compositions of the present invention to the mucous membranes of the oral cavity (i.e., oral mucosa).
  • suitable sites of administration within the oral mucosa include, without limitation, the mucous membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), the gums (gingival mucosa), the roof of the mouth (palatal mucosa), the lining of the lips, and combinations thereof.
  • the compositions of the present invention are administered to the sublingual mucosa, buccal mucosa, or a combination thereof.
  • variants refers to microorganisms which essentially have the same properties and functions as the original microorganisms. Such variants can be formed arbitrarily, for example, by UV irradiation, or other mutagenesis techniques known to a person skilled in the art, as well as taxonomical name changes, such as a change in the Bifidobacteria genus.
  • the phrase “combination therapy” embraces the administration of a naturally-occurring immunostimulatory ODN, e.g., CpG ODN, and a chemotherapeutic agent as part of a specific treatment regimen optionally including a maintenance phase, intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • “Combination therapy” embraces administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent e.g., CpG ODN
  • a second agent e.g., a chemotherapeutic agent
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • both the therapeutic agents may be administered orally or both therapeutic agents may be administered by intravenous or subcutaneous injection.
  • sequential means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of a CpG ODN and a chemotherapeutic agent, a sequential dosage regimen could include administration of the CpG ODN before, simultaneously, substantially simultaneously, or after administration of the chemotherapeutic agent, but both agents will be administered in a regular sequence or order.
  • sequential dosage regimen means, unless otherwise specified, to keep apart one from the other.
  • simultaneous means, unless otherwise specified, happening or done at the same time, i.e., the compounds of the invention are administered at the same time.
  • substantially simultaneously means that the compounds are administered within minutes of each other (e.g., within 10 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two compounds separately).
  • concurrent administration and substantially simultaneous administration are used interchangeably.
  • Sequential administration refers to temporally separated administration of the ODN and the chemotherapeutic agent.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent, a dendritic vaccine or other tumor vaccine) and non-drug therapies (such as, but not limited to, surgery or radiation treatment or both).
  • the combination therapy further comprises radiation treatment
  • the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • Such combination therapy may also alleviate one or more adverse or undesirable side effects of other therapeutic agents.
  • the term “adjuvant therapy” refers to treatment given after the primary treatment, including, without limitation, radiation, chemotherapy, hormone therapy, etc.
  • the goal of adjuvant therapy is to increase the patients' chances of remission or cure, to increase the patients' overall survival benefit, and to help decrease the risk of recurrence. Therefore, it will be understood that if the natural CpG ODN of the present disclosure is administered as an adjuvant, it will be administered to the patient after the primary treatment, e.g., the patient is given a regimen of chemotherapy, followed by a course of natural CpG ODN.
  • the dose of CpG ODN may be considered a therapeutic dose or a maintenance dose, depending on the goals of the adjuvant therapy.
  • the term “neoadjuvant therapy” refers to treatment given before the primary treatment, including, without limitation, chemotherapy. In the neoadjuvant setting, the dose of CpG ODN is a therapeutic dose.
  • first-line therapy refers to the first type of therapy given for a condition or disease, or the first therapy of choice for the treatment of a particular type of cancer. It necessarily follows that the term “second-line therapy” therefore refers to the treatment given when the initial or first-line therapy is unsuccessful, and “third-line therapy” refers to a treatment or treatment regimen that is given when both the initial treatment and the subsequent treatment are unsuccessful.
  • the term “lysing,” with reference to a cell suspension, refers to rupturing the cell walls and/or cell membranes, cellular components, organelles of at least a portion of the cells such that at least part of the contents, e.g. biological molecules of the cells are released.
  • at least a portion of the biological material is lysed to form a lysate.
  • the biological sample lyses under physico-chemical forces created by the combination of the appropriate solvent environment, along with pressure and either heat or cavitation, or a combination of the two.
  • Bio molecules that are released upon lysing include, but are not limited to, nucleic acids, carbohydrates, amino acids, proteins, peptides, DNA (ssDNA, dsDNA and msDNA (multi-copy single-stranded DNA)), RNA (including ssRNA), complex sugars (oligosaccharides), peptidoglycans, and combinations thereof.
  • Biological samples are typically aqueous, which means they contain an effective amount of water molecules to cause them to be in the liquid state.
  • lysis refers to the rupturing of a cell membrane or cell wall (e.g., by digestion using enzymes or other appropriate materials) and release of the cytoplasm from the cell.
  • lysate refers to the material produced by the destructive process of lysis, specifically a liquefied phase with lysed cell debris (e.g., ruptured cell walls and/or cell membranes) and DNA.
  • lysate refers to the products of lysing biological material, for example, the biological molecules that are released as listed above. Although most lysates will be readily soluble in the biological sample fluid, certain lysate portions, such as hydrophobic components, may require additional steps to ensure at least a portion of the lysate is solubilized. Examples of additional steps for ensuring solubilization of the lysates include a suitable surfactant (or dehydrant), such as sodium dodecyl sulfate (SDS), which is typically included in the buffer, or any combination thereof. Lysate solubilization may also be assisted using vigorous mixing, shearing, heating in surfactant, cavitation, bead beating, boiling, degassing, or any combination thereof.
  • surfactant or dehydrant
  • SDS sodium dodecyl sulfate
  • cell is intended to encompass prokaryotic cells, eukaryotic cells, phage particles, and organelles.
  • chemotherapeutic agent means a cytotoxic compound which inhibits the proliferation of tumor or cancers cells in a subject. Chemotherapeutic agents may, in some circumstances, have a cytotoxic effect on normal (non-cancerous and non-tumor) cells in a patient.
  • downstream refers to the process by which a cell decreases the quantity of a cellular component, such as RNA or a protein, in response to an external variable, such as a therapeutic agent.
  • upregulation refers to the process by which a cell increases the quantity of a cellular component, such as RNA or a protein, in response to an external variable, such as a therapeutic agent.
  • Lyme disease refers to an disease which exhibits the characteristics as summarized in Dattwyler, R. J. and Wormser, G. “Lyme borreliosis.” in Infectious Diseases Medicine and Surgery (eds.) S. Gorbach and J. Bartlett, 3rd Edition, Saunders Pub. New York, N.Y., 2003 and which is caused by a pathogenic Borrelia.
  • Applicant has created combination therapies and treatment regimens for the treatment of immune disorders, including, hepatic disorders and human immunodeficiency virus (HIV), cancers, and Lyme disease using a therapeutic agent derived from one or more gram-positive bacteria (such as a cell-wall fraction of a gram-positive bacteria), and a naturally-occurring immunostimulatory oligodeoxynucleotide.
  • a therapeutic agent derived from one or more gram-positive bacteria (such as a cell-wall fraction of a gram-positive bacteria), and a naturally-occurring immunostimulatory oligodeoxynucleotide.
  • T lymphocyte-related disorders including, but not limited to, chronic inflammatory diseases and disorders, such as Crohn's disease, reactive arthritis, including Lyme disease, insulin-dependent diabetes, organ-specific autoimmunity, including multiple sclerosis, Hashimoto's thyroiditis and Grave's disease, contact dermatitis, psoriasis, graft rejection, graft versus host disease, sarcoidosis, atopic conditions, such as asthma and allergy, including allergic rhinitis, gastrointestinal allergies, including food allergies, eosinophilia, conjunctivitis, glomerular nephritis, certain pathogen susceptibilities such as helminthic (e.g., leishmaniasis) and certain viral infections, including HIV, and bacterial infections, including tuberculosis and lepromatous leprosy.
  • chronic inflammatory diseases and disorders such as Crohn's disease, reactive arthritis, including Lyme disease, insulin-dependent diabetes, organ-specific autoimmunity, including
  • the therapeutically active compositions of the present disclosure include a first biologically active agent, preferably one or more cell wall fractions of one or more gram positive bacteria, such as in the form of a lysate; a second biologically-active agent, preferably a naturally-occurring CpG ODN; an optional promoter; and optionally, one or more other additives, including control-release ingredients, so as to allow the composition to be absorbed into, or interact with, a mucosal wall of the subject in need of therapy.
  • a first biologically active agent preferably one or more cell wall fractions of one or more gram positive bacteria, such as in the form of a lysate
  • a second biologically-active agent preferably a naturally-occurring CpG ODN
  • an optional promoter preferably a naturally-occurring CpG ODN
  • additives including control-release ingredients
  • the first biologically active therapeutic agent is a mixture of one or more lysate or cell wall fraction of a gram-positive bacteria, in an amount ranging from about 1 mg/kg to about 100 mg/kg, as required depending upon the specific therapeutic application.
  • the lysate or cell wall fraction of a gram-positive bacteria is from the group of gram-positive bacteria selected from the group consisting of Lactobacillus acidophilus, Lactobacillus buchneri, Lactobacillus casei, Lactobacillus catenaforme, Lactobacillus cellobiosus, Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus delbrueckii subsp.
  • lactis Lactobacillus helveticus, Lactobacillus jensenii, Lactobacillus leichmannii, Lactobacillus minutus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus rogosae, Lactobacillus salivarius, Lactobacillus sporogenes (also known as Bacillus coagulans ), Lactobacillus brevis, Lactobacillus gasseri, Lactobacillus fermentum, Bifidobacterium adolescentis, Bifidobacterium animalis (especially B.
  • Bifidobacterium angulatum Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium catenulatum, Bifidobacterium dentium, Bifidobacterium eriksonii, Bifidobacterium infantis, Bifidobacterium lactis ( Bifidobacterium animalis subsp.
  • lactis Bifidobacterium longum, Bifidobacterium plantarum, Bifidobacterium pseudo - catenulatum, Bifidobacterium pseudo - longum, Leptococcus lactis, Streptococcus lactis (also referred to as Lactococcus lactis subsp. lactis ), Streptococcus raffinolactis, Acidaminococcus fermenta, Cytophaga fermentans, Rhodoferax fermentans, Cellulomonas fermentans, Zymomonas mobilis , and Streptococcus thermophilus , as well as functionally equivalent variants thereof, all of which are suitable for carrying out the present invention.
  • These mixtures of well-known species can be easily prepared by any person having ordinary experience in this field.
  • the preferred first biologically thereapeutic active agents according to the present invention are lysates or cell wall extracts of gram-positive bacteria selected from the group consisting of the following: Streptococcus thermophilus, Bifidobacterium animalis (especially B. animalis , subspecies animalis ), Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii subsp.
  • Lactococcus lactis Bacillus coagulans ( Lactobaciullus sporogenes ), Bifidobacterium lactis ( Bifidobacterium animalis subsp. lactis ), Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus , and Lactobacillus helveticus , as well as functionally equivalent variants thereof. Some of these mixtures are commercially available in a lyophilized form.
  • the second biologically-active therapeutic agent is a naturally-occurring CpG ODN. It is preferred, but not necessary, that the naturally-occurring CpG ODN be obtained from the same bacteria or bacterial lysate from which the first biologically-active therapeutic agent is obtained.
  • the CpG ODN may be any CpG motif, including but not limited to, class-A (Type D), class-B (Type K), class-C, class P, or class S, or combinations thereof, as appropriate.
  • the second biologically-active therapeutic agent may be a single CpG ODN, or a combination of two or more CpG ODN's, including a combination of naturally-occurring and synthetic CpG ODN's, the only proviso being that at least one of the two or more CpG ODN's be naturally-occurring.
  • the present invention further contemplates the administration of a therapeutic or both therapeutic and maintenance dose of the CpG ODN component in a wide range of doses.
  • Exemplary therapeutic and/or maintenance doses of the CpG ODN component of the instant composition includes, but are not limited to, dose ranges of from about 0.001 mg/kg to about 5.0 mg/kg, preferably about 0.001 mg/kg to about 2.5 mg/kg, from one to up to three times per day.
  • the present invention contemplates, in addition to a therapeutic dose, the administration of a maintenance dose of a CpG ODN of about 0.001 to about 5.0 mg/Kg, as part of a maintenance regimen, such CpG ODN used as a maintenance does being either the same or not the same as the CpG ODN within the lysate of the gram-positive bacteria, as appropriate.
  • compositions of the present disclosure may further and optionally comprise one or more promoters, to assist in the therapeutic delivery of the active agent across the biological membrane.
  • the promoter useful in accordance with the present disclosure is an amino acid, N-alkylated peptide, sugar, amino sugar or amino sugar chelate.
  • An amino sugar chelate comprising one or more amino sugar ligands, one or more saturated hydroxylated carboxylic acid ligands, and a nutritionally acceptable metal, wherein at least one of the one or more amino sugar ligands is glucosamine, and wherein the metal is selected from the group consisting of manganese, magnesium, sodium, potassium, and zinc, and wherein the one or more saturated hydroxylated carboxylic acid ligands is gluconic acid, and wherein the glucosamine ligand to nutritionally acceptable metal ratio is 2:1.
  • the therapeutic formulations may include one or more acetylated or deacetylated amino sugars selected from the group consisting of N-acetylglucosamine (NAG; GlcNAc), galactosamine, N-acetylgalactosamine, mannosamine, N-acetyl cysteine (NAC) and N-acetylmannosamine in the form of monomers, oligomers, and/or polymers thereof including chitin, and human glucosaminoglycans, as well as derivatives thereof.
  • NAG N-acetylglucosamine
  • GlcNAc galactosamine
  • N-acetylgalactosamine mannosamine
  • N-acetyl cysteine (NAC) N-acetylmannosamine
  • monomers, oligomers, and/or polymers thereof including chitin, and human glucosaminoglycans, as well as derivatives thereof.
  • the promoter is a member selected from the group consisting of poly-L-lysine, glucosamine, poly-L-arginine, galactosamine, N-acetylmannosamine (NAM; N-Ac-Man), N-acetylglucosamine (NAG; N-Ac-Glc), N,N′-diacetylglucosamine (NAG-NAG; N,N′-diacetylchitobiose), N,N′,N′′,N′′′-tetraacetylglucosamine (NAG-NAG-NAG-NAG; N,N′,N′′,N′′′-tetraacetylchitotetraose), and mixtures thereof.
  • the promoter may be an acylated glycosyloxy sugar or an optionally acylated oligoglycosyloxy sugar moiety of 2 to 12 ⁇ -1,2 and/or ⁇ -1,6 linked sugars, wherein the sugar(s) are selected from the group consisting of D-mannose, D-galactose, D-glucose, D-glucosamine, N-acetylglucosamine, and 6-deoxy-L-mannose, wherein an oligoglycosyloxy sugar moiety may comprise the same or different sugars.
  • the therapeutic formulations of the invention may further comprise one or more additional therapeutic agents, such as the second therapeutic agents described below.
  • additional therapeutic agents such as the second therapeutic agents described below.
  • the compositions will usually be supplied as part of a sterile, pharmaceutical composition that will normally include a pharmaceutically acceptable carrier.
  • This composition, comprising additional therapeutic agents, can be in any suitable form (depending upon the desired method of administering it to a patient).
  • the second therapeutic agent is an anti-rheumatic drug, an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an immunosuppressive agent, an interferon, an interferon-based chemotherapeutic, a different bacterial wall lysate, or a cytotoxic drug.
  • Anti-rheumatic drugs include, but are not limited to, auranofin, azathioprine, chloroquine, D-penicillamine, gold sodium thiomalate hydroxychloroquine, Myocrisin and sulfasalazine methotrexate.
  • Anti-inflammatory agents include, but are not limited to, dexamethasone, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen, as well as non-steroidal anti-inflammatory agents (NSAIDS).
  • dexamethasone pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen, as well as non-steroidal anti-inflammatory agents (NSAIDS).
  • Chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chloramb
  • the second therapeutic agent is a TNF- ⁇ antagonist or an anti-TNF- ⁇ antibody of the disclosure.
  • TNF- ⁇ antagonists include, but are not limited to, soluble TNF- ⁇ receptors; etanercept (ENBREL®; Immunex) or a fragment, derivative or analog thereof; infliximab (REMICADE®; Centacor) or a derivative, analog or antigen-binding fragment thereof; IL-10, which is known to block TNF- ⁇ production via interferon- ⁇ -activated macrophages, TNFR-IgG; the murine product TBP-1; the vaccine CytoTAb (Protherics); antisense molecule 104838 (ISIS); the peptide RDP-58 (SangStat); thalidomide (Celgene); CDC-801 (Celgene); DPC-333 (Dupont); VX-745 (Vertex); AGIX-4207 (AtheroGenics); ITF-
  • the second therapeutic agents may be made from particulate cellular wall fragments of particular lactic acid bacteria (e.g., Del-Immune V®, Pure Research Products, LLC, Colorado, USA), which are intended to stimulate the immune system.
  • lactic acid bacteria e.g., Del-Immune V®, Pure Research Products, LLC, Colorado, USA
  • compositions of the present invention are in a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, and a dissolving tablet such as a slow-dissolving tablet, a quick-dissolving tablet, or a controlled-release tablet or other suitable controlled-release formulation.
  • a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, and a dissolving tablet such as a slow-dissolving tablet, a quick-dissolving tablet, or a controlled-release tablet or other suitable controlled-release formulation.
  • the composition is a lozenge or a dissolving tablet.
  • the active agent of the present disclosure is delivered across an oral mucosa of a subject, the oral mucosa being selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof.
  • the composition is administered sublingually so that the active ingredient is delivered across the sublingual mucosa.
  • the carrier is typically a solid, semi-solid, or liquid such as a binder, a gum base, or combinations thereof.
  • Suitable binders for use in the compositions of the present invention include, without limitation, sugar alcohols such as mannitol, sorbitol, and xylitol; sugars such as lactose, dextrose, sucrose, glucose, and powdered sugar; other substances such as inositol, molasses, maltodextrin, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, acacia gum, guar gum, tragacanth gum, alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, VEEGUM®, larch arabogalactan, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (e.g., Carb
  • Suitable gum bases for use in the compositions of the present invention include, for example, materials selected from among the many water-insoluble and saliva-insoluble gum base materials known in the art.
  • the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
  • suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof.
  • suitable natural polymers include, without limitation, substances of plant origin such as chicle, jelutong, gutta percha, crown gum, and combinations thereof.
  • Suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers (e.g., “butyl rubber”), polyethylene, polyisobutylene, polyvinylester (e.g., polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof.
  • the gum base comprises a mixture of butyl rubber (i.e., isobutylene and isoprene copolymer), polyisobutylene, and optionally, polyvinylacetate (e.g., having a molecular weight of approximately 12,000).
  • compositions of the present invention can further comprise a sweetening agent, a flavoring agent, a protecting agent, a plasticizer, a wax, an elastomeric solvent, a filler material, a preservative, or combinations thereof.
  • compositions of the present invention can further comprise a lubricating agent, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof.
  • the average particle size of the drug in the compositions described herein is about 20 microns, as compared to a typical average drug particle size of from about 75 to about 100 microns.
  • the average particle size of the drug in the compositions described herein is less than or equal to the average particle size of the carrier ingredients (e.g., gum base, binders, etc.).
  • the therapeutic composition may optionally include a buffer system to raise the pH of saliva to a pH of from about 8.0 to about 11, irrespective of the starting pH of saliva in the oral cavity of the subject to be treated.
  • a buffer system to raise the pH of saliva to a pH of from about 8.0 to about 11, irrespective of the starting pH of saliva in the oral cavity of the subject to be treated.
  • Suitable therapeutic agents for use in the present invention are described above.
  • Suitable carbonate salts and bicarbonate salts for use in the buffer systems of the present invention are also described above.
  • composition further comprises a non-biologic therapeutic agent, such as an NSAID.
  • Suitable citrate, phosphate, and borate salts include, without limitation, any salt of citric acid, phosphoric acid, or boric acid known in the art.
  • the citrate salt is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate.
  • the phosphate salt is selected from the group consisting of monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate, dibasic magnesium phosphate, monobasic ammonium phosphate, and dibasic ammonium phosphate.
  • the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate.
  • the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a citrate salt. In certain other instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a phosphate salt. In further instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and/or a borate salt.
  • the ternary buffer system comprises a carbonate salt, a bicarbonate salt, and a citrate, phosphate, or borate salt.
  • the buffer system comprises a carbonate salt or a bicarbonate salt and two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt, and a borate salt.
  • the buffer system is a binary buffer system comprising a carbonate salt or a bicarbonate salt and a metal oxide.
  • the buffer system is a binary buffer system comprising, a carbonate salt or a bicarbonate salt and a citrate, phosphate, or borate salt.
  • the buffer system is a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt.
  • the buffer system is a binary buffer system comprising a carbonate salt and a bicarbonate salt, preferably sodium carbonate and sodium bicarbonate.
  • the therapeutic composition of the invention may also include a controlled release additive.
  • a controlled release additive in the therapeutic composition substantially reduces the “intitial burst” of biologically active agent released from the therapeutic composition during the initial first 1-2 minutes after delivery to the subject's mucosa.
  • the term “substantially reduces” means a decrease of at least 15% of biologically active agent released from the therapeutic composition compared to a composition without the additive.
  • the controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition by about 15% to about 70%, more preferably about 30% to about 60%, compared to a therapeutic composition which does not include a controlled release additive.
  • the controlled release additive is any suitable controlled-release additive, preferably a thermoplastic polymer having poly(lactide-co-glycolide) (PLG) moieties and polyethylene glycol (PEG) moieties.
  • PLG poly(lactide-co-glycolide)
  • PEG polyethylene glycol
  • the controlled release additive is a PLG/PEG block copolymer which includes from about 50 mole % to about 90 mole % lactide monomers and about 50 mole % to about 10 mole % glycolide monomers. More preferably, the PLG/PEG block copolymer includes from about 50 mole % to about 75 mole % lactide monomers and about 50 mole % to about 25 mole % glycolide monomers.
  • the PEG moiety has a molecular weight of about 1,000 Daltons to about 10,000 Daltons, more preferably about 5000 Daltons.
  • the PEG portion of the block copolymer ranges from about 1 wt % to about 20 wt % of the total weight of the block copolymer. The percentage is dependent on the molecular weight of the block copolymer that is prepared and the molecular weight of the polyethylene glycol that is used. Thus, a block copolymer with a weight average molecular weight of 100,000 Daltons (I.V. approx. 0.8 dL/g) prepared with PEG having a molecular weight of 5,000 Daltons will contain about 5 wt % PEG. If PEG with a molecular weight of 1,000 Daltons is used, the block copolymer will include about 1 wt % of PEG.
  • the inherent viscosity (abbreviated as “I.V.”; units are in deciliters/gram) of the controlled release additive is a measure of its molecular weight.
  • the inherent viscosity of the controlled release additive suitable for use with the compositions of the present disclosure is from about 0.50 dL/g to about 1.0 dL/g (as measured in chloroform), more preferably from about 0.70 dL/g to about 0.90 dL/g.
  • Suitable polymeric controlled release additives include but are not limited to any PLG/PEG block copolymer with the previously mentioned attributes.
  • suitable polymeric controlled release additives include, without limitation, 50/50 PLG/PEG-5000 (0.81); 70/30 PLG/PEG-5000 (0.73); and 70/30 PLG/PEG-5000 (0.79).
  • the controlled release additive when included in the formulation, may be present in the therapeutic composition in an amount effective to reduce the initial burst of biologically active agent released from the therapeutic composition during the first 2 minutes after delivery to the mucosa.
  • the therapeutic composition includes about 1 wt % to about 50 wt %, more preferably about 2 wt % to about 20 wt % of the controlled release additive.
  • compositions of the present invention may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets (e.g., chewable, slow-dissolving, quick-dissolving), pills, capsules, lozenges, candies, gums, powders, solutions, suspensions, emulsions, aerosols, or the like.
  • the dosage form is a chewing gum, quick-dissolving tablet, candy, or lozenge.
  • the composition is in a dietary supplement, such as a tablet, pill, capsule, or other oral delivery formulation.
  • dosage forms such as chewing gums, candies, quick-dissolving tablets, or lozenges offer advantages over the traditional dosage forms for oral administration.
  • each of these dosage forms avoids hepatic first pass metabolism, degradation within the gastrointestinal tract, and drug loss during absorption. Consequently, the amount of the active therapeutic agent required per dose is less than that which would be required if formulated, for example, in a pill or tablet for oral administration.
  • the bioavailability of the therapeutic agent is increased, thereby reducing the time to onset of therapeutic activity.
  • dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of therapeutic agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers.
  • suitable pharmaceutical excipients such as carriers.
  • Methods for preparing such dosage forms are known or will be apparent to those skilled in the art.
  • a chewing gum dosage form of the present invention can be prepared according to procedures standard in the industry.
  • a tablet, lozenge, or candy dosage form (e.g., a sucker) of the present invention can be prepared according to the procedures set forth in, for example, Remington's “The Science and Practice of Pharmacy, 20th Ed.,” [Lippincott, Williams & Wilkins (2003); and, “Pharmaceutical Dosage Forms, Volume 1: Tablets,” 2nd Ed., Marcel Dekker, Inc., New York, N.Y. (1989)].
  • the dosage form to be administered will, in any event, contain a quantity of the active therapeutic agent in a therapeutically effective amount for relief of the condition being treated when administered in accordance with the teachings of this invention.
  • carrier refers to a typically inert substance used as a diluent or vehicle for a drug such as a therapeutic agent.
  • the term also encompasses a typically inert substance that imparts cohesive qualities to the composition.
  • Suitable carriers for use in the compositions of the present invention include, without limitation, a solid, semi-solid, or liquid such as a binder or a gum base.
  • Non-limiting examples of binders include mannitol, sorbitol, xylitol, maltodextrin, lactose, dextrose, sucrose, glucose, inositol, powdered sugar, molasses, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone, acacia gum, guar gum, tragacanth gum, alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, VEEGUM®, larch arabogalactan, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (e.g., Carbopol), calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol, and combinations thereof.
  • binders include mannitol, sorbito
  • binders can be pre-processed to improve their flowability and taste by methods known in the art such as freeze drying [see, e.g., “Fundamentals of Freeze-Drying,” Pharm. Biotechnol., Vol. 14, pp. 281-360 (2002); “Lyophililization of Unit Dose Pharmaceutical Dosage Forms,” Drug. Dev. Ind. Pharm., Vol. 29, pp. 595-602 (2003)]; solid-solution preparation; and lubricant dusting and wet-granulation preparation with a suitable lubricating agent (see, e.g., Remington: The Science and Practice of Pharmacy, supra).
  • freeze drying see, e.g., “Fundamentals of Freeze-Drying,” Pharm. Biotechnol., Vol. 14, pp. 281-360 (2002); “Lyophililization of Unit Dose Pharmaceutical Dosage Forms,” Drug. Dev. Ind. Pharm., Vol. 29, pp. 595-602 (2003)]
  • compositions of the present invention comprise from about 15% to about 90% by weight of the binder, and preferably from about 35% to about 80%.
  • binders e.g., to produce a highly friable dosage form.
  • Non-limiting examples of gum bases include materials selected from among the many water-insoluble and saliva-insoluble gum base materials known in the art.
  • the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.
  • suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof.
  • suitable natural polymers include, without limitation, substances of plant origin such as chicle, jelutong, gutta percha, crown gum, and combinations thereof.
  • Suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers (e.g., “butyl rubber”), polyethylene, polyisobutylene, polyvinylester (e.g., polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof.
  • the gum base comprises a mixture of butyl rubber (i.e., isobutylene and isoprene copolymer), polyisobutylene, and optionally, polyvinylacetate (e.g., having a molecular weight of approximately 12,000).
  • the gum base comprises from about 25% to about 75% by weight of these polymers, and preferably from about 30% to about 60%.
  • compositions of the present invention can additionally include lubricating agents; wetting agents; emulsifying agents; solubilizing agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates, butylated hydroxytoluene, and butylated hydroxyanisole; sweetening agents; flavoring agents; coloring agents; lipids such as vitamin E or an omega fatty acid; and disintegrating agents (i.e., dissolving agents) such as crospovidone as well as croscarmellose sodium and other cross-linked cellulose polymers.
  • lubricating agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates, butylated hydroxytoluene, and butylated hydroxyanisole
  • sweetening agents flavoring agents
  • coloring agents lipids such as vitamin E or an omega fatty acid
  • disintegrating agents i.e., dissolving agents
  • crospovidone as
  • Lubricating agents can be used to prevent adhesion of the dosage form to the surface of the dies and punches, and to reduce inter-particle friction. Lubricating agents may also facilitate ejection of the dosage form from the die cavity and improve the rate of granulation flow during processing.
  • suitable lubricating agents include, without limitation, magnesium stearate, calcium stearate, zinc stearate, stearic acid, simethicone, silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol, mineral oil, and combinations thereof.
  • the compositions of the present invention can comprise from about 0% to about 10% by weight of the lubricating agent, and preferably from about 1% to about 5%.
  • Sweetening agents can be used to improve the palatability of the composition by masking any unpleasant tastes it may have.
  • suitable sweetening agents include, without limitation, compounds selected from the saccharide family such as the mono-, di-, tri-, poly-, and oligosaccharides; sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, maltodextrin, and polydextrose; saccharin and salts thereof such as sodium and calcium salts; cyclamic acid and salts thereof; dipeptide sweeteners; chlorinated sugar derivatives such as sucralose and dihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and the like, and combinations thereof.
  • Hydrogenated starch hydrolysate, and the potassium, calcium, and sodium salts of 3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2-dioxide may also be used.
  • sorbitol, mannitol, and xylitol are preferred sweetening agents.
  • the compositions of the present invention can comprise from about 0% to about 80% by weight of the sweetening agent, preferably from about 5% to about 75%, and more preferably from about 25% to about 50%.
  • Flavoring agents can also be used to improve the palatability of the composition.
  • suitable flavoring agents include, without limitation, natural and/or synthetic (i.e., artificial) compounds such as peppermint, spearmint, wintergreen, cinnamon, menthol, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, lemon, grapefruit, orange, plum, apple, fruit punch, passion fruit, chocolate (e.g. white, milk, dark), vanilla, caramel, coffee, hazelnut, combinations thereof, and the like.
  • Coloring agents can be used to color code the composition, for example, to indicate the type and dosage of the therapeutic agent therein.
  • Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD & C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, and the like.
  • the compositions of the present invention can comprise from about 0% to about 10% by weight of the flavoring and/or coloring agent, preferably from about 0.1% to about 5%, and more preferably from about 2% to about 3%.
  • the compositions of the present invention comprise an active therapeutic agent derived from a gram-positive bacteria or a pharmaceutically acceptable salt thereof, a promoter, a carrier such as a gum base, a binary or ternary buffer system, and optionally a protecting agent.
  • the chewing gum composition may further comprise lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, and coloring agents.
  • the chewing gum composition comprises from about 0.001% to about 10.0% by weight of the active therapeutic agent (in whatever chosen form, measured as per its free base form), more typically from about 0.01% to about 5.0%, and still more typically from about 0.1% to about 3.0%.
  • the optional buffer system of the chewing gum composition can provide for a final salivary pH in excess of at least about 8.0, preferably at least about 9.5, and more preferably in the range of from about 9.9 to about 11.
  • the chewing gum composition typically comprises from about 20% to about 95% by weight of the gum base, more typically from about 30% to about 85%, and most typically from about 50% to about 70% of the gum base.
  • the chewing gum composition may further comprise a protecting agent.
  • the protecting agent coats at least part of the therapeutic agent, typically upon the mixing of the two agents.
  • the protecting agent may be mixed with the active therapeutic agent in a ratio of from about 0.1 to about 100 by weight, preferably in a ratio of from about 1 to about 50, and more preferably in a ratio of about 1 to about 10.
  • the protecting agent reduces the adhesion between the therapeutic agent and the gum base so that the therapeutic agent may be more easily released from the gum base.
  • the therapeutic agent may be delivered across the mucous membranes of the oral cavity within about 5 to about 20 minutes of chewing, preferably within about 10 minutes of chewing.
  • a variety of different protecting agents may be used.
  • suitable protecting agents include, without limitation, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, magnesium stearate, mineral oil, poloxamer, polyethylene gycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, stearic acid, cab-o-sil, talc, zinc stearate, and combinations thereof.
  • the gum base may additionally include plasticizers such as softeners or emulsifiers. Such plasticizers may, for example, help reduce the viscosity of the gum base to a desirable consistency and improve its overall texture and bite. Plasticizers may also facilitate the release of the therapeutic agent upon mastication. Non-limiting examples of plasticizers include lecithin, mono- and diglycerides, lanolin, stearic acid, sodium stearate, potassium stearate, glycerol triacetate, glycerol monostearate, glycerin, and combinations thereof.
  • the gum base typically comprises from about 0% to about 20% by weight of the plasticizer, and more typically from about 5% to about 15%.
  • the gum base may further comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean and cottonseed oil, and combinations thereof.
  • waxes such as beeswax and microcrystalline wax
  • fats or oils such as soybean and cottonseed oil
  • combinations thereof Typically, the gum base comprises from about 0% to about 25% by weight of these waxes and oils, and more typically comprises from about 15% to about 20%.
  • the gum base may further comprise one or more elastomeric solvents such as rosins and resins.
  • solvents include methyl, glycerol, and pentaerythritol esters of rosins, modified rosins such as hydrogenated, dimerized or polymerized rosins, or combinations thereof (e.g., pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated methyl ester of rosin such as polymers of ⁇ -pinene or ⁇ -pinene, terpene resins including polyterpene, and
  • the gum base may further comprise a filler material to enhance the chewability of the final chewing gum composition.
  • Fillers that are substantially non-reactive with other components of the final chewing gum formulation are preferable.
  • suitable fillers include, without limitation, calcium carbonate, magnesium silicate (i.e., talc), dicalcium phosphate, metallic mineral salts (e.g., alumina, aluminum hydroxide, and aluminum silicates), and combinations thereof.
  • the gum base comprises from about 0% to about 30% by weight of the filler, and more typically from about 10% to about 20%.
  • the gum base need not be prepared from its individual components.
  • the gum base can be purchased with the desired ingredients contained therein, and can be modified to include additional agents.
  • Several manufacturers produce gum bases suitable for use with the described chewing gum compositions. Examples of such gum bases include, without limitation, PHARMGUMTM M, S, or C(SPI Pharma Group; New Castle, Del.).
  • PHARMAGUMTM comprises a mixture of gum base, sweetening agent, plasticizer, and sugar.
  • the chewing gum composition includes a therapeutic agent centerfill.
  • a centerfill may be particularly suitable when immediate release of the therapeutic agent is preferred.
  • encapsulating the active therapeutic agent in a centerfill may help to mask any undesirable taste that the therapeutic agent may have.
  • the gum base surrounds, at least in part, a centerfill.
  • the centerfill comprises at least one therapeutic agent, and may be a liquid or semi-liquid material.
  • the centerfill material can be a synthetic polymer, a semi-synthetic polymer, low-fat, or fat-free and contain one or more sweetening agents, flavoring agents, coloring agents, and/or scenting agents.
  • the centerfill includes a buffer system, including a binary or ternary buffer system as described herein.
  • the chewing gum compositions can have any desired shape, size, and texture.
  • the composition can have the shape of a stick, tab, gumball, and the like.
  • the chewing gum can be any desirable color.
  • the chewing gum can be any shade of red, blue, green, orange, yellow, violet, indigo, and mixtures thereof, and can be color coded to indicate the type and dosage of the therapeutic agent therein.
  • the chewing gum can be individually wrapped or grouped together in pieces for packaging by methods well known in the art.
  • the compositions of the present invention comprise a therapeutic agent as described herein derived from one or more gram-positive bacteria, or a pharmaceutically acceptable salt thereof, naturally-occurring immunostimulatory oligodeoxynucleotide, such as a CpG ODN motif or equivalent, an optional promoter, a carrier such as a binder, and a buffer system, including binary or ternary buffer systems.
  • the tablet composition may further comprise lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents, and disintegrating agents.
  • the tablet compositions of the present invention comprise from about 0.001% to about 10.0% by weight of the active therapeutic agent (in whatever chosen form, measured as per its free base form), and more typically from about 1.0% to about 5.0%.
  • the buffer system of the tablet composition provides for a final salivary pH in excess of at least about 8.0, preferably at least about 9.5, and more preferably in the range of from about pH 9.9 to about pH 11.
  • the tablet is a dissolving tablet such as a slow-dissolving or quick-dissolving tablet that is dissolved by a subject's saliva, without the need for chewing.
  • a dissolving tablet placed on the subject's tongue can be used for buccal delivery of the therapeutic agent.
  • a dissolving tablet placed underneath the subject's tongue can be used for sublingual delivery of the therapeutic agent.
  • This type of dosage form may be particularly desirable for pediatric and geriatric patients, since small children and aged individuals often have difficulty chewing certain items.
  • the dissolving tablet is formulated to dissolve within about 1 to about 15 minutes, preferably within about 2 to about 10 minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, following administration.
  • quick-dissolving tablets dissolve faster than slow-dissolving tablets, which are typically dissolved gradually rather than rapidly by a subject's saliva.
  • the slow-dissolving or quick-dissolving tablet delivers the therapeutic agent across the sublingual mucosa over a period of time greater than about 1 minute.
  • the tablet is a chewable tablet that is chewed by a subject and formulated to dissolve either rapidly or gradually.
  • a chewable tablet placed on the subject's tongue can be used for buccal delivery of the therapeutic agent.
  • the chewable tablet can be moved around within the mouth and can sometimes be parked between the gums and the cheeks or underneath the tongue.
  • at least a portion of the therapeutic agent contained within a chewable tablet may also be delivered sublingually (i.e., across the sublingual mucosa).
  • the chewable tablet is formulated to dissolve within about 1 to about 15 minutes, preferably within about 2 to about 10 minutes and not less than 1 minute, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, following administration.
  • the dissolving and chewable tablets of the present invention are typically formulated to dissolve within about 1 to 15 minutes following administration, and preferably not less than about 1 minute.
  • these time frames are amenable to maximum exposure of the therapeutic agent to the oral mucosa (e.g., to the sublingual and/or buccal mucosa), they are not always amenable to user compliance (e.g., users may swallow too frequently and, therefore, hinder maximal transmucosal absorption). Consequently, in certain instances, it may be desirable to strike a balance between patient compliance and maximum exposure time of the therapeutic agent to the oral mucosa.
  • subtle changes to the tablet formulation such as, for example, replacing one flavoring agent for another (e.g., chocolate for spearmint) or replacing one binder or sweetening agent for another (e.g., lactose for mannitol or sorbitol) may be used to reduce salivation.
  • the carrier present in the tablets of the present invention is typically a binder that is useful in keeping the tablet in a semi-solid state, and may be a solid or a liquid, and may for example be a high-melting point fat or waxy material.
  • binders such as mannitol, sorbitol, lactose, sucrose, and inositol can impart properties to the tablet that permit or enhance its disintegration in the mouth.
  • the tablet composition may further comprise a protecting agent.
  • the protecting agent coats at least part of the therapeutic agent, typically upon the mixing of the two agents.
  • the protecting agent may be mixed with the therapeutic agent in a ratio of from about 0.1 to about 100 by weight, preferably in a ratio of from about 1 to about 50, and more preferably in a ratio of about 1 to about 10.
  • the protecting agent reduces the adhesion between the therapeutic agent and the binder so that the therapeutic agent may be more easily released from the binder. In this way, the therapeutic agent may be delivered across the mucous membranes of the oral cavity within about 5 to about 20 minutes, preferably within about 10 minutes.
  • Materials suitable as protecting agents are discussed in detail above and may be used alone or in combination in the tablet compositions of the present invention.
  • the tablet composition may also comprise one or more elastomeric solvents such as rosins and resins. Non-limiting examples of such solvents are discussed in detail above and may be used alone or in combination in the tablet compositions of the present invention.
  • the tablet composition may further comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean and cottonseed oil, and combinations thereof.
  • the tablet composition may additionally include plasticizers such as softeners or emulsifiers. Such plasticizers may, for example, help reduce the viscosity of the salivary solution of the dissolved tablet to a desirable consistency and improve its overall texture and bite and help facilitate the release of the therapeutic agent. Non-limiting examples of such plasticizers are discussed in detail above and may be used alone or in combination in the tablet compositions of the present invention.
  • the tablet composition includes a therapeutic agent centerfill.
  • a centerfill may be particularly suitable when immediate release of the therapeutic agent is preferred.
  • encapsulating the active therapeutic agent in a centerfill may help to mask any undesirable taste that the therapeutic agent may have.
  • the binder surrounds, at least in part, a centerfill.
  • the centerfill comprises at least one therapeutic agent in accordance with the present disclosure, and may be a liquid or semi-liquid material.
  • the centerfill material can be low-fat or fat free and contain one or more sweetening agents, flavoring agents, coloring agents, and/or scenting agents.
  • the centerfill includes a binary or ternary buffer system as described herein.
  • the tablet composition of the present invention is multilayered.
  • the dissolving or chewable tablet can be designed to provide more than one therapeutic agent, e.g., two or more active therapeutic agents, or one or more active therapeutic agents derived from a first gram-positive bacteria in combination with one or more active therapeutic agents derived from a second gram-positive bacteria.
  • the first layer contains a first active therapeutic agent derived from a first gram-positive bacteria
  • the second layer contains the same or a different active therapeutic agent derived from the same or a different gram-positive bacteria.
  • the first layer comprises the dissolving or chewable portion of the tablet, and the second (i.e., subsequent) layer is coated by the first layer.
  • This type of formulation may be particularly suitable when immediate release of the active therapeutic agent, followed by gastrointestinal absorption of a second therapeutic agent, is desirable. Gastrointestinal absorption of the second therapeutic agent may be desirable, for example, in order to mitigate co-morbid symptoms or to sustain the therapeutic benefit of the active therapeutic agent in the dissolving or the chewable portion of the tablet.
  • the second layer is present as a layer lateral to the first layer.
  • the second layer typically comprises at least one therapeutic agent, and can also comprise one or more sweetening agents, flavoring agents, coloring agents, and scenting agents as described above.
  • the second layer further includes a binary or ternary buffer system as described herein.
  • the combination of the active therapeutic agent with or without additional therapeutic agents need not take the form of a multilayered tablet, but instead comprises a single homogenous tablet layer.
  • This type of formulation may also be used in the case where gastrointestinal absorption of at least one therapeutic agent is desirable.
  • the relative extent of ionization of the two or more therapeutic agents determines how they are to be absorbed. For example, those therapeutic agents that are un-ionized are absorbed through the oral mucosa, while the ionized agents are swallowed for gastrointestinal absorption.
  • the tablet compositions can have any desired shape, size, and texture.
  • the tablet can have the shape of a stick, tab, pellet, sphere, and the like.
  • the tablet can be any desirable color.
  • the tablet can be any shade of red, blue, green, orange, yellow, violet, indigo, and mixtures thereof, and can be color coded to indicate the type and dosage of the therapeutic agent therein.
  • the tablets can be individually wrapped or grouped together in pieces for packaging by methods well known in the art.
  • the compositions of the present invention comprise the active agent from a gram positive bacteria or a pharmaceutically acceptable salt thereof, an optional promoter, a carrier such as a binder, and a buffer system, including a binary or ternary buffer system; the lozenge or candy composition may further comprise lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents, and disintegrating agents.
  • lubricating agents wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents, and disintegrating agents.
  • the lozenge or candy compositions of the present invention comprise from about 0.001% to about 10.0% by weight of the active therapeutic agent (in whatever chosen form, measured as per its free base form), preferably from about 1.0% to about 5.0%, and more preferably from about 2.5% to about 4.5%.
  • the foregoing percentages will vary depending upon the particular source of the active therapeutic agent utilized, the amount of the active therapeutic agent desired in the final formulation, as well as on the particular release rate of the active therapeutic agent desired.
  • the buffer system for the lozenge or candy composition when included or necessary, may be a single-compound buffer system, but is typically a binary or ternary buffer system comprising amorphous magnesium oxide or the like with a carbonate salt and/or a bicarbonate salt.
  • an exemplary ternary buffer system typically comprises from about 4.0% to about 7.0% by weight sodium carbonate; from about 8.0% to about 12.0% by weight dessicant-coated sodium bicarbonate; and from about 20% to about 30% by weight amorphous magnesium oxide.
  • the buffer system provides for a final salivary pH in excess of at least about 8.0 when necessary, preferably at least about 9.5, and more preferably in the range of from about 9.9 to about 11.
  • the lozenge or candy is dissolved by a subject's saliva, without the need for chewing.
  • a lozenge placed on the subject's tongue can be used for buccal delivery of the therapeutic agent.
  • a lozenge placed underneath the subject's tongue can be used for sublingual delivery of the therapeutic agent.
  • This type of dosage form may be particularly desirable for pediatric and geriatric patients, since small children and aged individuals often have difficulty chewing certain items.
  • the lozenge is formulated to dissolve within about 1 to about 15 minutes, preferably within about 2 to about 10 minutes, and preferably not less than about 1 minute, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, following administration.
  • the lozenge or candy delivers the therapeutic agent across the sublingual mucosa in a period of time greater than 1 minute.
  • the lozenges the present invention are typically formulated to dissolve within about 1 to about 15 minutes following administration, and preferably not less than about 1 minute.
  • these time frames are amenable to maximum exposure of the therapeutic agent to the oral mucosa (e.g., to the sublingual and/or buccal mucosa), they are not always amenable to user compliance (e.g., users may swallow too, frequently and, therefore, hinder maximal transmucosal absorption). Consequently, in certain instances, it may be desirable to strike a balance between patient compliance and maximum exposure time of the therapeutic agent to the oral mucosa.
  • subtle changes to the lozenge formulation such as, for example, replacing one flavoring agent for another (e.g., chocolate for spearmint) or replacing one binder or sweetening agent for another (e.g., lactose for mannitol or sorbitol) may be used to reduce salivation.
  • the carrier present in the lozenges of the present invention is typically a binder that is useful in keeping the lozenge in a semi-solid state, and may be a solid or a liquid, and may for example be a high-melting point fat or waxy material.
  • Materials suitable as binders are discussed in detail above and may be used alone or in combination in the lozenge compositions of the present invention.
  • binders such as mannitol, sorbitol, lactose, sucrose, and inositol can impart properties to the lozenge that permit or enhance its disintegration in the mouth.
  • the lozenge composition may further comprise a protecting agent.
  • the protecting agent coats at least part of the therapeutic agent, typically upon the mixing of the two agents.
  • the protecting agent may be mixed with the therapeutic agent in a ratio of from about 0.1 to about 100 by weight, preferably in a ratio of from about 1 to about 50, and more preferably in a ratio of about 1 to about 10.
  • the protecting agent reduces the adhesion between the therapeutic agent and the binder so that the therapeutic agent may be more easily released from the binder. In this way, the therapeutic agent may be delivered across the mucous membranes of the oral cavity within about 5 to about 20 minutes, preferably within about 10 minutes.
  • Materials suitable as protecting agents are discussed in detail above and may be used alone or in combination in the lozenge compositions of the present invention.
  • the lozenge composition may-also comprise one or more elastomeric solvents such as rosins and resins. Non-limiting examples of such solvents are discussed in detail above and may be used alone or in combination in the tablet compositions of the present invention.
  • the lozenge composition may further comprise waxes such as beeswax and microcrystalline wax, fats or oils such as soybean and cottonseed oil, and combinations thereof.
  • the lozenge composition may additionally include plasticizers such as softeners or emulsifiers. Such plasticizers may, for example, help reduce the viscosity of the salivary solution of the dissolved lozenge to a desirable consistency and improve its overall texture and bite and help facilitate the release of the therapeutic agent. Non-limiting examples of such plasticizers are discussed in detail above and may be used alone or in combination in the lozenge compositions of the present invention.
  • the lozenge composition includes a therapeutic agent centerfill.
  • a centerfill may be particularly suitable when immediate release of the therapeutic agent is preferred.
  • encapsulating the therapeutic agent in a centerfill may help to mask any undesirable taste that the therapeutic agent may have.
  • the binder surrounds, at least in part, a centerfill.
  • the centerfill comprises at least one therapeutic agent, and may be a liquid or semi-liquid material.
  • the centerfill material can be a synthetic polymer, a semi-synthetic polymer, low-fat, or fat free and contain one or more sweetening agents, flavoring agents, coloring agents, and/or scenting agents.
  • the centerfill includes a binary or ternary buffer system as described herein.
  • the lozenge composition of the present invention is multilayered.
  • the lozenge can be designed to provide more than one therapeutic agent, e.g., two or more the therapeutic agents, or one or more the therapeutic agent derived from a first gram-positive bacteria, in combination with one or more therapeutic agents derived from a second gram-positive bacteria.
  • the first layer contains may contain a first therapeutic agent derived from Lactobacillus
  • the second layer contains the same or different therapeutic agent or therapeutic agent derived from the same or a second gram-positive bacteria, such as a naturally-occurring CpG ODN or a motif thereof.
  • the first layer comprises the dissolving portion of the lozenge
  • the second (i.e., subsequent) layer is coated by the first layer.
  • This type of formulation may be particularly suitable when immediate release of the therapeutic agent, followed by gastrointestinal absorption of a second therapeutic agent, is desirable. Gastrointestinal absorption of the second therapeutic agent may be desirable, for example, in order to mitigate co-morbid symptoms or to sustain the therapeutic benefit of the primary therapeutic agent in the dissolving portion of the lozenge.
  • the second layer is present as a layer lateral to the first layer.
  • the second layer typically comprises at least one therapeutic agent, and can also comprise one or more sweetening agents, flavoring agents, coloring agents, and scenting agents as described above.
  • the second layer further includes a buffer system as described herein.
  • the combination of the therapeutic agents with or without non-bacterial therapeutic agents need not take the form of a multilayered lozenge, but instead comprises a single homogenous lozenge layer.
  • This type of formulation may also be used in the case where gastrointestinal absorption of at least one therapeutic agent is desirable.
  • the relative extent of ionization of the two or more therapeutic agents determines how they are to be absorbed. For example, those therapeutic agents that are un-ionized are absorbed through the oral mucosa, while the ionized agents are swallowed for gastrointestinal absorption.
  • the lozenge compositions can have any desired shape, size, and texture.
  • the lozenge can have the shape of a stick, tab, pellet, sphere, and the like.
  • the lozenge can be any desirable color.
  • the lozenge can be any shade of red, blue, green, orange, yellow, violet, indigo, and mixtures thereof, and can be color coded to indicate the type and dosage of the therapeutic agent therein.
  • the lozenges can be individually wrapped or grouped together in pieces for packaging by methods well known in the art.
  • compositions of the present invention can also take to form of a solution formulation for delivery of a therapeutic agent as described herein across the oral mucosa.
  • the solution formulation can be administered sublingually by using a two-chamber syringe delivery system, in which the upper chamber contains an unbuffered therapeutic agent solution, the lower chamber contains the dry buffer system components, and a non-permeable membrane separates the upper and lower chambers. Depressing the syringe ruptures the non-permeable membrane and allows mixing of the unbuffered therapeutic agent solution with the dry buffer system components. The resulting buffered therapeutic agent solution is then released from the tip of the syringe.
  • a solution formulation of the present invention can be used to deliver the active therapeutic composition across the subject's sublingual mucosa.
  • the present invention further provides a composition for delivery of a therapeutic composition across the oral mucosa of a subject for the treatment of a hepatic disease and/or disorder, the composition comprising: (a) a gram-positive bacteria extract, lysate, or a pharmaceutically acceptable salt thereof, preferably from the Lactobacillus species of gram-positive bacteria; (b) a naturally-occurring immunostimulatory oligodeoxynucleotide; (c) an optional, active agent promoter; and, optionally, (d) a buffer system comprising a carbonate salt and/or a bicarbonate salt, wherein the buffer system raises the pH of saliva to a pH greater than about 9.9 irrespective of the starting pH of saliva.
  • the composition is a solution that is prepared just prior to administration to the oral mucosa.
  • the buffer system comprises sodium bicarbonate and sodium carbonate wherein the ratio of sodium bicarbonate to sodium carbonate ranges from about 1:1 to about 5:1 by weight.
  • sodium carbonate is used in an amount that is equivalent to, or in excess of sodium bicarbonate.
  • the compositions are those that provide peak plasma levels of the active ingredient in less than 15 minutes (e.g, about 1 to about 15 minutes), preferably in about 5 minutes to about 10 minutes.
  • compositions of the present invention are useful in therapeutic applications, e.g., for treating immune diseases or disorders, including hepatic diseases or disorders, such as hepatitis A, B and/or C, in subjects in need of such treatment.
  • the methods of the present invention are useful in the treatment of a variety of hepatic disorders, in particular those characterized by an associated link with the alternative pathway in the complement system of the subject. Therefore, according to the present disclosure, a hepatic disorder is any liver disease or disorder in the liver or the surrounding vasculature.
  • the methods and compositions of the present invention are useful in the treatment of a variety of hepatic disorders, including those resulting from infection, iatrogenic disorders, hereditary disorders, autoimmune disorders, cholestatic syndromes, sarcoidosis, organ transplantation, hepatic cancer, and the like.
  • Diseases or disorders within the scope of the present disclosure include, but are not limited to, the diseases and disorders detailed in Table 1.
  • Hepatitis Any inflammation of the liver, as for example in acute hepatitis, chronic hepatitis, alcoholic hepatitis and cirrhosis. 2.
  • Cholestatic Syndromes Any inflammation of the intrahepatic bile ducts, including those resulting in hepatic dysfunction and cirrhosis as for example in primary biliary cirrhosis, primary sclerosing cholangitis and adult idiopathic ductopenia.
  • C. Transplantations Any inflammation of the liver or hepatic ducts including that associated with hepatic transplantation, liver injury in graft versus host disease and recipients of renal and other allografts, for example hyperacute allograft rejection, and xenograft rejection.
  • cancer refers to a malignant neoplasm that has undergone characteristic anaplasia with loss of differentiation, increase rate of growth, invasion of surrounding tissue, and is capable of metastasis.
  • thyroid cancer is a malignant neoplasm that arises in or from thyroid tissue
  • breast cancer is a malignant neoplasm that arises in or from breast tissue (such as a ductal carcinoma).
  • Residual cancer is cancer that remains in a subject after any form of treatment given to the subject to reduce or eradicate thyroid cancer.
  • Metastatic cancer is a cancer at one or more sites in the body other than the site of origin of the original (primary) cancer from which the metastatic cancer is derived. Cancer includes, but is not limited to, solid tumors.
  • tumor refers to an abnormal growth of cells, which can be benign or malignant. Cancer is a malignant tumor, which is characterized by abnormal or uncontrolled cell growth. Other features often associated with malignancy include metastasis, interference with the normal functioning of neighboring cells, release of cytokines or other secretory products at abnormal levels and suppression or aggravation of inflammatory or immunological response, invasion of surrounding or distant tissues or organs, such as lymph nodes, etc. “Metastatic disease” refers to cancer cells that have left the original tumor site and migrate to other parts of the body for example via the bloodstream or lymph system.
  • the amount of a tumor in an individual is the “tumor burden” which can be measured as the number, volume, or weight of the tumor.
  • a tumor that does not metastasize is referred to as “benign.”
  • a tumor that invades the surrounding tissue and/or can metastasize is referred to as “malignant.”
  • hematological tumors include leukemias, including acute leukemias (such as 11q23-positive acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lympho
  • solid tumors such as sarcomas and carcinomas
  • solid tumors include but are not limited to fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer (including basal breast carcinoma, ductal carcinoma and lobular breast carcinoma), lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
  • compositions described herein when used in the treatment of one or more cancer types, or tumors, may optionally include, or be combined with, one or more other anti-cancer agents, or compounds.
  • anti-cancer agents include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; a
  • Still another disorder that may be treatable with the compositions of the present invention includes Lyme disease and other tick-borne infections, including anemia caused by Babesia microti , Ehrlichiosis, tularemia (such as that caused by Francisella tularensis ) and diseases caused by Rikettsia rickettsii.
  • Particularly preferred disorders within the context of the invention are chronic hepatitis particularly hepatitis resulting from infection, particularly viral infection. Included in this category are the established serological categories of chronic hepatitis, including viral (HBV, HDV, HCV), autoimmune hepatitis (classic lupoid type and subtypes), autoimmune overlap syndromes, drug induced (for example nitrofurantoin, alpha methyldopa, isoniazid) and so-called “cryptogenic” hepatitis
  • viral HBV, HDV, HCV
  • autoimmune hepatitis classic lupoid type and subtypes
  • autoimmune overlap syndromes autoimmune overlap syndromes
  • drug induced for example nitrofurantoin, alpha methyldopa, isoniazid
  • so-called “cryptogenic” hepatitis the skilled artisan will make reference to chapters 8 and 9, and especially Tables 9.2 and 9.3 in “McSween's Pathology of the Liver,
  • chronic liver diseases not included within the definition of chronic hepatitis may have histological features of chronic hepatitis (for example, piecemeal necrosis). These disorders such as, for example, diseases of intra or extrahepatic bile ducts, are included within the definition herein.
  • hepatitis viruses hepatitis A (HAV), hepatitis B (HBV), hepatitis C(HCV), hepatitis D (HDV, delta agent) hepatitis E, hepatitis F and other viruses such as Epstein-Barr virus, cytomegalovirus, adenovirus, paramyovirus, and the like.
  • HAV hepatitis A
  • HBV hepatitis B
  • HCV hepatitis C(HCV)
  • HDV hepatitis D
  • hepatitis E hepatitis E
  • hepatitis F hepatitis F
  • A-G hepatitis virus
  • HCV hepatitis C virus
  • Chronic cholestatic syndromes are characterized by progressive inflammatory destruction of intrahepatic bile ducts resulting in hepatic dysfunction, fibrosis and cirrhosis.
  • Examples of this type of disorder include primary biliary cirrhosis, primary sclerosing cholangitis and adult idiopathic ductopenia.
  • Hereditary disorders treatable by the methods disclosed herein include those inflammatory disorders associated with a gene-linked trait. Examples include but are not limited to Wilson's disease, ⁇ 1-antitrypsin deficiency and inherited metabolic disorders such as galactosemia and tyrosineanemia.
  • compositions of the present invention provide the rapid delivery of an active therapeutic agent composition of the present disclosure across the oral mucosa, irrespective of the starting pH of saliva.
  • the delivery of the therapeutic agent across the oral mucosa avoids hepatic first pass metabolism, degradation within the gastrointestinal tract, and therapeutic agent loss during absorption.
  • the therapeutic agent reaches the systemic circulation in a substantially shorter period of time and at a substantially higher concentration than with traditional oral (e.g., tablet) administration.
  • compositions of the present invention have particular utility in the area of human and veterinary therapeutics.
  • administered dosages will be effective to deliver picomolar to micromolar concentrations of the active composition to the appropriate site.
  • compositions of the present invention may preferably carried out via any of the accepted modes of administration to the mucous membranes of the oral cavity.
  • suitable sites of administration within the oral mucosa include, without limitation, the mucous membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), the gums (gingival mucosa), the roof of the mouth (palatal mucosa), the lining of the lips, and combinations thereof. These regions differ from each other with respect to their anatomy, drug permeability, and physiological response to drugs.
  • the compositions of the present invention are administered to the sublingual mucosa, buccal mucosa, or a combination thereof.
  • the oral mucosa possessing a rich blood supply and suitable drug permeability, is an especially attractive route of administration for systemic delivery of therapeutic agents. Furthermore, delivery of a therapeutic agent across the oral mucosa bypasses hepatic first pass metabolism, avoids enzymatic degradation within the gastrointestinal tract, and provides a more suitable enzymatic flora for drug absorption.
  • sublingual delivery refers to the administration of a therapeutic agent across the mucous membranes lining the floor of the mouth and/or the ventral tongue.
  • uccal delivery refers to the administration of a therapeutic agent across the mucous membranes lining the cheeks.
  • the oral mucosa is composed of an outermost layer of stratified squamous epithelium. Beneath this layer lies a basement membrane, i.e., the lamina basement, followed by the submucosa as the innermost layer.
  • the epithelium of the oral mucosa is similar to the stratified squamous epithelia found in the rest of the body in that it contains a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium.
  • the epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer cell layers.
  • the epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers.
  • the turnover time for buccal mucosal epithelium is representative of the turnover time for sublingual mucosal epithelium as well as other epithelia in the oral mucosa [Harris, et al., J. Pharm. Sci, Vol. 81, pp. 1-10 (1992)].
  • the thickness of the oral mucosa varies depending on the site in the oral cavity. For example, the buccal mucosa measures at about 500-800 ⁇ m in thickness, while the hard and soft palatal mucosa, the sublingual mucosa, the ventral tongue, and the gingival mucosa measure at about 100-200 ⁇ m in thickness.
  • the composition of the epithelium also varies depending on the site in the oral cavity.
  • the mucosae of areas subject to mechanical stress i.e., the gingivae and hard palate
  • the mucosae of the soft palate, the sublingual region, and the buccal region are not keratinized [Harris et al., supra].
  • the keratinized epithelia contain neutral lipids like ceramides and acylceramides, which have been associated with providing a barrier function. As a result, these epithelia are relatively impermeable to water.
  • non-keratinized epithelia such as sublingual and buccal epithelia
  • acylceramides have only small amounts of ceramide
  • Squier, et al., in “Oral Mucosal Drug Delivery,” Ed. M. J. Rathbone, Marcel Dekker, Inc., New York, N.Y., pp. 1-26 (1996) ].
  • Non-keratinized epithelia also contain small amounts of neutral but polar lipids, e.g., cholesterol sulfate and glucosyl ceramides. As such, these epithelia have been found to be considerably more permeable to water than keratinized epithelia.
  • the oral mucosa is a somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa.
  • the permeability of the buccal mucosa is estimated to be about 4-4000 times greater than that of skin [Galey, et al., J. Invest. Dermat., 67:713-717 (1976)].
  • the permeability of different regions of the oral mucosa generally decrease in the order of sublingual mucosa greater than buccal mucosa, and buccal mucosa greater than palatal mucosa.
  • This permeability is generally based upon the relative thickness and degree of keratinization of these membranes, with the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa being thicker and non-keratinized, and the palatal mucosa being intermediate in thickness, but keratinized.
  • the epithelial cells of the oral mucosa are surrounded by mucus comprising primarily complexes of proteins and carbohydrates that may or may not be attached to certain regions on the cell surface.
  • the mucus may play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another [Tabak et al., J. Oral Pathol., 11:1-17 (1982)].
  • mucus In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells such as goblet cells; however, in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva [Tabak, et al., supra; Rathbone, et al., Adv. Drug Del. Rev., 13:1-22 (1994)].
  • the mucus network carries a negative charge due to the sialic acid and sulfate residues present on the carbohydrates.
  • mucus can form a strongly cohesive gel structure that binds to the epithelial cell surface as a gelatinous layer.
  • the buffer systems of the present invention neutralize the sialic acid residues present on the carbohydrates and prevent them from interacting with the therapeutic agent, thereby further enhancing drug permeation.
  • Saliva is the protective fluid for all tissues of the oral cavity.
  • Saliva is an aqueous fluid with about 1% organic and inorganic materials.
  • the major determinant of the salivary composition is the flow rate, which in turn depends upon factors such as the time of day, the type of stimulus, and the degree of stimulation.
  • the salivary pH typically ranges from about 5.5 to about 7.0, depending on the flow rate. For example, at high flow rates, the sodium and bicarbonate concentrations increase, leading to an increase in the pH. Because the daily salivary volume is between about 0.5 to about 2 liters, the oral cavity provides an aqueous environment for the hydration and/or dissolution of the oral mucosal dosage forms of the present invention.
  • the sublingual mucosa is the most highly permeable region of the oral cavity, and provides rapid absorption and high bioavailability of a drug in a convenient, accessible, and well-accepted route of administration [Harris, et al., supra].
  • Suitable sublingual dosage forms include, without limitation, tablets (e.g., quick-dissolving, slow-dissolving), lozenges, candy, and soft gelatin capsules filled with liquid drug. Such systems create a very high drug concentration in the sublingual region before they are systemically absorbed across the sublingual mucosa.
  • the sublingual mucosa is particularly well-suited for producing a rapid onset of action, and sublingual dosage forms can be used to deliver drugs with shorter delivery period requirements and/or less frequent dosing regimens.
  • the buccal mucosa is considerably less permeable than the sublingual area, rapid absorption and high bioavailability of a drug can also be observed with buccal administration.
  • Suitable buccal dosage forms include, without limitation, chewing gums, tablets (e.g., quick-dissolving, slow-dissolving), lozenges, candy, and the like. Both the buccal mucosa and the sublingual mucosa are far superior to the gastrointestinal tract for providing increased absorption and bioavailability of a drug.
  • penetration enhancers can be included in the dosage forms of the present invention.
  • the penetration enhancers may be of the type that alters the nature of the oral mucosa to enhance penetration, or of the type that alters the nature of the therapeutic agent to enhance penetration through the oral mucosa.
  • Suitable penetration enhancers include, without limitation, polyoxyethylene 23-lauryl ether, aprotin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid, propylene glycol, lysophosphatidylcholine, menthol, methoxysalicylate, methyloleate, oleic acid; phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium ethylenediaminetetraacetic acid (“EDTA”), sodium deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl suflate, sodium salicylate, sodium taurocholate, sodium taurodeoxycholate, as well as certain sulfoxides and glycosides, and combinations thereof.
  • EDTA sodium ethylenediaminetetraacetic acid
  • any method of delivery that delivers the active therapeutic agent to the mucosal wall where it can begin to act therapeutically is envisioned, such alternative mucosal delivery formulations including but not limited to suppositories (both rectal and vaginal), sprays (both oral and nasal), subdermal implants, and controlled release capsules that allow the formulation to move past the stomach region of the patient, e.g., pH controlled release capsules.
  • CpG ODNs CpG oligodeoxynucleotides
  • the active ingredient is a gram positive bacteria, such as described herein above.
  • Lactobacillus delbrueckii ssp. Bulgaricus was used, employing a fermentation and cell isolation process as carried out by Kerry Ingredients & Flavours (Beloit, Wis.) and as described generally below.
  • Lysing and Purification The wet cell mass was reconstituted and the pH is adjusted to 6.8-7.0. Lysozyme chloride (extracted from hen egg whites) was added to make a solution with a concentration of 500 ppm of lysozyme chloride. The slurry was agitated and the temperature is maintained at 40-50° C. for 24 hours. After lysing, the active components were in the liquid phase. This liquid material containing the water soluble active components was recovered through centrifugation to remove the solid material, and then washed three times with DI water. The resultant mixture was frozen in pellets and the remaining solid material in the centrifuge was discarded.
  • the frozen pellets were freeze dried to form a dry powder and milled, as necessary.
  • This material was blended with a promoter, such as N-acetyl D-glucosamine HCl (NAG), to form a mixture of lysed Lactobacillus delbrueckii subsp. Bulgaricus and NAG.
  • a promoter such as N-acetyl D-glucosamine HCl (NAG)
  • NAG N-acetyl D-glucosamine HCl
  • other formulation excipients to generate a solid form pill or powder were added, as appropriate. This product was then used in the following screening tests.
  • TLR stimulation was tested by assessing NF- ⁇ B activation in HEK293 cells expressing a given TLR or NLR.
  • the activities of the samples were tested on seven different human TLRs: TLR2, 3, 4, 5, 7, 8 and 9 (Invivogen, San Diego, Calif.), and on two different human NLRs (NOD1 and NOD2).
  • Each ligand was tested at a final concentration of 1/100 of the stock solution on the TLR or NLR cells, and compared to control ligands, as described below. This step was performed in triplicate.
  • control ligands, control cell lines, and sample product used in the examples were as shown in Table 2.
  • TLR2 Control Ligands
  • TLR3 Poly(I:C) at 1 ⁇ g/mL
  • TLR4 E.
  • TLR5 TLR7: CL097 at 1 ⁇ g/mL
  • TLR8 CL075 at 1 ⁇ g/mL
  • TLR9 CpG ODN 2006 at 100 ng/mL NOD1: C12iEDAP at 10 ⁇ g/mL NOD2: L18-MDP at 100 ng/mL
  • Control Cell HEK293/Null1: TNF ⁇ at 1 ⁇ g/mL Lines (control for human TLR 2, 3, 5, 8, 9 and NOD 1)
  • HEK293/Null1-k TNF ⁇ at 1 ⁇ g/mL (control for human TLR7)
  • HEK293/Null2 TNF ⁇ at 1 ⁇ g/mL (control for human TLR4 and NOD2) Sample Lysate of Lactobacillus delbrueckii subsp. Bulgaricus ( 1/10 dilution prepared in sterile, endotoxin-free water)
  • TLR stimulation in the screening is tested by assessing NF- ⁇ B activation in the HEK293 cells expressing a given TLR.
  • the secreted alkaline phosphatase reporter is under the control of a promoter inducible by the transcription factor NF- ⁇ B.
  • TLR stimulation in the screening was tested by assessing NF- ⁇ B activation in the HEK293 cells expressing a given TLR or NLR. This reporter gene allows the monitoring of signaling through the TLR/NLR, based on the activation of NF- ⁇ B.
  • a 96-well plate 200 ⁇ L total volume
  • the appropriate cells 50,000-75,000 cells/well
  • 20 ⁇ L of the Sample (lysate product) or the positive control ligands to the wells 20 ⁇ L of the Sample (lysate product) or the positive control ligands to the wells.
  • the media added to the wells is designed for the detection of NF- ⁇ B induced SEAP (secreted alkaline phosphatase) expression. After a 16-20 hr incubation, the OD (optical density) at 650 nm was read on an Molecular Devices Spectra Max 340PC absorbance detector and recorded.
  • compositions may include one or more synthetic CpG ODN's, such as the commercially-available Genasense or IMOxine®, in addition to the at least one naturally-occurring CpG ODN and the bacteria lysate fraction.
  • synthetic CpG ODN's such as the commercially-available Genasense or IMOxine®
  • the various methods and embodiments of the methods of manufacture and assembly of the system, as well as location specifications, can be included in combination with each other to produce variations of the disclosed methods and embodiments. Discussion of singular elements can include plural elements and vice-versa.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112223A1 (en) * 2016-12-14 2018-06-21 Progenity Inc. Treatment of a disease of the gastrointestinal tract with a tlr modulator
US20210123057A1 (en) * 2019-10-29 2021-04-29 Northwestern University Sequence Multiplicity Within Spherical Nucleic Acids
CN114515295A (zh) * 2022-03-31 2022-05-20 东莞市人民医院 CpG ODN在制备防治药物性肝损伤的药物中的应用
CN117180317A (zh) * 2023-11-02 2023-12-08 深圳市第二人民医院(深圳市转化医学研究院) 詹氏乳杆菌来源纳米囊泡在制备防治卵巢早衰治疗药物中的应用
WO2024021965A1 (zh) * 2022-07-28 2024-02-01 杭州师范大学 靶向m2型巨噬细胞的联合脂质体及其应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20200106088A (ko) 2012-01-16 2020-09-10 엘라자베스 맥켄나 간 질환들 및 장애들의 치료를 위한 조성물들 및 방법들
US20170232047A1 (en) * 2012-01-16 2017-08-17 Elizabeth McKenna Control of Cellular Redox Levels
WO2014047588A1 (en) 2012-09-21 2014-03-27 Elizabeth Mckenna Naturally occurring cpg oligonucleotide compositions and therapeutic applications thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8007783B2 (en) * 2006-08-22 2011-08-30 Carl Miller Quality of life for hepatitis C patients with a formulation for administration to the oral mucosa including Lactobacillus delbrueckii subsp. bulgaricus and N-acetyl D-glucosamine

Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3806290A (en) 1972-07-12 1974-04-23 Warner Lambert Co Apparatus for center-filled chewing gum
US4322405A (en) 1981-04-06 1982-03-30 Laboratoires Om Societe Anonyme Method for treating rheumatoid arthritis
JPH04264034A (ja) 1991-02-18 1992-09-18 Snow Brand Milk Prod Co Ltd 生体内過酸化脂質抑制剤
US6162432A (en) 1991-10-07 2000-12-19 Biogen, Inc. Method of prophylaxis or treatment of antigen presenting cell driven skin conditions using inhibitors of the CD2/LFA-3 interaction
IT1254210B (it) 1992-02-10 1995-09-14 Simone Claudio De Composizioni dietetiche e/o farmaceutiche a base di batteri lattici liofilizzati, loro preparazione e impiego
US5716615A (en) 1992-02-10 1998-02-10 Renata Maria Anna Cavaliere Vesely Dietary and pharmaceutical compositions containing lyophilized lactic bacteria, their preparation and use
US6207646B1 (en) 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6239116B1 (en) 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
DE69535905D1 (de) 1994-07-15 2009-02-26 Coley Pharm Group Inc Immunomodulatorische Oligonukleotide
IT1283225B1 (it) 1996-03-11 1998-04-16 Renata Maria Anna Ve Cavaliere Ceppi di batteri, composizione farmaceutica contenente uno o piu' di tali ceppi e uso dei medesimi per la prevenzione e la terapia delle
JPH09301877A (ja) 1996-05-13 1997-11-25 Youshindou:Kk 肝炎治療・予防剤
JPH09301878A (ja) 1996-05-13 1997-11-25 Youshindou:Kk 腫瘍増殖抑制剤
AR022986A1 (es) 1996-08-12 2002-09-04 Gist Brocades Bv Produccion y uso de composiciones que comprenden concentraciones altas de actividad de vitamina b12
EP1039935A4 (en) 1997-02-28 2005-04-27 Univ Iowa Res Found USE OF NUCLEIC ACIDS CONTAINING NON-METHYLATED CpG DINUCLEOTIDES IN THE TREATMENT OF LIPOPOLYSACCHARIDE-ASSOCIATED ILLNESSES
WO1998040100A1 (en) * 1997-03-10 1998-09-17 Ottawa Civic Loeb Research Institute USE OF NUCLEIC ACIDS CONTAINING UNMETHYLATED CpG DINUCLEOTIDE AS AN ADJUVANT
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
AU7690898A (en) 1997-05-20 1998-12-11 Ottawa Civic Hospital Loeb Research Institute Vectors and methods for immunization or therapeutic protocols
US6281191B1 (en) 1997-12-29 2001-08-28 Vladimir I. Slesarev Compositions and methods for treating hepatitis-C
DE69935507T2 (de) 1998-04-03 2007-12-06 University Of Iowa Research Foundation Verfahren und produkte zur stimulierung des immunsystems mittels immunotherapeutischer oligonukleotide und zytokine
JP4074006B2 (ja) * 1998-06-24 2008-04-09 アサマ化成株式会社 ＩｇＥ抗体産生抑制物質の製造方法並びにそれを用いた食品
JP2000262247A (ja) * 1999-03-19 2000-09-26 Asama Kasei Kk 免疫調節剤、免疫調節食品および免疫調節飼料
EP1178118A1 (en) 2000-08-02 2002-02-06 Dsm N.V. Isolation of microbial oils
WO2002069939A2 (en) 2001-03-05 2002-09-12 Ortho-Mcneil Pharmaceutical, Inc. Taste masked pharmaceutical compositions
JP3853673B2 (ja) 2001-03-09 2006-12-06 森永乳業株式会社 Ｃ型慢性肝炎治療剤
WO2003015711A2 (en) 2001-08-17 2003-02-27 Coley Pharmaceutical Group, Inc. Combination motif immune stimulatory oligonucleotides with improved activity
US20030119774A1 (en) * 2001-09-25 2003-06-26 Marianna Foldvari Compositions and methods for stimulating an immune response
US7838026B2 (en) 2001-09-28 2010-11-23 Mcneil-Ppc, Inc. Burst-release polymer composition and dosage forms comprising the same
GB0203306D0 (en) 2002-02-12 2002-03-27 Norferm Da Method
CA2502960A1 (en) 2002-10-22 2004-05-06 Board Of Regents, The University Of Texas System Active specific immunotherapy of cancer metastasis
UA79834C2 (en) 2002-11-01 2007-07-25 Viropharma Inc Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
EP1663302B1 (en) 2003-09-03 2012-06-13 Alpharma, LLC Method for vaccination of poultry by bacteriophage lysate
JP3976742B2 (ja) 2004-02-27 2007-09-19 江守商事株式会社 インターフェロンアルファを誘導する免疫刺激オリゴヌクレオチド
JP2005247780A (ja) 2004-03-05 2005-09-15 Masakazu Maruyama ウイルス性肝炎治療剤
WO2007013613A1 (ja) * 2005-07-29 2007-02-01 Suntory Limited フコイダン又はフコイダン加水分解生成物と免疫賦活素材とを含む組成物
PT1991678E (pt) 2006-02-15 2015-11-25 Adiutide Pharmaceuticals Gmbh Composições e métodos para formulações de oligonucleótidos
EP1872792A1 (en) 2006-06-29 2008-01-02 Biotech Tools S.A. A method for the production of hydrolyzed allergen
US8304226B2 (en) 2006-08-22 2012-11-06 Carl Miller Quality of life of hepatitis C patients with a formulation for administration to the oral mucosa including freeze dried lysate of selected Lactobacillus or Bifidobacterium species and N-acetyl D-glucosamine
DE202008006598U1 (de) 2008-04-11 2008-10-02 Alk-Abelló A/S Allergie-Impfstoff-Formulierung zur mucosalen Verabreichung
US8728461B2 (en) 2008-07-04 2014-05-20 Nippon Meat Packers, Inc. Lactic acid bacterium having high immunoglobulin-A-inducing ability
BRPI0822997A2 (pt) * 2008-09-04 2015-06-23 Om Pharma Extratos imunomoduladores de bactérias lactobacillus e métodos para fabricação e uso dos mesmos
EP2437730A4 (en) 2009-05-20 2014-02-26 Lingual Consegna Pty Ltd ORAL AND / OR SUBLINGUAL THERAPEUTIC FORMULATION
JP6019492B2 (ja) * 2009-08-28 2016-11-02 国立大学法人 千葉大学 乳酸菌および抗原物質を含み、口腔内に投与されることを特徴とする抗アレルギー剤
FR2951377B1 (fr) 2009-10-21 2012-06-22 Oreal Association d'un lysat de probiotique et d'un derive c-glycoside
GB201009273D0 (en) * 2010-06-03 2010-07-21 Glaxosmithkline Biolog Sa Novel vaccine
KR20200106088A (ko) * 2012-01-16 2020-09-10 엘라자베스 맥켄나 간 질환들 및 장애들의 치료를 위한 조성물들 및 방법들
WO2014047588A1 (en) 2012-09-21 2014-03-27 Elizabeth Mckenna Naturally occurring cpg oligonucleotide compositions and therapeutic applications thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8007783B2 (en) * 2006-08-22 2011-08-30 Carl Miller Quality of life for hepatitis C patients with a formulation for administration to the oral mucosa including Lactobacillus delbrueckii subsp. bulgaricus and N-acetyl D-glucosamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Te et al. (Gastroenterol. Hepatol., 3:218-225, 2007) *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112223A1 (en) * 2016-12-14 2018-06-21 Progenity Inc. Treatment of a disease of the gastrointestinal tract with a tlr modulator
US11426566B2 (en) 2016-12-14 2022-08-30 Biora Therapeutics, Inc. Treatment of a disease of the gastrointestinal tract with a TLR modulator
US20210123057A1 (en) * 2019-10-29 2021-04-29 Northwestern University Sequence Multiplicity Within Spherical Nucleic Acids
CN114515295A (zh) * 2022-03-31 2022-05-20 东莞市人民医院 CpG ODN在制备防治药物性肝损伤的药物中的应用
WO2024021965A1 (zh) * 2022-07-28 2024-02-01 杭州师范大学 靶向m2型巨噬细胞的联合脂质体及其应用
CN117180317A (zh) * 2023-11-02 2023-12-08 深圳市第二人民医院(深圳市转化医学研究院) 詹氏乳杆菌来源纳米囊泡在制备防治卵巢早衰治疗药物中的应用

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IL237865B (en) 2021-04-29
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US20170266277A9 (en) 2017-09-21
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